mitochondrion

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A mitochondrion (; ) is an
organelle In cell biology, an organelle is a specialized subunit, usually within a cell (biology), cell, that has a specific function. The name ''organelle'' comes from the idea that these structures are parts of cells, as Organ (anatomy), organs are to the ...
found in the cells of most
Eukaryote Eukaryotes () are organisms whose Cell (biology), cells have a cell nucleus, nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the ...

s, such as
animal Animals are multicellular, eukaryotic organisms in the biological kingdom Animalia. With few exceptions, animals consume organic material, breathe oxygen, are able to move, can reproduce sexually, and go through an ontogenetic stage i ...

s,
plant Plants are predominantly Photosynthesis, photosynthetic eukaryotes of the Kingdom (biology), kingdom Plantae. Historically, the plant kingdom encompassed all living things that were not animals, and included algae and fungi; however, all curr ...

s and
fungi A fungus (plural, : fungi or funguses) is any member of the group of Eukaryote, eukaryotic organisms that includes microorganisms such as yeasts and Mold (fungus), molds, as well as the more familiar mushrooms. These organisms are classified ...

. Mitochondria have a double
membrane A membrane is a selective barrier; it allows some things to pass through but stops others. Such things may be molecules, ions, or other small particles. Membranes can be generally classified into synthetic membranes and biological membranes. Bi ...
structure and use
aerobic respiration Cellular respiration is the process by which biological fuels are oxidised in the presence of an inorganic electron acceptor such as oxygen to produce large amounts of energy, to drive the bulk production of ATP. Cellular respiration may be des ...
to generate
adenosine triphosphate Adenosine triphosphate (ATP) is an organic compound that provides energy to drive many processes in living cell (biology), cells, such as muscle contraction, nerve impulse propagation, condensate dissolution, and chemical synthesis. Found in all ...

(ATP), which is used throughout the cell as a source of
chemical energy Chemical energy is the energy of chemical substances that is released when they undergo a chemical reaction and transform into other substances. Some examples of storage media of chemical energy include batteries, Schmidt-Rohr, K. (2018). "How ...
. They were discovered by Albert von Kölliker in 1857 in the voluntary muscles of insects. The term ''mitochondrion'' was coined by in 1898. The mitochondrion is popularly nicknamed the "powerhouse of the cell", a phrase coined by
Philip Siekevitz Philip Siekevitz (February 25, 1918 – December 5, 2009) was an American cell biologist who spent most of his career at Rockefeller University. He was involved in early studies of protein synthesis and protein trafficking, trafficking, established ...
in a 1957 article of the same name. Some cells in some
multicellular organism A multicellular organism is an organism that consists of more than one cell (biology), cell, in contrast to unicellular organism. All species of animals, Embryophyte, land plants and most fungi are multicellular, as are many algae, whereas a few ...
s lack mitochondria (for example, mature mammalian
red blood cell Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek language, Greek ''erythros'' for "red" and ''k ...

s). A large number of
unicellular organism A unicellular organism, also known as a single-celled organism, is an organism that consists of a single cell (biology), cell, unlike a multicellular organism that consists of multiple cells. Organisms fall into two general categories: prokaryoti ...
s, such as
microsporidia Microsporidia are a group of spore-forming unicellular parasites. These spores contain an extrusion apparatus that has a coiled polar tube ending in an anchoring disc at the apical part of the spore. They were once considered protozoans or prot ...
,
parabasalid The parabasalids are a group of flagellated protists within the supergroup Excavata. Most of these eukaryotic organisms form a symbiosis, symbiotic relationship in animals. These include a variety of forms found in the intestines of termites and ...
s and
diplomonad The diplomonads (Greek for "two units") are a group of flagellates, most of which are parasitic. They include ''Giardia duodenalis'', which causes giardiasis in humans. They are placed among the metamonads, and appear to be particularly close r ...
s, have reduced or transformed their mitochondria into other structures. One
eukaryote Eukaryotes () are organisms whose Cell (biology), cells have a cell nucleus, nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the ...

, ''
Monocercomonoides ''Monocercomonoides'' is a genus of flagellate Excavata belonging to the order Oxymonadida. It was established by Bernard V. Travis and was first described as those with "polymastiginid flagellates having three anterior Flagellum, flagella and a ...
'', is known to have completely lost its mitochondria, and one multicellular organism, '''', is known to have retained mitochondrion-related organelles in association with a complete loss of their mitochondrial genome. Mitochondria are commonly between 0.75 and 3  μm in crossection, but vary considerably in size and structure. Unless specifically stained, they are not visible. In addition to supplying cellular energy, mitochondria are involved in other tasks, such as signaling,
cellular differentiation Cellular differentiation is the process in which a stem cell alters from one type to a differentiated one. Usually, the cell changes to a more specialized type. Differentiation happens multiple times during the development of a multicellular ...
, and
cell death Cell death is the event of a biological cell ceasing to carry out its functions. This may be the result of the natural process of old cells dying and being replaced by new ones, as in programmed cell death, or may result from factors such as dis ...

, as well as maintaining control of the
cell cycle The cell cycle, or cell-division cycle, is the series of events that take place in a cell that cause it to divide into two daughter cells. These events include the duplication of its DNA ( DNA replication) and some of its organelles, and su ...

and
cell growth Cell growth refers to an increase in the total mass of a cell (biology), cell, including both cytoplasmic, cell nucleus, nuclear and organelle volume. Cell growth occurs when the overall rate of cellular biosynthesis (production of biomolecules o ...
. Mitochondrial biogenesis is in turn temporally coordinated with these cellular processes. Mitochondria have been implicated in several human disorders and conditions, such as
mitochondrial disease Mitochondrial disease is a group of disorders caused by mitochondrial dysfunction. Mitochondria are the organelles that generate energy for the cell and are found in every cell of the human body except red blood cells. They convert the energy of ...
s, cardiac dysfunction, heart failure and
autism The autism spectrum, often referred to as just autism or in the context of a professional diagnosis autism spectrum disorder (ASD) or autism spectrum condition (ASC), is a neurodevelopmental disorder, neurodevelopmental condition (or conditions) ...

. The number of mitochondria in a cell can vary widely by
organism In biology, an organism () is any life, living system that functions as an individual entity. All organisms are composed of cells (cell theory). Organisms are classified by taxonomy (biology), taxonomy into groups such as Multicellular o ...

, tissue, and cell type. A mature red blood cell has no mitochondria, whereas a liver cell can have more than 2000. The mitochondrion is composed of compartments that carry out specialized functions. These compartments or regions include the outer membrane, intermembrane space, inner membrane, e, and matrix. Although most of a eukaryotic cell's is contained in the
cell nucleus The cell nucleus (pl. nuclei; from Latin or , meaning ''kernel'' or ''seed'') is a membrane-bound organelle found in eukaryote, eukaryotic cell (biology), cells. Eukaryotic cells usually have a single nucleus, but a few cell types, such as ma ...

, the mitochondrion has ("mitogenome") that is substantially similar to
bacteria Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometre The micrometre (Amer ...

l genomes. This finding has led to general acceptance of the - that free-living prokaryotic ancestors of modern mitochondria permanently fused with eukaryotic cells in the distant past, evolving such that modern animals, plants, fungi, and other eukaryotes are able to to generate .

Structure

Mitochondria may have a number of different shapes. A mitochondrion contains outer and inner membranes composed of
phospholipid bilayer The lipid bilayer (or phospholipid bilayer) is a thin polar membrane made of two layers of lipid molecules. These membranes are flat sheets that form a continuous barrier around all cell (biology), cells. The cell membranes of almost all organis ...
s and
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metabo ...
s. The two membranes have different properties. Because of this double-membraned organization, there are five distinct parts to a mitochondrion: # The outer mitochondrial membrane, # The intermembrane space (the space between the outer and inner membranes), # The inner mitochondrial membrane, # The e space (formed by infoldings of the inner membrane), and # The matrix (space within the inner membrane), which is a fluid. Mitochondria have folding to increase surface area, which in turn increases ATP (adenosine triphosphate) production. Mitochondria stripped of their outer membrane are called
mitoplast A mitoplast is a mitochondrion that has been stripped of its outer mitochondrial membrane, outer membrane leaving the Inner mitochondrial membrane, inner membrane and mitochondrial matrix, matrix intact. How Mitoplasts Are Most Commonly Created ...
s.

Outer membrane

The outer mitochondrial membrane, which encloses the entire organelle, is 60 to 75
angstrom The angstromEntry "angstrom" in the Oxford online dictionary. Retrieved on 2019-03-02 from https://en.oxforddictionaries.com/definition/angstrom.Entry "angstrom" in the Merriam-Webster online dictionary. Retrieved on 2019-03-02 from https://www.m ...
s (Å) thick. It has a protein-to-phospholipid ratio similar to that of the
cell membrane The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the cytoplasm, interior of all Cell (biology), cells from th ...
(about 1:1 by weight). It contains large numbers of
integral membrane protein An integral, or intrinsic, membrane protein (IMP) is a type of membrane protein that is permanently attached to the biological membrane. All transmembrane protein, ''transmembrane proteins'' are IMPs, but not all IMPs are transmembrane proteins. ...
s called porins. A major trafficking protein is the pore-forming voltage-dependent anion channel (VDAC). The VDAC is the primary transporter of
nucleotide Nucleotides are Organic compound, organic molecules consisting of a nucleoside and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both of which are essential ...
s,
ion An ion () is an atom Every atom is composed of a atomic nucleus, nucleus and one or more electrons bound to the nucleus. The nucleus is made of one or more protons and a number of neutrons. Only the most common variety of hydrogen has n ...
s and
metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...
s between the
cytosol The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cell (biology), cells (Fluid compartments#Intracellular compartment, intracellular fluid (ICF)). It is separated into compartments by membranes. For ...
and the intermembrane space. It is formed as a
beta barrel In protein structures, a beta barrel is a beta sheet The beta sheet, (β-sheet) (also β-pleated sheet) is a common structural motif, motif of the regular protein secondary structure. Beta sheets consist of beta strands (β-strands) connected la ...
that spans the outer membrane, similar to that in the
gram-negative bacteria Gram-negative bacteria are bacteria that do not retain the Crystal violet, crystal violet stain used in the Gram staining method of bacterial differentiation. They are characterized by their cell envelopes, which are composed of a thin peptidogly ...
l membrane. Larger proteins can enter the mitochondrion if a signaling sequence at their
N-terminus The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the amin ...
binds to a large multisubunit
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metabo ...
called translocase in the outer membrane, which then actively moves them across the membrane. Mitochondrial pro-proteins are imported through specialised translocation complexes. The outer membrane also contains
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different molecule ...
s involved in such diverse activities as the elongation of
fatty acid In chemistry, particularly in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated and unsaturated compounds#Organic chemistry, saturated or unsaturated. Most naturally occurring fatty acids have an B ...
s,
oxidation Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate (chemistry), substrate change. Oxidation is the loss of Electron, electrons or an increase in the oxidation state, while reduction ...
of
epinephrine Adrenaline, also known as epinephrine, is a hormone and medication A medication (also called medicament, medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to medical diagnosis, diagnose, cure, treat, or preve ...
tryptophan Tryptophan (symbol Trp or W) is an α-amino acid that is used in the biosynthesis of proteins. Tryptophan contains an Alpha_and_beta_carbon , α-amino group, an α-carboxylic acid group, and a side chain indole, making it a polar molecule with ...
. These enzymes include
monoamine oxidase Monoamine oxidases (MAO) () are a family of enzymes that catalysis, catalyze the oxidation of monoamines, employing oxygen to clip off their amine group. They are found bound to the outer membrane of mitochondria in most cell types of the body. ...
,
rotenone Rotenone is an odorless, colorless, crystalline isoflavone used as a broad-spectrum insecticide, piscicide, and pesticide. It occurs naturally in the seeds and stems of several plants, such as the jicama vine plant, and the roots of several member ...
kynurenine -Kynurenine is a metabolite of the amino acid -tryptophan used in the production of Niacin (substance), niacin. Kynurenine is synthesized by the enzyme tryptophan dioxygenase, which is made primarily but not exclusively in the liver, and indoleam ...
hydroxylase In chemistry, hydroxylation can refer to: *(i) most commonly, hydroxylation describes a chemistry, chemical process that introduces a hydroxyl group () into an organic compound. *(ii) the ''degree of hydroxylation'' refers to the number of OH gr ...
and fatty acid Co-A
ligase In biochemistry Biochemistry or biological chemistry is the study of chemical processes within and relating to living organisms. A sub-discipline of both chemistry and biology, biochemistry may be divided into three fields: structural bi ...
. Disruption of the outer membrane permits proteins in the intermembrane space to leak into the cytosol, leading to cell death. The outer mitochondrial membrane can associate with the endoplasmic reticulum (ER) membrane, in a structure called MAM (mitochondria-associated ER-membrane). This is important in the ER-mitochondria calcium signaling and is involved in the transfer of lipids between the ER and mitochondria. Outside the outer membrane are small (diameter: 60 Å) particles named sub-units of Parson.

Intermembrane space

The mitochondrial intermembrane space is the space between the outer membrane and the inner membrane. It is also known as perimitochondrial space. Because the outer membrane is freely permeable to small molecules, the concentrations of small molecules, such as ions and sugars, in the intermembrane space is the same as in the
cytosol The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cell (biology), cells (Fluid compartments#Intracellular compartment, intracellular fluid (ICF)). It is separated into compartments by membranes. For ...
. However, large proteins must have a specific signaling sequence to be transported across the outer membrane, so the protein composition of this space is different from the protein composition of the
cytosol The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cell (biology), cells (Fluid compartments#Intracellular compartment, intracellular fluid (ICF)). It is separated into compartments by membranes. For ...
. One
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metabo ...
that is localized to the intermembrane space in this way is
cytochrome c The cytochrome complex, or cyt ''c'', is a small hemeprotein found loosely associated with the inner mitochondrial membrane, inner membrane of the mitochondrion. It belongs to the cytochrome c family of proteins and plays a major role in cell apo ...
.

Inner membrane

The inner mitochondrial membrane contains proteins with three types of functions: # Those that perform the
electron transport chain An electron transport chain (ETC) is a series of protein complexes and other molecules that electron transfer, transfer electrons from electron donors to electron acceptors via redox reactions (both Redox#Definitions, reduction and oxidation occu ...
redox Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate (chemistry), substrate change. Oxidation is the loss of Electron, electrons or an increase in the oxidation state, while reduction ...
reactions #
ATP synthase ATP synthase is a protein that catalyzes the formation of the energy storage molecule adenosine triphosphate (ATP) using adenosine diphosphate (ADP) and inorganic phosphate (Pi). It is classified under ligases as it changes ADP by the formation o ...
, which generates ATP in the matrix # Specific
transport proteins A transport protein (variously referred to as a transmembrane pump, transporter, escort protein, acid transport protein, cation transport protein, or anion transport protein) is a protein that serves the function of moving other materials within ...
that regulate
metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...
passage into and out of the
mitochondrial matrix In the mitochondrion, the matrix is the space within the Inner mitochondrial membrane, inner membrane. The word "matrix" stems from the fact that this space is viscous, compared to the relatively aqueous cytoplasm. The mitochondrial matrix contain ...
It contains more than 151 different
polypeptide Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called Protein, proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapepti ...
s, and has a very high protein-to-phospholipid ratio (more than 3:1 by weight, which is about 1 protein for 15 phospholipids). The inner membrane is home to around 1/5 of the total protein in a mitochondrion. Additionally, the inner membrane is rich in an unusual phospholipid,
cardiolipin Cardiolipin (IUPAC name 1,3-bis(''sn''-3’-phosphatidyl)-''sn''-glycerol) is an important component of the inner mitochondrial membrane, where it constitutes about 20% of the total lipid composition. It can also be found in the membranes of most ...
. This phospholipid was originally discovered in
cow Cattle (''Bos taurus'') are large, domestication, domesticated, Cloven hoof, cloven-hooved, herbivores. They are a prominent modern member of the subfamily Bovinae and the most widespread species of the genus ''Bos''. Adult females are referr ...
hearts in 1942, and is usually characteristic of mitochondrial and bacterial plasma membranes. Cardiolipin contains four fatty acids rather than two, and may help to make the inner membrane impermeable, and its disruption can lead to multiple clinical disorders including neurological disorders and cancer. Unlike the outer membrane, the inner membrane does not contain porins, and is highly impermeable to all molecules. Almost all ions and molecules require special membrane transporters to enter or exit the matrix. Proteins are ferried into the matrix via the
translocase of the inner membrane The translocase of the inner membrane (TIM) is a complex of proteins found in the inner mitochondrial membrane of the mitochondria. Components of the TIM complex facilitate the translocation of proteins across the inner membrane and into the mitoc ...
(TIM) complex or via OXA1L. In addition, there is a membrane potential across the inner membrane, formed by the action of the
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different molecule ...
s of the
electron transport chain An electron transport chain (ETC) is a series of protein complexes and other molecules that electron transfer, transfer electrons from electron donors to electron acceptors via redox reactions (both Redox#Definitions, reduction and oxidation occu ...
. Inner membrane fusion is mediated by the inner membrane protein OPA1.

Cristae

The inner mitochondrial membrane is compartmentalized into numerous folds called e, which expand the surface area of the inner mitochondrial membrane, enhancing its ability to produce ATP. For typical liver mitochondria, the area of the inner membrane is about five times as large as the outer membrane. This ratio is variable and mitochondria from cells that have a greater demand for ATP, such as muscle cells, contain even more cristae. Mitochondria within the same cell can have substantially different crista-density, with the ones that are required to produce more energy having much more crista-membrane surface. These folds are studded with small round bodies known as F particles or oxysomes.

Matrix

The matrix is the space enclosed by the inner membrane. It contains about 2/3 of the total proteins in a mitochondrion. The matrix is important in the production of ATP with the aid of the ATP synthase contained in the inner membrane. The matrix contains a highly concentrated mixture of hundreds of enzymes, special mitochondrial
ribosomes Ribosomes ( ) are macromolecular machines, found within all cells, that perform biological protein synthesis (mRNA translation). Ribosomes link amino acids Amino acids are organic compounds that contain both amino and carboxylic acid f ...
,
tRNA Transfer RNA (abbreviated tRNA and formerly referred to as sRNA, for soluble RNA) is an adaptor molecule composed of RNA, typically 76 to 90 nucleotides in length (in eukaryotes), that serves as the physical link between the Messenger RNA, mRNA a ...
, and several copies of the
mitochondrial DNA Mitochondrial DNA (mtDNA or mDNA) is the DNA located in mitochondria, cellular organelles within eukaryotic cells that convert chemical energy from food into a form that cells can use, such as adenosine triphosphate (ATP). Mitochondrial DN ...
genome In the fields of molecular biology and genetics, a genome is all the genetic information of an organism. It consists of nucleotide sequences of DNA (or RNA in RNA viruses). The nuclear genome includes protein-coding genes and non-coding gene ...
. Of the enzymes, the major functions include oxidation of
pyruvate Pyruvic acid (CH3COCOOH) is the simplest of the keto acids, alpha-keto acids, with a carboxylic acid and a ketone functional group. Pyruvate, the conjugate acid, conjugate base, CH3COCOO−, is an intermediate in several metabolic pathways throug ...
and
fatty acids In chemistry, particularly in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated and unsaturated compounds#Organic chemistry, saturated or unsaturated. Most naturally occurring fatty acids have an B ...
, and the
citric acid cycle The citric acid cycle (CAC)—also known as the Krebs cycle or the TCA cycle (tricarboxylic acid cycle)—is a series of chemical reactions to release stored energy through the Redox, oxidation of acetyl-CoA derived from carbohydrates, fats, and p ...
. The DNA molecules are packaged into nucleoids by proteins, one of which is
TFAM Mitochondrial transcription factor A, abbreviated as ''TFAM'' or ''mtTFA'', is a protein that in humans is encoded by the ''TFAM'' gene. Function This gene encodes a mitochondrial transcription factor that is a key activator of mitochondrial ...
.

Function

The most prominent roles of mitochondria are to produce the energy currency of the cell, ATP (i.e., phosphorylation of
ADP Adp or ADP may refer to: Aviation * Aéroports de Paris, airport authority for the Parisian region in France * Aeropuertos del Perú, airport operator for airports in northern Peru * SLAF Anuradhapura, an airport in Sri Lanka * Ampara Airpor ...
), through respiration and to regulate cellular
metabolism Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cell ...
. The central set of reactions involved in ATP production are collectively known as the
citric acid cycle The citric acid cycle (CAC)—also known as the Krebs cycle or the TCA cycle (tricarboxylic acid cycle)—is a series of chemical reactions to release stored energy through the Redox, oxidation of acetyl-CoA derived from carbohydrates, fats, and p ...
, or the Krebs cycle, and
oxidative phosphorylation Oxidative phosphorylation (UK , US ) or electron transport-linked phosphorylation or terminal oxidation is the metabolic pathway in which Cell (biology), cells use enzymes to Redox, oxidize nutrients, thereby releasing chemical energy in order t ...
. However, the mitochondrion has many other functions in addition to the production of ATP.

Energy conversion

A dominant role for the mitochondria is the production of ATP, as reflected by the large number of proteins in the inner membrane for this task. This is done by oxidizing the major products of
glucose Glucose is a simple sugar with the Chemical formula#Molecular formula, molecular formula . Glucose is overall the most abundant monosaccharide, a subcategory of carbohydrates. Glucose is mainly made by plants and most algae during photosynthesis f ...
:
pyruvate Pyruvic acid (CH3COCOOH) is the simplest of the keto acids, alpha-keto acids, with a carboxylic acid and a ketone functional group. Pyruvate, the conjugate acid, conjugate base, CH3COCOO−, is an intermediate in several metabolic pathways throug ...
, and
NADH Nicotinamide adenine dinucleotide (NAD) is a Cofactor (biochemistry), coenzyme central to metabolism. Found in all living cell (biology), cells, NAD is called a dinucleotide because it consists of two nucleotides joined through their phosphat ...
, which are produced in the cytosol. This type of
cellular respiration Cellular respiration is the process by which biological fuels are oxidised in the presence of an inorganic electron acceptor such as oxygen to produce large amounts of energy, to drive the bulk production of ATP. Cellular respiration may be des ...
, known as
aerobic respiration Cellular respiration is the process by which biological fuels are oxidised in the presence of an inorganic electron acceptor such as oxygen to produce large amounts of energy, to drive the bulk production of ATP. Cellular respiration may be des ...
, is dependent on the presence of
oxygen Oxygen is the chemical element with the chemical symbol, symbol O and atomic number 8. It is a member of the chalcogen Group (periodic table), group in the periodic table, a highly Chemical reaction, reactive nonmetal, and an oxidizing a ...
. When oxygen is limited, the glycolytic products will be metabolized by anaerobic fermentation, a process that is independent of the mitochondria. The production of ATP from glucose and oxygen has an approximately 13-times higher yield during aerobic respiration compared to fermentation. Plant mitochondria can also produce a limited amount of ATP either by breaking the sugar produced during photosynthesis or without oxygen by using the alternate substrate
nitrite The nitrite polyatomic ion, ion has the chemical formula . Nitrite (mostly sodium nitrite) is widely used throughout chemical and pharmaceutical industries. The nitrite anion is a pervasive intermediate in the nitrogen cycle in nature. The name ...
. ATP crosses out through the inner membrane with the help of a specific protein, and across the outer membrane via porins. ADP returns via the same route.

Pyruvate and the citric acid cycle

Pyruvate Pyruvic acid (CH3COCOOH) is the simplest of the keto acids, alpha-keto acids, with a carboxylic acid and a ketone functional group. Pyruvate, the conjugate acid, conjugate base, CH3COCOO−, is an intermediate in several metabolic pathways throug ...
molecules produced by
glycolysis Glycolysis is the metabolic pathway that converts glucose () into pyruvic acid, pyruvate (). The Thermodynamic free energy, free energy released in this process is used to form the high-energy molecules adenosine triphosphate (ATP) and NADH, red ...
are actively transported across the inner mitochondrial membrane, and into the matrix where they can either be
oxidized Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate (chemistry), substrate change. Oxidation is the loss of Electron, electrons or an increase in the oxidation state, while reduction ...
and combined with
coenzyme A Coenzyme A (CoA, SHCoA, CoASH) is a coenzyme, notable for its role in the Fatty acid metabolism#Synthesis, synthesis and Fatty acid metabolism#.CE.B2-Oxidation, oxidation of fatty acids, and the oxidation of pyruvic acid, pyruvate in the citric ac ...
to form CO,
acetyl-CoA Acetyl-CoA (acetyl coenzyme A) is a molecule that participates in many biochemical reactions in protein, carbohydrate and lipid metabolism Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining che ...
, and
NADH Nicotinamide adenine dinucleotide (NAD) is a Cofactor (biochemistry), coenzyme central to metabolism. Found in all living cell (biology), cells, NAD is called a dinucleotide because it consists of two nucleotides joined through their phosphat ...
, or they can be carboxylated (by pyruvate carboxylase) to form oxaloacetate. This latter reaction "fills up" the amount of oxaloacetate in the citric acid cycle and is therefore an anaplerotic reaction, increasing the cycle's capacity to metabolize acetyl-CoA when the tissue's energy needs (e.g., in
muscle Skeletal muscles (commonly referred to as muscles) are Organ (biology), organs of the vertebrate muscular system and typically are attached by tendons to bones of a skeleton. The muscle cells of skeletal muscles are much longer than in the other ...
) are suddenly increased by activity. In the citric acid cycle, all the intermediates (e.g.
citrate Citric acid is an organic compound with the chemical formula HOC(CO2H)(CH2CO2H)2. It is a Transparency and translucency, colorless Weak acid, weak organic acid. It occurs naturally in Citrus, citrus fruits. In biochemistry, it is an intermedi ...
, iso-citrate, alpha-ketoglutarate, succinate,
fumarate Fumaric acid is an organic compound with the formula HO2CCH=CHCO2H. A white solid, fumaric acid occurs widely in nature. It has a fruit-like taste and has been used as a food additive. Its E number is E297. The salt (chemistry), salts and ester ...
,
malate Malic acid is an organic compound with the molecular formula . It is a dicarboxylic acid that is made by all living organisms, contributes to the sour taste of fruits, and is used as a food additive. Malic acid has two stereoisomeric forms (L ...
and oxaloacetate) are regenerated during each turn of the cycle. Adding more of any of these intermediates to the mitochondrion therefore means that the additional amount is retained within the cycle, increasing all the other intermediates as one is converted into the other. Hence, the addition of any one of them to the cycle has an anaplerotic effect, and its removal has a cataplerotic effect. These anaplerotic and cataplerotic reactions will, during the course of the cycle, increase or decrease the amount of oxaloacetate available to combine with acetyl-CoA to form citric acid. This in turn increases or decreases the rate of ATP production by the mitochondrion, and thus the availability of ATP to the cell. Acetyl-CoA, on the other hand, derived from pyruvate oxidation, or from the beta-oxidation of
fatty acids In chemistry, particularly in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated and unsaturated compounds#Organic chemistry, saturated or unsaturated. Most naturally occurring fatty acids have an B ...
, is the only fuel to enter the citric acid cycle. With each turn of the cycle one molecule of acetyl-CoA is consumed for every molecule of oxaloacetate present in the mitochondrial matrix, and is never regenerated. It is the oxidation of the acetate portion of acetyl-CoA that produces CO and water, with the energy thus released captured in the form of ATP. In the liver, the
carboxylation Carboxylation is a chemical reaction in which a carboxylic acid is produced by treating a Substrate (chemistry), substrate with carbon dioxide. The opposite reaction is decarboxylation. In chemistry, the term carbonation is sometimes used synonymou ...
of
cytosol The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cell (biology), cells (Fluid compartments#Intracellular compartment, intracellular fluid (ICF)). It is separated into compartments by membranes. For ...
ic pyruvate into intra-mitochondrial oxaloacetate is an early step in the gluconeogenic pathway, which converts lactate and de-aminated
alanine Alanine (symbol Ala or A), or α-alanine, is an α-amino acid that is used in the biosynthesis of proteins. It contains an amine, amine group and a carboxylic acid, carboxylic acid group, both attached to the central carbon atom which also carrie ...
into glucose, under the influence of high levels of
glucagon Glucagon is a peptide hormone, produced by alpha cells of the pancreas. It raises concentration of glucose and fatty acids in the bloodstream, and is considered to be the main catabolic hormone of the body. It is also used as a Glucagon (medicati ...
and/or
epinephrine Adrenaline, also known as epinephrine, is a hormone and medication A medication (also called medicament, medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to medical diagnosis, diagnose, cure, treat, or preve ...
in the blood. Here, the addition of oxaloacetate to the mitochondrion does not have a net anaplerotic effect, as another citric acid cycle intermediate (malate) is immediately removed from the mitochondrion to be converted to cytosolic oxaloacetate, and ultimately to glucose, in a process that is almost the reverse of
glycolysis Glycolysis is the metabolic pathway that converts glucose () into pyruvic acid, pyruvate (). The Thermodynamic free energy, free energy released in this process is used to form the high-energy molecules adenosine triphosphate (ATP) and NADH, red ...
. The enzymes of the citric acid cycle are located in the mitochondrial matrix, with the exception of
succinate dehydrogenase Succinate dehydrogenase (SDH) or succinate-coenzyme Q reductase (SQR) or respiratory complex II is an enzyme complex, found in many bacterial Cell (biology), cells and in the inner mitochondrial membrane of eukaryotes. It is the only enzyme that ...
, which is bound to the inner mitochondrial membrane as part of Complex II. The citric acid cycle oxidizes the acetyl-CoA to carbon dioxide, and, in the process, produces reduced cofactors (three molecules of
NADH Nicotinamide adenine dinucleotide (NAD) is a Cofactor (biochemistry), coenzyme central to metabolism. Found in all living cell (biology), cells, NAD is called a dinucleotide because it consists of two nucleotides joined through their phosphat ...
and one molecule of FADH) that are a source of electrons for the
electron transport chain An electron transport chain (ETC) is a series of protein complexes and other molecules that electron transfer, transfer electrons from electron donors to electron acceptors via redox reactions (both Redox#Definitions, reduction and oxidation occu ...
, and a molecule of GTP (which is readily converted to an ATP).

The electrons from NADH and FADH are transferred to oxygen (O) and hydrogen (protons) in several steps via an electron transport chain. NADH and FADH molecules are produced within the matrix via the citric acid cycle and in the cytoplasm by
glycolysis Glycolysis is the metabolic pathway that converts glucose () into pyruvic acid, pyruvate (). The Thermodynamic free energy, free energy released in this process is used to form the high-energy molecules adenosine triphosphate (ATP) and NADH, red ...
.
Reducing equivalent Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate (chemistry), substrate change. Oxidation is the loss of Electron, electrons or an increase in the oxidation state, while reduction ...
s from the cytoplasm can be imported via the malate-aspartate shuttle system of
antiporter An antiporter (also called exchanger or counter-transporter) is a cotransporter and integral membrane protein involved in secondary active transport of two or more different molecules or ions across a phospholipid membrane such as the plasma membr ...
proteins or fed into the electron transport chain using a glycerol phosphate shuttle. The major energy-releasing reactions Voet, D.; Voet, J. G. (2004). ''Biochemistry'', 3rd edition, p. 804, Wiley. Atkins, P.; de Paula, J. (2006) "Physical Chemistry", 8th ed.; pp. 225-229, Freeman: New York, 2006. that make the mitochondrion the "powerhouse of the cell" occur at protein complexes I, III and IV in the inner mitochondrial membrane (
NADH dehydrogenase (ubiquinone) Respiratory complex I, (also known as NADH:ubiquinone oxidoreductase, Type I NADH dehydrogenase and mitochondrial complex I) is the first large protein complex of the respiratory chains of many organisms from bacteria to humans. It catalyzes th ...
, cytochrome c reductase, and
cytochrome c oxidase The enzyme cytochrome c oxidase or Complex IV, (was , now reclassified as a translocasEC 7.1.1.9 is a large transmembrane protein complex found in bacteria, archaea, and mitochondria of eukaryotes. It is the last enzyme in the Cellular respirati ...
). At
complex IV The enzyme cytochrome c oxidase or Complex IV, (was , now reclassified as a translocasEC 7.1.1.9 is a large transmembrane protein complex found in bacteria, archaea, and mitochondria of eukaryotes. It is the last enzyme in the Cellular respirati ...
, O2 reacts with the reduced form of iron in
cytochrome c The cytochrome complex, or cyt ''c'', is a small hemeprotein found loosely associated with the inner mitochondrial membrane, inner membrane of the mitochondrion. It belongs to the cytochrome c family of proteins and plays a major role in cell apo ...
: O2 + 4H+(aq) + 4 Fe^(cyt\,c) -> 2H2O + 4 Fe^(cyt\,c) $\Delta_r G^=-218 \text$ releasing a lot of free energy from the reactants without breaking bonds of an organic fuel. The free energy put in to remove an electron from Fe2+ is released at
complex III Complex commonly refers to: * Complexity Complexity characterises the behaviour of a system or model whose components interaction, interact in multiple ways and follow local rules, leading to nonlinearity, randomness, collective dynamics, hiera ...
when Fe3+ of cytochrome c reacts to oxidize ubiquinol (QH2): 2 Fe^(cyt\,c) + QH2 -> 2 Fe^(cyt\,c) + Q + 2H+(aq) $\Delta_r G^=-30 \text$ The
ubiquinone Coenzyme Q, also known as ubiquinone and marketed as CoQ10, is a coenzyme A cofactor is a non-protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), resid ...
(Q) generated reacts, in
complex I Respiratory complex I, (also known as NADH:ubiquinone oxidoreductase, Type I NADH dehydrogenase and mitochondrial complex I) is the first large protein complex of the Electron transport chain, respiratory chains of many organisms from bacteria to ...
, with NADH: Q + H+(aq) + NADH -> QH2 + NAD+ $\Delta_r G^=-81 \text$ While the reactions are controlled by an electron transport chain, free electrons are not amongst the reactants or products in the three reactions shown and therefore do not affect the free energy released, which is used to pump
protons A proton is a stable subatomic particle, symbol , H+, or 1H+ with a positive electric charge Electric charge is the physical property of matter that causes charged matter to experience a force when placed in an electromagnetic field. Ele ...
(H) into the intermembrane space. This process is efficient, but a small percentage of electrons may prematurely reduce oxygen, forming
reactive oxygen species In chemistry, reactive oxygen species (ROS) are highly Reactivity (chemistry), reactive chemicals formed from diatomic oxygen (). Examples of ROS include peroxides, superoxide, hydroxyl radical, singlet oxygen, and alpha-oxygen. The reduction of ...
such as
superoxide In chemistry, a superoxide is a Chemical compound, compound that contains the superoxide ion, which has the chemical formula . The systematic name of the anion is dioxide(1−). The reactive oxygen species, reactive oxygen ion superoxide is p ...
. This can cause
oxidative stress Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. Disturbances in the normal ...
in the mitochondria and may contribute to the decline in mitochondrial function associated with aging. As the proton concentration increases in the intermembrane space, a strong
electrochemical gradient An electrochemical gradient is a gradient of electrochemical potential, usually for an ion that can move across a membrane. The gradient consists of two parts, the chemical gradient, or difference in Concentration, solute concentration across a me ...
is established across the inner membrane. The protons can return to the matrix through the
ATP synthase ATP synthase is a protein that catalyzes the formation of the energy storage molecule adenosine triphosphate (ATP) using adenosine diphosphate (ADP) and inorganic phosphate (Pi). It is classified under ligases as it changes ADP by the formation o ...
complex, and their potential energy is used to synthesize ATP from ADP and inorganic phosphate (P). This process is called
chemiosmosis Chemiosmosis is the movement of ions across a semipermeable membrane bound structure, down their electrochemical gradient An electrochemical gradient is a gradient of electrochemical potential, usually for an ion that can move across a membrane ...
, and was first described by Peter Mitchell, who was awarded the 1978
Nobel Prize in Chemistry ) , image = Nobel Prize.png , alt = A golden medallion with an embossed image of a bearded man facing left in profile. To the left of the man is the text "ALFR•" then "NOBEL", and on the right, the text (smaller) "NAT•" then "M ...
for his work. Later, part of the 1997 Nobel Prize in Chemistry was awarded to Paul D. Boyer and John E. Walker for their clarification of the working mechanism of ATP synthase.

Heat production

Under certain conditions, protons can re-enter the mitochondrial matrix without contributing to ATP synthesis. This process is known as ''proton leak'' or mitochondrial uncoupling and is due to the
facilitated diffusion Facilitated diffusion (also known as facilitated transport or passive-mediated transport) is the process of spontaneous passive transport Passive transport is a type of membrane transport that does not require Energy (biology), energy to move ...
of protons into the matrix. The process results in the unharnessed potential energy of the proton
electrochemical Electrochemistry is the branch of physical chemistry concerned with the relationship between Electric potential, electrical potential difference, as a measurable and quantitative phenomenon, and identifiable chemical change, with the potential dif ...
gradient being released as heat. The process is mediated by a proton channel called thermogenin, or UCP1. Thermogenin is primarily found in
brown adipose tissue Brown adipose tissue (BAT) or brown fat makes up the adipose organ together with white adipose tissue (or white fat). Brown adipose tissue is found in almost all mammals. Classification of brown fat refers to two distinct cell populations with si ...
, or brown fat, and is responsible for non-shivering thermogenesis. Brown adipose tissue is found in mammals, and is at its highest levels in early life and in hibernating animals. In humans, brown adipose tissue is present at birth and decreases with age.

Storage of calcium ions

The concentrations of free calcium in the cell can regulate an array of reactions and is important for
signal transduction Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a biochemical cascade, series of molecular events, most commonly protein phosphorylation catalyzed by protein kinases, which ultimately re ...
in the cell. Mitochondria can transiently store calcium, a contributing process for the cell's homeostasis of calcium. Their ability to rapidly take in calcium for later release makes them good "cytosolic buffers" for calcium. The endoplasmic reticulum (ER) is the most significant storage site of calcium, and there is a significant interplay between the mitochondrion and ER with regard to calcium. The calcium is taken up into the matrix by the
mitochondrial calcium uniporter The mitochondrial calcium uniporter (MCU) is a transmembrane protein that allows the passage of calcium ions from a cell's cytosol into Mitochondrion, mitochondria. Its activity is regulated by MICU1 (gene), MICU1 and MICU2, which together with t ...
on the
inner mitochondrial membrane The inner mitochondrial membrane (IMM) is the mitochondrial membrane which separates the mitochondrial matrix from the intermembrane space. Structure The structure of the inner mitochondrial membrane is extensively folded and compartmentalized. Th ...
. It is primarily driven by the mitochondrial
membrane potential Membrane potential (also transmembrane potential or membrane voltage) is the difference in electric potential between the interior and the exterior of a biological Cell (biology), cell. That is, there is a difference in the energy required for e ...
. Release of this calcium back into the cell's interior can occur via a sodium-calcium exchange protein or via "calcium-induced-calcium-release" pathways. This can initiate calcium spikes or calcium waves with large changes in the membrane potential. These can activate a series of
second messenger system Second messengers are intracellular signaling In biology, cell signaling (cell signalling in British English) or cell communication is the ability of a Cell (biology), cell to receive, process, and transmit signals with its environment and with i ...
proteins that can coordinate processes such as neurotransmitter release in nerve cells and release of
hormone A hormone (from the Ancient Greek, Greek participle , "setting in motion") is a class of cell signaling, signaling molecules in multicellular organisms that are sent to distant organs by complex biological processes to regulate physiology and beh ...
s in endocrine cells. Ca influx to the mitochondrial matrix has recently been implicated as a mechanism to regulate respiratory
bioenergetics Bioenergetics is a field in biochemistry and cell biology that concerns energy flow through living systems. This is an active area of Biology, biological research that includes the study of the transformation of energy in living organisms and the ...
by allowing the electrochemical potential across the membrane to transiently "pulse" from ΔΨ-dominated to pH-dominated, facilitating a reduction of
oxidative stress Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. Disturbances in the normal ...
. In neurons, concomitant increases in cytosolic and mitochondrial calcium act to synchronize neuronal activity with mitochondrial energy metabolism. Mitochondrial matrix calcium levels can reach the tens of micromolar levels, which is necessary for the activation of
isocitrate dehydrogenase Isocitrate dehydrogenase (IDH) () and () is an enzyme that catalyzes the oxidative decarboxylation of isocitrate, producing alpha-Ketoglutaric acid, alpha-ketoglutarate (α-ketoglutarate) and carbon dioxide, CO2. This is a two-step process, whic ...
, one of the key regulatory enzymes of the Krebs cycle.

Cellular proliferation regulation

The relationship between cellular proliferation and mitochondria has been investigated. Tumor cells require ample ATP to synthesize bioactive compounds such as
lipid Lipids are a broad group of naturally-occurring molecules which includes fats, waxes, sterols, fat-soluble vitamins (such as vitamins Vitamin A, A, Vitamin D, D, Vitamin E, E and Vitamin K, K), monoglycerides, diglycerides, phospholipids, and o ...
s,
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metabo ...
s, and
nucleotide Nucleotides are Organic compound, organic molecules consisting of a nucleoside and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both of which are essential ...
s for rapid proliferation. The majority of ATP in tumor cells is generated via the
oxidative phosphorylation Oxidative phosphorylation (UK , US ) or electron transport-linked phosphorylation or terminal oxidation is the metabolic pathway in which Cell (biology), cells use enzymes to Redox, oxidize nutrients, thereby releasing chemical energy in order t ...
pathway (OxPhos). Interference with OxPhos cause
cell cycle The cell cycle, or cell-division cycle, is the series of events that take place in a cell that cause it to divide into two daughter cells. These events include the duplication of its DNA ( DNA replication) and some of its organelles, and su ...

arrest suggesting that mitochondria play a role in cell proliferation. Mitochondrial ATP production is also vital for
cell division Cell division is the process by which a parent cell (biology), cell divides into two daughter cells. Cell division usually occurs as part of a larger cell cycle in which the cell grows and replicates its chromosome(s) before dividing. In eukar ...
and differentiation in infection in addition to basic functions in the cell including the regulation of cell volume, solute
concentration In chemistry, concentration is the Abundance (chemistry), abundance of a constituent divided by the total volume of a mixture. Several types of mathematical description can be distinguished: ''mass concentration (chemistry), mass concentration'', ...
, and cellular architecture. ATP levels differ at various stages of the cell cycle suggesting that there is a relationship between the abundance of ATP and the cell's ability to enter a new cell cycle. ATP's role in the basic functions of the cell make the
cell cycle The cell cycle, or cell-division cycle, is the series of events that take place in a cell that cause it to divide into two daughter cells. These events include the duplication of its DNA ( DNA replication) and some of its organelles, and su ...

sensitive to changes in the availability of mitochondrial derived ATP. The variation in ATP levels at different stages of the cell cycle support the hypothesis that mitochondria play an important role in cell cycle regulation. Although the specific mechanisms between mitochondria and the cell cycle regulation is not well understood, studies have shown that low energy cell cycle checkpoints monitor the energy capability before committing to another round of cell division.

Mitochondria play a central role in many other
metabolic Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cell ...
tasks, such as: * Signaling through mitochondrial
reactive oxygen species In chemistry, reactive oxygen species (ROS) are highly Reactivity (chemistry), reactive chemicals formed from diatomic oxygen (). Examples of ROS include peroxides, superoxide, hydroxyl radical, singlet oxygen, and alpha-oxygen. The reduction of ...
* Regulation of the
membrane potential Membrane potential (also transmembrane potential or membrane voltage) is the difference in electric potential between the interior and the exterior of a biological Cell (biology), cell. That is, there is a difference in the energy required for e ...
*
Apoptosis Apoptosis (from grc, wikt:ἀπόπτωσις, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemistry, Biochemical events lead to characteristic cell changes (Morp ...
-programmed cell death * Calcium signaling (including calcium-evoked apoptosis) * Regulation of cellular
metabolism Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cell ...
* Certain
heme Heme, or haem (pronounced / hi:m/ ), is a precursor to hemoglobin, which is necessary to bind oxygen Oxygen is the chemical element with the chemical symbol, symbol O and atomic number 8. It is a member of the chalcogen Group (period ...
porphyrin Porphyrins ( ) are a group of heterocyclic compound, heterocyclic macrocycle organic compounds, composed of four modified pyrrole subunits interconnected at their Alpha and beta carbon, α carbon atoms via methine bridges (=CH−). The parent of ...
)'' *
Steroid A steroid is a biologically active organic compound with four rings arranged in a specific molecular configuration. Steroids have two principal biological functions: as important components of cell membranes that alter membrane fluidity; and a ...
synthesis. * Hormonal signaling Mitochondria are sensitive and responsive to hormones, in part by the action of mitochondrial estrogen receptors (mtERs). These receptors have been found in various tissues and cell types, including brain and heart * Immune signaling * Neuronal mitochondria also contribute to cellular quality control by reporting neuronal status towards microglia through specialised somatic-junctions. * Mitochondria of developing neurons contribute to intercellular signaling towards
microglia Microglia are a type of neuroglia (glial cell) located throughout the brain and spinal cord. Microglia account for about 7% of cells found within the brain. As the resident macrophage cells, they act as the first and main form of active immune de ...
, which communication is indispensable for proper regulation of brain development. Some mitochondrial functions are performed only in specific types of cells. For example, mitochondria in liver cells contain enzymes that allow them to detoxify
ammonia Ammonia is an inorganic chemical compound, compound of nitrogen and hydrogen with the chemical formula, formula . A Binary compounds of hydrogen, stable binary hydride, and the simplest pnictogen hydride, ammonia is a colourless gas with a dis ...
, a waste product of protein metabolism. A mutation in the genes regulating any of these functions can result in
mitochondrial disease Mitochondrial disease is a group of disorders caused by mitochondrial dysfunction. Mitochondria are the organelles that generate energy for the cell and are found in every cell of the human body except red blood cells. They convert the energy of ...
s. Mitochondrial proteins (proteins transcribed from mitochondrial DNA) vary depending on the tissue and the species. In humans, 615 distinct types of proteins have been identified from
cardiac The heart is a muscular organ in most animals. This organ pumps blood through the blood vessels of the circulatory system. The pumped blood carries oxygen Oxygen is the chemical element with the chemical symbol, symbol O and ...
mitochondria, whereas in
rats Rats are various medium-sized, long-tailed rodents. Species of rats are found throughout the order Rodentia, but stereotypical rats are found in the genus ''Rattus''. Other rat genera include ''Neotoma'' (pack rats), ''Bandicota'' (bandicoot ...
, 940 proteins have been reported. The mitochondrial
proteome The proteome is the entire set of protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, ...
is thought to be dynamically regulated.

Organization and distribution

Mitochondria (or related structures) are found in all
eukaryote Eukaryotes () are organisms whose Cell (biology), cells have a cell nucleus, nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the ...

Monocercomonoides ''Monocercomonoides'' is a genus of flagellate Excavata belonging to the order Oxymonadida. It was established by Bernard V. Travis and was first described as those with "polymastiginid flagellates having three anterior Flagellum, flagella and a ...
''). Although commonly depicted as bean-like structures they form a highly dynamic network in the majority of cells where they constantly undergo fission and fusion. The population of all the mitochondria of a given cell constitutes the chondriome. Mitochondria vary in number and location according to cell type. A single mitochondrion is often found in unicellular organisms, while human liver cells have about 1000–2000 mitochondria per cell, making up 1/5 of the cell volume. The mitochondrial content of otherwise similar cells can vary substantially in size and membrane potential, with differences arising from sources including uneven partitioning at cell division, leading to extrinsic differences in ATP levels and downstream cellular processes. The mitochondria can be found nestled between
myofibril A myofibril (also known as a muscle fibril or sarcostyle) is a basic rod-like organelle of a muscle cell. Skeletal muscles are composed of long, tubular cells known as Skeletal muscle#Skeletal muscle fibers, muscle fibers, and these cells contain ...
s of
muscle Skeletal muscles (commonly referred to as muscles) are Organ (biology), organs of the vertebrate muscular system and typically are attached by tendons to bones of a skeleton. The muscle cells of skeletal muscles are much longer than in the other ...
or wrapped around the
sperm Sperm is the male reproductive Cell (biology), cell, or gamete, in anisogamous forms of sexual reproduction (forms in which there is a larger, female reproductive cell and a smaller, male one). Animals produce motile sperm with a tail known as ...
flagellum A flagellum (; ) is a hairlike appendage that protrudes from certain plant and animal sperm cells, and from a wide range of microorganisms to provide Motility#Cellular level, motility. Many protists with flagella are termed as flagellates. A m ...
. Often, they form a complex 3D branching network inside the cell with the
cytoskeleton The cytoskeleton is a complex, dynamic network of interlinking protein filaments present in the cytoplasm of all Cell (biology), cells, including those of bacteria and archaea. In eukaryotes, it extends from the cell nucleus to the cell membrane ...
. The association with the cytoskeleton determines mitochondrial shape, which can affect the function as well: different structures of the mitochondrial network may afford the population a variety of physical, chemical, and signalling advantages or disadvantages. Mitochondria in cells are always distributed along microtubules and the distribution of these organelles is also correlated with the
endoplasmic reticulum The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough endoplasmic reticulum ...
. Recent evidence suggests that
vimentin Vimentin is a structural protein that in humans is encoded by the ''VIM'' gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian inheritance#History, Mendelian units of heredity..." ...
, one of the components of the cytoskeleton, is also critical to the association with the cytoskeleton.

Mitochondria-associated ER membrane (MAM)

The mitochondria-associated ER membrane (MAM) is another structural element that is increasingly recognized for its critical role in cellular physiology and
homeostasis In biology, homeostasis ( British also homoeostasis) (/hɒmɪə(ʊ)ˈsteɪsɪs/) is the state of steady internal, physical, and chemical conditions maintained by living systems. This is the condition of optimal functioning for the organism ...
. Once considered a technical snag in cell fractionation techniques, the alleged ER vesicle contaminants that invariably appeared in the mitochondrial fraction have been re-identified as membranous structures derived from the MAM—the interface between mitochondria and the ER. Physical coupling between these two organelles had previously been observed in electron micrographs and has more recently been probed with
fluorescence microscopy A fluorescence microscope is an optical microscope that uses fluorescence instead of, or in addition to, scattering, reflection (physics), reflection, and attenuation or absorption (electromagnetic radiation), absorption, to study the propertie ...
. Such studies estimate that at the MAM, which may comprise up to 20% of the mitochondrial outer membrane, the ER and mitochondria are separated by a mere 10–25 nm and held together by protein tethering complexes. Purified MAM from subcellular fractionation is enriched in enzymes involved in phospholipid exchange, in addition to channels associated with Ca signaling. These hints of a prominent role for the MAM in the regulation of cellular lipid stores and signal transduction have been borne out, with significant implications for mitochondrial-associated cellular phenomena, as discussed below. Not only has the MAM provided insight into the mechanistic basis underlying such physiological processes as intrinsic apoptosis and the propagation of calcium signaling, but it also favors a more refined view of the mitochondria. Though often seen as static, isolated 'powerhouses' hijacked for cellular metabolism through an ancient endosymbiotic event, the evolution of the MAM underscores the extent to which mitochondria have been integrated into overall cellular physiology, with intimate physical and functional coupling to the endomembrane system.

Phospholipid transfer

The MAM is enriched in enzymes involved in lipid biosynthesis, such as phosphatidylserine synthase on the ER face and phosphatidylserine decarboxylase on the mitochondrial face. Because mitochondria are dynamic organelles constantly undergoing fission and fusion events, they require a constant and well-regulated supply of phospholipids for membrane integrity. But mitochondria are not only a destination for the phospholipids they finish synthesis of; rather, this organelle also plays a role in inter-organelle trafficking of the intermediates and products of phospholipid biosynthetic pathways, ceramide and cholesterol metabolism, and glycosphingolipid anabolism. Such trafficking capacity depends on the MAM, which has been shown to facilitate transfer of lipid intermediates between organelles. In contrast to the standard vesicular mechanism of lipid transfer, evidence indicates that the physical proximity of the ER and mitochondrial membranes at the MAM allows for lipid flipping between opposed bilayers. Despite this unusual and seemingly energetically unfavorable mechanism, such transport does not require ATP. Instead, in yeast, it has been shown to be dependent on a multiprotein tethering structure termed the ER-mitochondria encounter structure, or ERMES, although it remains unclear whether this structure directly mediates lipid transfer or is required to keep the membranes in sufficiently close proximity to lower the energy barrier for
lipid Lipids are a broad group of naturally-occurring molecules which includes fats, waxes, sterols, fat-soluble vitamins (such as vitamins Vitamin A, A, Vitamin D, D, Vitamin E, E and Vitamin K, K), monoglycerides, diglycerides, phospholipids, and o ...
flipping. The MAM may also be part of the secretory pathway, in addition to its role in intracellular lipid trafficking. In particular, the MAM appears to be an intermediate destination between the rough ER and the Golgi in the pathway that leads to
very-low-density lipoprotein Very-low-density lipoprotein (VLDL), density relative to extracellular water, is a type of lipoprotein made by the liver. VLDL is one of the five major groups of lipoproteins (chylomicrons, VLDL, intermediate-density lipoprotein, LDL, low-density ...
, or VLDL, assembly and secretion. The MAM thus serves as a critical metabolic and trafficking hub in lipid metabolism.

Calcium signaling

A critical role for the ER in calcium signaling was acknowledged before such a role for the mitochondria was widely accepted, in part because the low affinity of Ca channels localized to the outer mitochondrial membrane seemed to contradict this organelle's purported responsiveness to changes in intracellular Ca flux. But the presence of the MAM resolves this apparent contradiction: the close physical association between the two organelles results in Ca microdomains at contact points that facilitate efficient Ca transmission from the ER to the mitochondria. Transmission occurs in response to so-called "Ca puffs" generated by spontaneous clustering and activation of IP3R, a canonical ER membrane Ca channel. The fate of these puffs—in particular, whether they remain restricted to isolated locales or integrated into Ca waves for propagation throughout the cell—is determined in large part by MAM dynamics. Although reuptake of Ca by the ER (concomitant with its release) modulates the intensity of the puffs, thus insulating mitochondria to a certain degree from high Ca exposure, the MAM often serves as a firewall that essentially buffers Ca puffs by acting as a sink into which free ions released into the cytosol can be funneled. This Ca tunneling occurs through the low-affinity Ca receptor
VDAC1 Voltage-dependent anion-selective channel 1 (VDAC-1) is a beta barrel protein that in humans is encoded by the ''VDAC1'' gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian inherita ...
, which recently has been shown to be physically
tethered A tether is a cord, fixture, or flexible attachment that characteristically anchors something movable to something fixed; it also maybe used to connect two movable objects, such as an item being towing, towed by its tow. Applications for tethers ...
to the IP3R clusters on the ER membrane and enriched at the MAM. The ability of mitochondria to serve as a Ca sink is a result of the electrochemical gradient generated during oxidative phosphorylation, which makes tunneling of the cation an exergonic process. Normal, mild calcium influx from cytosol into the mitochondrial matrix causes transient depolarization that is corrected by pumping out protons. But transmission of Ca is not unidirectional; rather, it is a two-way street. The properties of the Ca pump SERCA and the channel IP3R present on the ER membrane facilitate feedback regulation coordinated by MAM function. In particular, the clearance of Ca by the MAM allows for spatio-temporal patterning of Ca signaling because Ca alters IP3R activity in a biphasic manner.
SERCA SERCA, or sarcoplasmic reticulum, sarco/endoplasmic reticulum Calcium, Ca2+-ATPase, or SR Calcium, Ca2+-ATPase, is a calcium ATPase-type P-type ATPase, P-ATPase. Its major function is to transport calcium from the cytosol into the sarcoplasmic retic ...
is likewise affected by mitochondrial feedback: uptake of Ca by the MAM stimulates ATP production, thus providing energy that enables SERCA to reload the ER with Ca for continued Ca efflux at the MAM. Thus, the MAM is not a passive buffer for Ca puffs; rather it helps modulate further Ca signaling through feedback loops that affect ER dynamics. Regulating ER release of Ca at the MAM is especially critical because only a certain window of Ca uptake sustains the mitochondria, and consequently the cell, at homeostasis. Sufficient intraorganelle Ca signaling is required to stimulate metabolism by activating dehydrogenase enzymes critical to flux through the citric acid cycle. However, once Ca signaling in the mitochondria passes a certain threshold, it stimulates the intrinsic pathway of apoptosis in part by collapsing the mitochondrial membrane potential required for metabolism. Studies examining the role of pro- and anti-apoptotic factors support this model; for example, the anti-apoptotic factor Bcl-2 has been shown to interact with IP3Rs to reduce Ca filling of the ER, leading to reduced efflux at the MAM and preventing collapse of the mitochondrial membrane potential post-apoptotic stimuli. Given the need for such fine regulation of Ca signaling, it is perhaps unsurprising that dysregulated mitochondrial Ca has been implicated in several neurodegenerative diseases, while the catalogue of tumor suppressors includes a few that are enriched at the MAM.

Molecular basis for tethering

Recent advances in the identification of the tethers between the mitochondrial and ER membranes suggest that the scaffolding function of the molecular elements involved is secondary to other, non-structural functions. In yeast, ERMES, a multiprotein complex of interacting ER- and mitochondrial-resident membrane proteins, is required for lipid transfer at the MAM and exemplifies this principle. One of its components, for example, is also a constituent of the protein complex required for insertion of transmembrane beta-barrel proteins into the lipid bilayer. However, a homologue of the ERMES complex has not yet been identified in mammalian cells. Other proteins implicated in scaffolding likewise have functions independent of structural tethering at the MAM; for example, ER-resident and mitochondrial-resident mitofusins form heterocomplexes that regulate the number of inter-organelle contact sites, although mitofusins were first identified for their role in fission and fusion events between individual mitochondria.
Glucose Glucose is a simple sugar with the Chemical formula#Molecular formula, molecular formula . Glucose is overall the most abundant monosaccharide, a subcategory of carbohydrates. Glucose is mainly made by plants and most algae during photosynthesis f ...
-related protein 75 (grp75) is another dual-function protein. In addition to the matrix pool of grp75, a portion serves as a chaperone that physically links the mitochondrial and ER Ca channels VDAC and IP3R for efficient Ca transmission at the MAM. Another potential tether is Sigma-1R, a non-opioid receptor whose stabilization of ER-resident IP3R may preserve communication at the MAM during the metabolic stress response.

Perspective

The MAM is a critical signaling, metabolic, and trafficking hub in the cell that allows for the integration of ER and mitochondrial physiology. Coupling between these organelles is not simply structural but functional as well and critical for overall cellular physiology and
homeostasis In biology, homeostasis ( British also homoeostasis) (/hɒmɪə(ʊ)ˈsteɪsɪs/) is the state of steady internal, physical, and chemical conditions maintained by living systems. This is the condition of optimal functioning for the organism ...
. The MAM thus offers a perspective on mitochondria that diverges from the traditional view of this organelle as a static, isolated unit appropriated for its metabolic capacity by the cell. Instead, this mitochondrial-ER interface emphasizes the integration of the mitochondria, the product of an endosymbiotic event, into diverse cellular processes. Recently it has also been shown, that mitochondria and MAM-s in neurons are anchored to specialised intercellular communication sites (so called somatic-junctions).
Microglia Microglia are a type of neuroglia (glial cell) located throughout the brain and spinal cord. Microglia account for about 7% of cells found within the brain. As the resident macrophage cells, they act as the first and main form of active immune de ...
l processes monitor and protect neuronal functions at these sites, and MAM-s are supposed to have an important role in this type of cellular quality-control.

Origin and evolution

There are two hypotheses about the origin of mitochondria: endosymbiotic and autogenous. The endosymbiotic hypothesis suggests that mitochondria were originally
prokaryotic A prokaryote () is a Unicellular organism, single-celled organism that lacks a cell nucleus, nucleus and other membrane-bound organelles. The word ''prokaryote'' comes from the Greek language, Greek wikt:πρό#Ancient Greek, πρό (, 'before') a ...
cells, capable of implementing oxidative mechanisms that were not possible for eukaryotic cells; they became
endosymbiont An ''endosymbiont'' or ''endobiont'' is any organism In biology, an organism () is any life, living system that functions as an individual entity. All organisms are composed of cells (cell theory). Organisms are classified by taxonom ...
s living inside the eukaryote. In the autogenous hypothesis, mitochondria were born by splitting off a portion of DNA from the nucleus of the eukaryotic cell at the time of divergence with the prokaryotes; this DNA portion would have been enclosed by membranes, which could not be crossed by proteins. Since mitochondria have many features in common with
bacteria Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometre The micrometre (Amer ...

, the endosymbiotic hypothesis is the more widely accepted of the two accounts. A mitochondrion contains DNA, which is organized as several copies of a single, usually
circular Circular may refer to: * The shape of a circle * Circular (album), ''Circular'' (album), a 2006 album by Spanish singer Vega * Circular letter (disambiguation) ** Flyer (pamphlet), a form of advertisement * Circular reasoning, a type of logical fa ...
chromosome A chromosome is a long DNA molecule with part or all of the genetic material of an organism. In most chromosomes the very long thin DNA fibers are coated with packaging proteins; in eukaryotic cells the most important of these proteins are ...
. This mitochondrial chromosome contains genes for
redox Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate (chemistry), substrate change. Oxidation is the loss of Electron, electrons or an increase in the oxidation state, while reduction ...
proteins, such as those of the respiratory chain. The
CoRR hypothesis The CoRR hypothesis states that the location of genetic information in cytoplasmic organelles permits regulation of its expression by the reduction-oxidation ("redox") state of its gene products. CoRR is short for "co-location for redox regulation ...
proposes that this co-location is required for redox regulation. The mitochondrial
genome In the fields of molecular biology and genetics, a genome is all the genetic information of an organism. It consists of nucleotide sequences of DNA (or RNA in RNA viruses). The nuclear genome includes protein-coding genes and non-coding gene ...
codes for some
RNA Ribonucleic acid (RNA) is a polymer A polymer (; Greek ''wikt:poly-, poly-'', "many" + ''wikt:-mer, -mer'', "part") is a Chemical substance, substance or material consisting of very large molecules called macromolecules, composed of many ...
s of
ribosome Ribosomes ( ) are molecular machine, macromolecular machines, found within all cell (biology), cells, that perform Translation (biology), biological protein synthesis (mRNA translation). Ribosomes link amino acids together in the order specifie ...
s, and the 22
tRNA Transfer RNA (abbreviated tRNA and formerly referred to as sRNA, for soluble RNA) is an adaptor molecule composed of RNA, typically 76 to 90 nucleotides in length (in eukaryotes), that serves as the physical link between the Messenger RNA, mRNA a ...
s necessary for the translation of
mRNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of Protein biosynthesis, synthesizing a protein. mRNA is ...
s into protein. The circular structure is also found in prokaryotes. The proto-mitochondrion was probably closely related to ''
Rickettsia ''Rickettsia'' is a genus of Motility, nonmotile, gram-negative, Endospore, nonspore-forming, highly pleomorphism (microbiology), pleomorphic bacteria that may occur in the forms of cocci (0.1 μm in diameter), Bacillus (shape), bacilli (1–4 ...
''. However, the exact relationship of the ancestor of mitochondria to the
alphaproteobacteria Alphaproteobacteria is a Class (biology), class of bacteria in the phylum Pseudomonadota (formerly Proteobacteria). The Magnetococcales and Mariprofundales are considered basal or sister to the Alphaproteobacteria. The Alphaproteobacteria are hig ...
and whether the mitochondrion was formed at the same time or after the nucleus, remains controversial. For example, it has been suggested that the SAR11 clade of bacteria shares a relatively recent common ancestor with the mitochondria, while
phylogenomic Phylogenomics is the intersection of the fields of evolution Evolution is change in the heredity, heritable Phenotypic trait, characteristics of biological populations over successive generations. These characteristics are the Gene express ...
analyses indicate that mitochondria evolved from a
Pseudomonadota Pseudomonadota (synonym Proteobacteria) is a major phylum of Gram-negative bacteria. The renaming of phyla in 2021 remains controversial among microbiologists, many of whom continue to use the earlier names of long standing in the literature. The ...
lineage that is closely related to or a member of
alphaproteobacteria Alphaproteobacteria is a Class (biology), class of bacteria in the phylum Pseudomonadota (formerly Proteobacteria). The Magnetococcales and Mariprofundales are considered basal or sister to the Alphaproteobacteria. The Alphaproteobacteria are hig ...
. Some papers describe mitochondria as sister to the alphaproteobactera, together forming the sister the marineproteo1 group, together forming the sister to Magnetococcidae. The ribosomes coded for by the mitochondrial DNA are similar to those from bacteria in size and structure. They closely resemble the bacterial 70S ribosome and not the 80S
cytoplasm In cell biology, the cytoplasm is all of the material within a eukaryote, eukaryotic Cell (biology), cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear envelope, nuc ...
ic ribosomes, which are coded for by nuclear DNA. The endosymbiotic relationship of mitochondria with their host cells was popularized by
Lynn Margulis Lynn Margulis (born Lynn Petra Alexander; March 5, 1938 – November 22, 2011) was an American evolution Evolution is change in the heredity, heritable Phenotypic trait, characteristics of biological populations over successive generatio ...
. The endosymbiotic hypothesis suggests that mitochondria descended from aerobic bacteria that somehow survived
endocytosis Endocytosis is a cellular process in which substances are brought into the cell. The material to be internalized is surrounded by an area of cell membrane The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, an ...
by another cell, and became incorporated into the
cytoplasm In cell biology, the cytoplasm is all of the material within a eukaryote, eukaryotic Cell (biology), cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear envelope, nuc ...
. The ability of these bacteria to conduct
respiration Respiration may refer to: Biology * Cellular respiration Cellular respiration is the process by which biological fuels are oxidised in the presence of an inorganic electron acceptor such as oxygen to produce large amounts of energy, to drive ...
in host cells that had relied on
glycolysis Glycolysis is the metabolic pathway that converts glucose () into pyruvic acid, pyruvate (). The Thermodynamic free energy, free energy released in this process is used to form the high-energy molecules adenosine triphosphate (ATP) and NADH, red ...
and
fermentation Fermentation is a metabolism, metabolic process that produces chemical changes in organic Substrate (chemistry), substrates through the action of enzymes. In biochemistry, it is narrowly defined as the extraction of energy from carbohydrates in ...
would have provided a considerable evolutionary advantage. This symbiotic relationship probably developed 1.7 to 2 billion years ago. A few groups of unicellular eukaryotes have only vestigial mitochondria or derived structures: The
microsporidia Microsporidia are a group of spore-forming unicellular parasites. These spores contain an extrusion apparatus that has a coiled polar tube ending in an anchoring disc at the apical part of the spore. They were once considered protozoans or prot ...
ns,
metamonad The metamonads are microscopic eukaryotic Eukaryotes () are organisms whose Cell (biology), cells have a cell nucleus, nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organis ...
s, and archamoebae. These groups appear as the most primitive eukaryotes on
phylogenetic trees A phylogenetic tree (also phylogeny or evolutionary tree Felsenstein J. (2004). ''Inferring Phylogenies'' Sinauer Associates: Sunderland, MA.) is a branching diagram A diagram is a symbolic Depiction, representation of information using Visu ...
constructed using
rRNA Ribosomal ribonucleic acid (rRNA) is a type of non-coding RNA which is the primary component of ribosomes, essential to all cells. rRNA is a ribozyme which carries out protein synthesis in ribosomes. Ribosomal RNA is transcribed from ribosomal ...
information, which once suggested that they appeared before the origin of mitochondria. However, this is now known to be an artifact of ''
long-branch attraction In phylogenetics In biology, phylogenetics (; from Greek language, Greek wikt:φυλή, φυλή/wikt:φῦλον, φῦλον [] "tribe, clan, race", and wikt:γενετικός, γενετικός [] "origin, source, birth") is the study of th ...
'': They are derived groups and retain genes or organelles derived from mitochondria (e. g.,
mitosome A mitosome is an organelle found in some unicellular eukaryote, eukaryotic organisms, like in members of the supergroup Excavata. The mitosome was found and named in 1999, and its function has not yet been well characterized. It was termed a ''cry ...
s and
hydrogenosome A hydrogenosome is a membrane A membrane is a selective barrier; it allows some things to pass through but stops others. Such things may be molecules, ions, or other small particles. Membranes can be generally classified into synthetic membr ...
s). Hydrogenosomes, mitosomes, and related organelles as found in some
loricifera Loricifera (from Latin, ''wikt:lorica, lorica'', corselet (armour) + ''ferre'', to bear) is a phylum of very small to microscopic marine cycloneuralian sediment-dwelling animals that had been determined to be 37 described species, in 9&nbs ...
(e. g. '' Spinoloricus'') and
myxozoa Myxozoa (etymology: Greek language, Greek: μύξα ''myxa'' "slime" or "mucus" + thematic vowel o + ζῷον ''zoon'' "animal") is a subphylum of aquatic cnidarian animals – all obligate parasites. It contains the smallest animals ever known ...
(e. g. ''
Henneguya zschokkei ''Henneguya zschokkei'' or ''Henneguya salminicola'' is a species of a myxosporean endoparasite. It afflicts several salmon in the genus ''Oncorhynchus''. It causes milky flesh or tapioca disease. ''H. zschokkei'' is notable for its absence of Mi ...
'') are together classified as MROs, mitochondrion-related organelles.
Monocercomonoides ''Monocercomonoides'' is a genus of flagellate Excavata belonging to the order Oxymonadida. It was established by Bernard V. Travis and was first described as those with "polymastiginid flagellates having three anterior Flagellum, flagella and a ...
appear to have lost their mitochondria completely and at least some of the mitochondrial functions seem to be carried out by cytoplasmic proteins now''.''

Mitochondrial genetics

Mitochondria contain their own genome. The human mitochondrial genome is a circular double-stranded molecule of about 16
kilobase A base pair (bp) is a fundamental unit of double-stranded nucleic acids Nucleic acids are biopolymers, macromolecules, essential to all Organism, known forms of life. They are composed of nucleotides, which are the monomers made of three compone ...
s. It encodes 37 genes: 13 for subunits of respiratory complexes I, III, IV and V, 22 for mitochondrial
tRNA Transfer RNA (abbreviated tRNA and formerly referred to as sRNA, for soluble RNA) is an adaptor molecule composed of RNA, typically 76 to 90 nucleotides in length (in eukaryotes), that serves as the physical link between the Messenger RNA, mRNA a ...
(for the 20 standard amino acids, plus an extra gene for leucine and serine), and 2 for
rRNA Ribosomal ribonucleic acid (rRNA) is a type of non-coding RNA which is the primary component of ribosomes, essential to all cells. rRNA is a ribozyme which carries out protein synthesis in ribosomes. Ribosomal RNA is transcribed from ribosomal ...
(12S and 16S rRNA). One mitochondrion can contain two to ten copies of its DNA. One of the two mitochondrial DNA (mtDNA) strands has a disproportionately higher ratio of the heavier nucleotides adenine and guanine, and this is termed the heavy strand (or H strand), whereas the other strand is termed the light strand (or L strand). The weight difference allows the two strands to be separated by
centrifugation Centrifugation is a mechanical process which involves the use of the centrifugal force to separate particles from a solution according to their size, shape, density, medium viscosity and rotor speed. The denser components of the mixture migrate ...
. mtDNA has one long non-coding stretch known as the non-coding region (NCR), which contains the heavy strand promoter (HSP) and light strand promoter (LSP) for RNA transcription, the origin of replication for the H strand (OriH) localized on the L strand, three conserved sequence boxes (CSBs 1–3), and a termination-associated sequence (TAS). The origin of replication for the L strand (OriL) is localized on the H strand 11,000 bp downstream of OriH, located within a cluster of genes coding for tRNA. As in prokaryotes, there is a very high proportion of coding DNA and an absence of repeats. Mitochondrial genes are transcribed as multigenic transcripts, which are cleaved and polyadenylated to yield mature
mRNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of Protein biosynthesis, synthesizing a protein. mRNA is ...
s. Most proteins necessary for mitochondrial function are encoded by genes in the
cell nucleus The cell nucleus (pl. nuclei; from Latin or , meaning ''kernel'' or ''seed'') is a membrane-bound organelle found in eukaryote, eukaryotic cell (biology), cells. Eukaryotic cells usually have a single nucleus, but a few cell types, such as ma ...

and the corresponding proteins are imported into the mitochondrion. The exact number of genes encoded by the nucleus and the
mitochondrial genome Mitochondrial DNA (mtDNA or mDNA) is the DNA located in mitochondrion, mitochondria, cellular organelles within eukaryotic cells that convert chemical energy from food into a form that cells can use, such as adenosine triphosphate (ATP). Mit ...
differs between species. Most mitochondrial genomes are circular. In general, mitochondrial DNA lacks
intron An intron is any Nucleic acid sequence, nucleotide sequence within a gene that is not expressed or operative in the final RNA product. The word ''intron'' is derived from the term ''intragenic region'', i.e. a region inside a gene."The notion of ...
s, as is the case in the human mitochondrial genome; however, introns have been observed in some eukaryotic mitochondrial DNA, such as that of
yeast Yeasts are eukaryotic, single-celled microorganisms classified as members of the fungus kingdom (biology), kingdom. The first yeast originated hundreds of millions of years ago, and at least 1,500 species are currently recognized. They are est ...
and
protist A protist () is any eukaryotic organism (that is, an organism whose Cell (biology), cells contain a cell nucleus) that is not an animal, plant, or fungus. While it is likely that protists share a Common descent, common ancestor (the last eukary ...
s, including ''
Dictyostelium ''Dictyostelium'' is a genus of single- and multi-celled eukaryote, eukaryotic, Phagocytosis, phagotrophic bacterivores. Though they are Protista and in no way Fungus, fungal, they traditionally are known as "slime molds". They are present i ...
discoideum''. Between protein-coding regions, tRNAs are present. Mitochondrial tRNA genes have different sequences from the nuclear tRNAs, but lookalikes of mitochondrial tRNAs have been found in the nuclear chromosomes with high sequence similarity. In animals, the mitochondrial genome is typically a single circular chromosome that is approximately 16 kb long and has 37 genes. The genes, while highly conserved, may vary in location. Curiously, this pattern is not found in the human body louse (''
Pediculus humanus ''Pediculus humanus'' is a species of louse that infects humans. It comprises two subspecies: *''Pediculus humanus humanus'' Linnaeus, 1758 – body louse *''Pediculus humanus capitis'' Charles De Geer, De Geer, 1767 – head louse References ...
''). Instead, this mitochondrial genome is arranged in 18 minicircular chromosomes, each of which is 3–4 kb long and has one to three genes. This pattern is also found in other
sucking lice Sucking lice (Anoplura, formerly known as Siphunculata) have around 500 species and represent the smaller of the two traditional superfamily (taxonomy), superfamilies of lice. As opposed to the paraphyletic chewing lice, which are now divided amo ...
, but not in chewing lice. Recombination has been shown to occur between the minichromosomes.

Human population genetic studies

The near-absence of
genetic recombination Genetic recombination (also known as genetic reshuffling) is the exchange of genetic material between different organisms which leads to production of offspring with combinations of traits that differ from those found in either parent. In eukaryot ...
in mitochondrial DNA makes it a useful source of information for studying
population genetics Population genetics is a subfield of genetics that deals with genetic differences within and between populations, and is a part of evolutionary biology. Studies in this branch of biology examine such phenomena as Adaptation (biology), adaptation, ...
and
evolutionary biology Evolutionary biology is the subfield of biology that studies the evolution, evolutionary processes (natural selection, common descent, speciation) that produced the Biodiversity, diversity of life on Earth. It is also defined as the study of ...
. Because all the mitochondrial DNA is inherited as a single unit, or
haplotype A haplotype ( haploid genotype) is a group of alleles in an organism that are inherited together from a single parent. Many organisms contain genetic material (DNA) which is inherited from two parents. Normally these organisms have their DNA o ...
, the relationships between mitochondrial DNA from different individuals can be represented as a gene tree. Patterns in these gene trees can be used to infer the evolutionary history of populations. The classic example of this is in
human evolutionary genetics Human evolutionary genetics studies how one human genome differs from another human genome, the evolutionary past that gave rise to the human genome, and its current effects. Differences between genomes have anthropological, medical, historical and ...
, where the
molecular clock The molecular clock is a figurative term for a technique that uses the mutation rate of biomolecules to deduce the time in prehistory Prehistory, also known as pre-literary history, is the period of human history between the use of the ...
can be used to provide a recent date for
mitochondrial Eve In human genetics, the Mitochondrial Eve (also ''mt-Eve, mt-MRCA'') is the Matrilineality, matrilineal most recent common ancestor (MRCA) of all world population, living humans. In other words, she is defined as the most recent woman from whom ...
. This is often interpreted as strong support for a recent modern human expansion out of Africa. Another human example is the sequencing of mitochondrial DNA from
Neanderthal Neanderthals (, also ''Homo neanderthalensis'' and erroneously ''Homo sapiens neanderthalensis''), also written as Neandertals, are an Extinction, extinct species or subspecies of archaic humans who lived in Eurasia until about 40,000 years ag ...
bones. The relatively large evolutionary distance between the mitochondrial DNA sequences of Neanderthals and living humans has been interpreted as evidence for the lack of interbreeding between Neanderthals and modern humans. However, mitochondrial DNA reflects only the history of the females in a population. This can be partially overcome by the use of paternal genetic sequences, such as the non-recombining region of the
Y-chromosome The Y chromosome is one of two sex chromosome A chromosome is a long DNA molecule with part or all of the genetic material of an organism. In most chromosomes the very long thin DNA fibers are coated with packaging proteins; in eukaryotic ...
. Recent measurements of the
molecular clock The molecular clock is a figurative term for a technique that uses the mutation rate of biomolecules to deduce the time in prehistory Prehistory, also known as pre-literary history, is the period of human history between the use of the ...
for mitochondrial DNA reported a value of 1 mutation every 7884 years dating back to the most recent common ancestor of humans and apes, which is consistent with estimates of mutation rates of autosomal DNA (10 per base per generation).

Alternative genetic code

While slight variations on the standard genetic code had been predicted earlier, none was discovered until 1979, when researchers studying human mitochondrial genes determined that they used an alternative code. Nonetheless, the mitochondria of many other eukaryotes, including most plants, use the standard code. Many slight variants have been discovered since, including various alternative mitochondrial codes. Further, the AUA, AUC, and AUU codons are all allowable start codons. Some of these differences should be regarded as pseudo-changes in the genetic code due to the phenomenon of
RNA editing RNA editing (also RNA modification) is a molecular process through which some cells can make discrete changes to specific nucleotide sequences within an RNA molecule after it has been generated by RNA polymerase In molecular biology, RNA p ...
, which is common in mitochondria. In higher plants, it was thought that CGG encoded for
tryptophan Tryptophan (symbol Trp or W) is an α-amino acid that is used in the biosynthesis of proteins. Tryptophan contains an Alpha_and_beta_carbon , α-amino group, an α-carboxylic acid group, and a side chain indole, making it a polar molecule with ...
and not
arginine Arginine is the amino acid with the formula (H2N)(HN)CN(H)(CH2)3CH(NH2)CO2H. The molecule features a guanidino group appended to a standard amino acid framework. At physiological pH, the carboxylic acid is deprotonated (−CO2−) and both the ...
; however, the codon in the processed RNA was discovered to be the UGG codon, consistent with the standard
genetic code The genetic code is the set of rules used by living cells to translate information encoded within genetic material ( DNA or RNA sequences of nucleotide triplets, or codons) into protein Proteins are large biomolecules and macromolecules ...
for tryptophan. Of note, the arthropod mitochondrial genetic code has undergone parallel evolution within a phylum, with some organisms uniquely translating AGG to lysine.

Replication and inheritance

Mitochondria divide by mitochondrial fission, a form of
binary fission Binary may refer to: Science and technology Mathematics * Binary number, a representation of numbers using only two digits (0 and 1) * Binary function, a function that takes two arguments * Binary operation, a mathematical operation that ta ...
that is also done by bacteria although the process is tightly regulated by the host eukaryotic cell and involves communication between and contact with several other organelles. The regulation of this division differs between eukaryotes. In many single-celled eukaryotes, their growth and division are linked to the
cell cycle The cell cycle, or cell-division cycle, is the series of events that take place in a cell that cause it to divide into two daughter cells. These events include the duplication of its DNA ( DNA replication) and some of its organelles, and su ...

. For example, a single mitochondrion may divide synchronously with the nucleus. This division and segregation process must be tightly controlled so that each daughter cell receives at least one mitochondrion. In other eukaryotes (in mammals for example), mitochondria may replicate their DNA and divide mainly in response to the energy needs of the cell, rather than in phase with the cell cycle. When the energy needs of a cell are high, mitochondria grow and divide. When energy use is low, mitochondria are destroyed or become inactive. In such examples mitochondria are apparently randomly distributed to the daughter cells during the division of the
cytoplasm In cell biology, the cytoplasm is all of the material within a eukaryote, eukaryotic Cell (biology), cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear envelope, nuc ...
. Mitochondrial dynamics, the balance between mitochondrial fusion and fission, is an important factor in pathologies associated with several disease conditions. The hypothesis of mitochondrial binary fission has relied on the visualization by fluorescence microscopy and conventional
transmission electron microscopy Transmission electron microscopy (TEM) is a microscopy technique in which a beam of electrons is transmitted through a specimen to form an image. The specimen is most often an ultrathin section less than 100 nm thick or a suspension on a gr ...
(TEM). The resolution of fluorescence microscopy (~200 nm) is insufficient to distinguish structural details, such as double mitochondrial membrane in mitochondrial division or even to distinguish individual mitochondria when several are close together. Conventional TEM has also some technical limitations in verifying mitochondrial division.
Cryo-electron tomography Electron cryotomography (CryoET) is an imaging technique used to produce high-resolution (~1–4 nm) three-dimensional views of samples, often (but not limited to) biological macromolecule A macromolecule is a very large molecule importa ...
was recently used to visualize mitochondrial division in frozen hydrated intact cells. It revealed that mitochondria divide by budding. An individual's mitochondrial genes are inherited only from the mother, with rare exceptions. In humans, when an
egg cell The egg cell, or ovum (plural ova), is the female Reproduction, reproductive cell, or gamete, in most anisogamous organisms (organisms that reproduce sexually with a larger, female gamete and a smaller, male one). The term is used when the fema ...
is fertilized by a sperm, the mitochondria, and therefore the mitochondrial DNA, usually come from the egg only. The sperm's mitochondria enter the egg, but do not contribute genetic information to the embryo. Instead, paternal mitochondria are marked with
ubiquitin Ubiquitin is a small (8.6 kDa The dalton or unified atomic mass unit (symbols: Da or u) is a Non-SI units mentioned in the SI, non-SI unit of mass widely used in physics and chemistry. It is defined as of the mass of an chemical bond, unbound ...
to select them for later destruction inside the
embryo An embryo is an initial stage of development of a multicellular organism. In organisms that Sexual reproduction, reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell ...
. The egg cell contains relatively few mitochondria, but these mitochondria divide to populate the cells of the adult organism. This mode is seen in most organisms, including the majority of animals. However, mitochondria in some species can sometimes be inherited paternally. This is the norm among certain
conifer Conifers are a group of conifer cone, cone-bearing Spermatophyte, seed plants, a subset of gymnosperms. Scientifically, they make up the phylum, division Pinophyta (), also known as Coniferophyta () or Coniferae. The division contains a single ...
ous plants, although not in
pine tree A pine is any conifer tree or shrub in the genus ''Pinus'' () of the family (biology), family Pinaceae. ''Pinus'' is the sole genus in the subfamily Pinoideae. The World Flora Online created by the Royal Botanic Gardens, Kew and Missouri Botanic ...
s and yews. For Mytilids, paternal inheritance only occurs within males of the species. It has been suggested that it occurs at a very low level in humans. Uniparental inheritance leads to little opportunity for
genetic recombination Genetic recombination (also known as genetic reshuffling) is the exchange of genetic material between different organisms which leads to production of offspring with combinations of traits that differ from those found in either parent. In eukaryot ...
between different lineages of mitochondria, although a single mitochondrion can contain 2–10 copies of its DNA. What recombination does take place maintains genetic integrity rather than maintaining diversity. However, there are studies showing evidence of recombination in mitochondrial DNA. It is clear that the enzymes necessary for recombination are present in mammalian cells. Further, evidence suggests that animal mitochondria can undergo recombination. The data are more controversial in humans, although indirect evidence of recombination exists. Entities undergoing uniparental inheritance and with little to no recombination may be expected to be subject to Muller's ratchet, the accumulation of deleterious mutations until functionality is lost. Animal populations of mitochondria avoid this buildup through a developmental process known as the mtDNA bottleneck. The bottleneck exploits stochastic processes in the cell to increase the cell-to-cell variability in mutant load as an organism develops: a single egg cell with some proportion of mutant mtDNA thus produces an embryo where different cells have different mutant loads. Cell-level selection may then act to remove those cells with more mutant mtDNA, leading to a stabilization or reduction in mutant load between generations. The mechanism underlying the bottleneck is debated, with a recent mathematical and experimental metastudy providing evidence for a combination of random partitioning of mtDNAs at cell divisions and random turnover of mtDNA molecules within the cell.

DNA repair

Mitochondria can repair oxidative
DNA damage DNA repair is a collection of processes by which a cell (biology), cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolism, metabolic activities and environmental factors such as r ...
by mechanisms analogous to those occurring in the
cell nucleus The cell nucleus (pl. nuclei; from Latin or , meaning ''kernel'' or ''seed'') is a membrane-bound organelle found in eukaryote, eukaryotic cell (biology), cells. Eukaryotic cells usually have a single nucleus, but a few cell types, such as ma ...

. The proteins employed in
mtDNA Mitochondrial DNA (mtDNA or mDNA) is the DNA located in mitochondrion, mitochondria, cellular organelles within eukaryotic cells that convert chemical energy from food into a form that cells can use, such as adenosine triphosphate (ATP). Mit ...
repair are encoded by nuclear
gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian inheritance#History, Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanin ...
s, and are translocated to the mitochondria. The
DNA repair DNA repair is a collection of processes by which a cell (biology), cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolism, metabolic activities and environmental factors such as r ...
pathways in mammalian mitochondria include
base excision repair Base excision repair (BER) is a cellular mechanism, studied in the fields of biochemistry and genetics, that DNA repair, repairs damaged DNA throughout the cell cycle. It is responsible primarily for removing small, non-helix-distorting base les ...
, double-strand break repair, direct reversal and
mismatch repair DNA mismatch repair (MMR) is a system for recognizing and repairing erroneous insertion, deletion, and mis-incorporation of bases that can arise during DNA replication and recombination, as well as repairing some forms of DNA damage. Mismat ...
. Alternatively, DNA damage may be bypassed, rather than repaired, by translesion synthesis. Of the several DNA repair process in mitochondria, the base excision repair pathway has been most comprehensively studied. Base excision repair is carried out by a sequence of enzyme-catalyzed steps that include recognition and excision of a damaged DNA base, removal of the resulting abasic site, end processing, gap filling and ligation. A common damage in mtDNA that is repaired by base excision repair is 8-oxoguanine produced by oxidation of
guanine Guanine () (symbol A symbol is a mark, sign, or word that indicates, signifies, or is understood as representing an idea, object, or relationship. Symbols allow people to go beyond what is known or seen by creating linkages between othe ...
. Double-strand breaks can be repaired by
homologous recombination Homologous recombination is a type of genetic recombination in which genetic information is exchanged between two similar or identical molecules of double-stranded or single-stranded nucleic acids (usually DNA as in Cell (biology), cellular organi ...
al repair in both mammalian mtDNA and plant mtDNA. Double-strand breaks in mtDNA can also be repaired by
microhomology-mediated end joining Microhomology-mediated end joining (MMEJ), also known as alternative nonhomologous end-joining (Alt-NHEJ) is one of the pathways for repairing double-strand breaks in DNA. As reviewed by McVey and Lee, the foremost distinguishing property of MMEJ ...
. Although there is evidence for the repair processes of direct reversal and mismatch repair in mtDNA, these processes are not well characterized.

Lack of mitochondrial DNA

Some organisms have lost mitochondrial DNA altogether. In these cases, genes encoded by the mitochondrial DNA have been lost or transferred to the nucleus. ''
Cryptosporidium ''Cryptosporidium'', sometimes informally called crypto, is a genus of apicomplexan parasitic alveolates that can cause a respiratory and gastrointestinal illness ( cryptosporidiosis) that primarily involves watery diarrhea (intestinal cry ...
'' have mitochondria that lack any DNA, presumably because all their genes have been lost or transferred. In ''Cryptosporidium'', the mitochondria have an altered ATP generation system that renders the parasite resistant to many classical mitochondrial inhibitors such as
cyanide Cyanide is a naturally occurring, rapidly acting, toxic chemical that can exist in many different forms. In chemistry Chemistry is the scientific study of the properties and behavior of matter. It is a natural science that covers th ...
,
azide In chemistry, azide is a Linear molecular geometry, linear, polyatomic anion with the Chemical formula, formula and Chemical structure, structure . It is the conjugate base of hydrazoic acid . Organic azides are organic compounds with the formu ...
, and atovaquone. Mitochondria that lack their own DNA have been found in a marine parasitic
dinoflagellate The dinoflagellates (Greek language, Greek δῖνος ''dinos'' "whirling" and Latin language, Latin ''flagellum'' "whip, scourge") are a monophyletic group of single-celled eukaryotes constituting the phylum Dinoflagellata and are usually consid ...
from the genus '' Amoebophyra''. This microorganism, ''A. cerati'', has functional mitochondria that lack a genome. In related species, the mitochondrial genome still has three genes, but in ''A. cerati'' only a single mitochondrial gene — the cytochrome c oxidase I gene (''cox1'') — is found, and it has migrated to the genome of the nucleus.

Dysfunction and disease

Mitochondrial diseases

Damage and subsequent dysfunction in mitochondria is an important factor in a range of human diseases due to their influence in cell metabolism. Mitochondrial disorders often present as neurological disorders, including
autism The autism spectrum, often referred to as just autism or in the context of a professional diagnosis autism spectrum disorder (ASD) or autism spectrum condition (ASC), is a neurodevelopmental disorder, neurodevelopmental condition (or conditions) ...

. They can also manifest as
myopathy In medicine, myopathy is a disease of the muscle in which the muscle fibers do not function properly. This results in muscular weakness. ''Myopathy'' means muscle disease (Greek language, Greek : myo- ''muscle'' + patheia ''pathos, -pathy'' : ''s ...
,
diabetes Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increase ...
, multiple endocrinopathy, and a variety of other systemic disorders. Diseases caused by mutation in the mtDNA include
Kearns–Sayre syndrome Kearns–Sayre syndrome (KSS), oculocraniosomatic disorder or oculocranionsomatic neuromuscular disorder with ragged red fibers is a mitochondrial myopathy with a typical onset before 20 years of age. KSS is a more severe syndromic variant of chron ...
,
MELAS syndrome Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is one of the family of mitochondrial diseases, which also include MIDD (maternally inherited diabetes and deafness, MERRF syndrome, and Leber's hereditary optic neur ...
and
Leber's hereditary optic neuropathy Leber's hereditary optic neuropathy (LHON) is a mitochondrially inherited (transmitted from mother to offspring) degeneration of retinal ganglion cell A retinal ganglion cell (RGC) is a type of neuron located near the inner surface (the gangl ...
. In the vast majority of cases, these diseases are transmitted by a female to her children, as the
zygote A zygote (, ) is a eukaryote, eukaryotic cell (biology), cell formed by a fertilization event between two gametes. The zygote's genome is a combination of the DNA in each gamete, and contains all of the genetic information of a new individual ...
derives its mitochondria and hence its mtDNA from the ovum. Diseases such as Kearns-Sayre syndrome, Pearson syndrome, and progressive external
ophthalmoplegia Ophthalmoparesis refers to weakness (-paresis) or paralysis (-plegia) of one or more extraocular muscles which are responsible for eye movements. It is a physical finding in certain neurologic, ophthalmologic, and endocrine disease. Interna ...
are thought to be due to large-scale mtDNA rearrangements, whereas other diseases such as MELAS syndrome, Leber's hereditary optic neuropathy, MERRF syndrome, and others are due to
point mutation A point mutation is a genetic mutation where a single nucleotide base is changed, inserted or deleted from a DNA or RNA sequence of an organism's genome. Point mutations have a variety of effects on the downstream protein product—consequences ...
s in mtDNA. It has also been reported that drug tolerant cancer cells have an increased number and size of mitochondria which suggested an increase in mitochondrial biogenesis. Interestingly, a recent study in ''Nature Nanotechnology'' has reported that cancer cells can hijack the mitochondria from immune cells via physical tunneling nanotubes. In other diseases, defects in nuclear genes lead to dysfunction of mitochondrial proteins. This is the case in
Friedreich's ataxia Friedreich's ataxia (FRDA or FA) is an autosomal-recessive genetic disease that causes difficulty walking, a loss of sensation in the arms and legs, and impaired speech that worsens over time. Symptoms generally start between 5 and 20 years ...
, hereditary spastic paraplegia, and
Wilson's disease Wilson's disease is a genetic disorder A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosomal ...
. These diseases are inherited in a
dominance relationship In genetics Genetics is the study of genes, genetic variation, and heredity in organisms.Hartl D, Jones E (2005) It is an important branch in biology because heredity is vital to organisms' evolution. Gregor Mendel, a Moravian Augustinian ...
, as applies to most other genetic diseases. A variety of disorders can be caused by nuclear mutations of oxidative phosphorylation enzymes, such as coenzyme Q10 deficiency and
Barth syndrome Barth syndrome (BTHS) is a rare but serious X-linked genetic disorder, caused by changes in phospholipid structure and metabolism. It may affect multiple body systems (though mainly characterized by pronounced pediatric-onset cardiomyopathy), and ...
. Environmental influences may interact with hereditary predispositions and cause mitochondrial disease. For example, there may be a link between
pesticide Pesticides are substances that are meant to control pests. This includes herbicide, insecticide, nematicide, molluscicide, piscicide, avicide, rodenticide, bactericide, insect repellent, animal repellent, microbicide, fungicide, ...
exposure and the later onset of
Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a chronic condition, long-term neurodegeneration, degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disea ...
. Other pathologies with etiology involving mitochondrial dysfunction include
schizophrenia Schizophrenia is a mental disorder characterized by continuous or relapsing episodes of psychosis. Major symptoms include hallucinations (typically hearing voices), delusions, and disorganized thinking. Other symptoms include social w ...
,
bipolar disorder Bipolar disorder, previously known as manic depression, is a mental disorder characterized by periods of Depression (mood), depression and periods of abnormally elevated Mood (psychology), mood that last from days to weeks each. If the elevat ...
,
dementia Dementia is a disorder which manifests as a Syndrome, set of related symptoms, which usually surfaces when the brain is damaged by injury or disease. The symptoms involve progressive impairments in memory, thinking, and behavior, which negativ ...
,
Alzheimer's disease Alzheimer's disease (AD) is a neurodegeneration, neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in short-term me ...
, Parkinson's disease,
epilepsy Epilepsy is a group of non-communicable neurological disorders characterized by recurrent Seizure, epileptic seizures. Epileptic seizures can vary from brief and nearly undetectable periods to long periods of vigorous shaking due to abnormal el ...
,
stroke A stroke is a disease, medical condition in which poor cerebral circulation, blood flow to the brain causes cell death. There are two main types of stroke: brain ischemia, ischemic, due to lack of blood flow, and intracranial hemorrhage, hemorr ...
,
cardiovascular disease Cardiovascular disease (CVD) is a class of diseases that involve the heart or blood vessels. CVD includes coronary artery diseases (CAD) such as angina pectoris, angina and myocardial infarction (commonly known as a heart attack). Other CVDs in ...
,
chronic fatigue syndrome Chronic fatigue syndrome (CFS), also called myalgic encephalomyelitis (ME) or ME/CFS, is a complex, debilitating, long-term medical condition. The Pathophysiology, causes and mechanisms of the disease are not fully understood. Distinguishing c ...
,
retinitis pigmentosa Retinitis pigmentosa (RP) is a genetic disorder of the Human eye, eyes that causes vision impairment, loss of vision. Symptoms include nyctalopia, trouble seeing at night and decreasing peripheral vision (side and upper or lower visual field). As ...
, and
diabetes mellitus Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a hyperglycemia, high blood sugar level (hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, Polydipsia, increase ...
. Mitochondria-mediated oxidative stress plays a role in cardiomyopathy in type 2 diabetics. Increased fatty acid delivery to the heart increases fatty acid uptake by cardiomyocytes, resulting in increased fatty acid oxidation in these cells. This process increases the reducing equivalents available to the electron transport chain of the mitochondria, ultimately increasing reactive oxygen species (ROS) production. ROS increases uncoupling proteins (UCPs) and potentiate proton leakage through the
adenine nucleotide translocator Adenine nucleotide translocator (ANT), also known as the ADP/ATP translocase (ANT), ADP/ATP carrier protein (AAC) or mitochondrial ADP/ATP carrier, exchanges free ATP with free ADP across the inner mitochondrial membrane. ANT is the most abun ...
(ANT), the combination of which uncouples the mitochondria. Uncoupling then increases oxygen consumption by the mitochondria, compounding the increase in fatty acid oxidation. This creates a vicious cycle of uncoupling; furthermore, even though oxygen consumption increases, ATP synthesis does not increase proportionally because the mitochondria are uncoupled. Less ATP availability ultimately results in an energy deficit presenting as reduced cardiac efficiency and contractile dysfunction. To compound the problem, impaired sarcoplasmic reticulum calcium release and reduced mitochondrial reuptake limits peak cytosolic levels of the important signaling ion during muscle contraction. Decreased intra-mitochondrial calcium concentration increases dehydrogenase activation and ATP synthesis. So in addition to lower ATP synthesis due to fatty acid oxidation, ATP synthesis is impaired by poor calcium signaling as well, causing cardiac problems for diabetics.

Relationships to aging

There may be some leakage of the electrons transferred in the respiratory chain to form
reactive oxygen species In chemistry, reactive oxygen species (ROS) are highly Reactivity (chemistry), reactive chemicals formed from diatomic oxygen (). Examples of ROS include peroxides, superoxide, hydroxyl radical, singlet oxygen, and alpha-oxygen. The reduction of ...
. This was thought to result in significant
oxidative stress Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. Disturbances in the normal ...
in the mitochondria with high mutation rates of mitochondrial DNA. Hypothesized links between aging and oxidative stress are not new and were proposed in 1956, which was later refined into the mitochondrial free radical theory of aging. A vicious cycle was thought to occur, as oxidative stress leads to mitochondrial DNA mutations, which can lead to enzymatic abnormalities and further oxidative stress. A number of changes can occur to mitochondria during the aging process. Tissues from elderly humans show a decrease in enzymatic activity of the proteins of the respiratory chain. However, mutated mtDNA can only be found in about 0.2% of very old cells. Large deletions in the mitochondrial genome have been hypothesized to lead to high levels of
oxidative stress Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. Disturbances in the normal ...
and neuronal death in
Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a chronic condition, long-term neurodegeneration, degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disea ...
. Mitochondrial dysfunction has also been shown to occur in
amyotrophic lateral sclerosis Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND) or Lou Gehrig's disease, is a neurodegenerative disease that results in the progressive loss of motor neurons that control Skeletal muscle, voluntary muscles. ALS ...
. Since mitochondria cover a pivotal role in the ovarian function, by providing ATP necessary for the development from germinal vesicle to mature
oocyte An oocyte (, ), oöcyte, or ovocyte is a female gametocyte or germ cell Germ or germs may refer to: Science * Germ (microorganism), an informal word for a pathogen * Germ cell, cell that gives rise to the gametes of an organism that reprod ...
, a decreased mitochondria function can lead to inflammation, resulting in premature ovarian failure and accelerated ovarian aging. The resulting dysfunction is then reflected in quantitative (such as mtDNA copy number and mtDNA deletions), qualitative (such as mutations and strand breaks) and oxidative damage (such as dysfunctional mitochondria due to ROS), which are not only relevant in ovarian aging, but perturb oocyte-cumulus crosstalk in the ovary, are linked to genetic disorders (such as Fragile X) and can interfere with embryo selection.

History

The first observations of intracellular structures that probably represented mitochondria were published in 1857, by the physiologist Albert von Kolliker. Richard Altmann, in 1890, established them as cell organelles and called them "bioblasts." In 1898, Carl Benda coined the term "mitochondria" from the
Greek Greek may refer to: Greece Anything of, from, or related to Greece, a country in Southern Europe: *Greeks, an ethnic group. *Greek language, a branch of the Indo-European language family. **Proto-Greek language, the assumed last common ancestor ...
, , "thread", and , , "granule." Leonor Michaelis discovered that Janus green can be used as a supravital stain for mitochondria in 1900. In 1904, Friedrich Meves, made the first recorded observation of mitochondria in plants in cells of the white waterlily, ''
Nymphaea alba ''Nymphaea alba'', the white waterlily, European white water lily or white nenuphar , is an aquatic flowering plant in the family Nymphaeaceae. It is native to North Africa, temperate Asia, Europe and tropical Asia (Jammu and Kashmir). Descript ...
'' and in 1908, along with Claudius Regaud, suggested that they contain proteins and lipids. Benjamin F. Kingsbury, in 1912, first related them with cell respiration, but almost exclusively based on morphological observations. In 1913, particles from extracts of guinea-pig liver were linked to respiration by
Otto Heinrich Warburg Otto Heinrich Warburg (, ; 8 October 1883 – 1 August 1970), son of physicist Emil Warburg, was a German physiologist Physiology (; ) is the scientific study of functions and mechanisms in a living system. As a sub-discipline of biol ...
, which he called "grana." Warburg and
Heinrich Otto Wieland Heinrich Otto Wieland (; 4 June 1877 – 5 August 1957) was a German chemist. He won the 1927 Nobel Prize in Chemistry for his research into the bile acids. Career In 1901 Wieland received his doctorate at the University of Munich while studyin ...
, who had also postulated a similar particle mechanism, disagreed on the chemical nature of the respiration. It was not until 1925, when David Keilin discovered cytochromes, that the
respiratory chain An electron transport chain (ETC) is a series of protein complexes and other molecules that electron transfer, transfer electrons from electron donors to electron acceptors via redox reactions (both Redox#Definitions, reduction and oxidation occu ...
was described. In 1939, experiments using minced muscle cells demonstrated that cellular respiration using one oxygen molecule can form four
adenosine triphosphate Adenosine triphosphate (ATP) is an organic compound that provides energy to drive many processes in living cell (biology), cells, such as muscle contraction, nerve impulse propagation, condensate dissolution, and chemical synthesis. Found in all ...

(ATP) molecules, and in 1941, the concept of the phosphate bonds of ATP being a form of energy in cellular metabolism was developed by
Fritz Albert Lipmann Fritz Albert Lipmann (; June 12, 1899 – July 24, 1986) was a German-American biochemist Biochemists are scientists who are trained in biochemistry. They study chemical processes and chemical transformations in living organisms. Biochemists s ...
. In the following years, the mechanism behind cellular respiration was further elaborated, although its link to the mitochondria was not known. The introduction of tissue fractionation by
Albert Claude Albert Claude (; 24 August 1899 – 22 May 1983) was a Belgium, Belgian-United States, American cell biologist and medical doctor who shared the Nobel Prize in Physiology or Medicine in 1974 with Christian de Duve and George Emil Palade. His elem ...
allowed mitochondria to be isolated from other cell fractions and biochemical analysis to be conducted on them alone. In 1946, he concluded that cytochrome oxidase and other enzymes responsible for the respiratory chain were isolated to the mitochondria. Eugene Kennedy and Albert Lehninger discovered in 1948 that mitochondria are the site of
oxidative phosphorylation Oxidative phosphorylation (UK , US ) or electron transport-linked phosphorylation or terminal oxidation is the metabolic pathway in which Cell (biology), cells use enzymes to Redox, oxidize nutrients, thereby releasing chemical energy in order t ...
in eukaryotes. Over time, the fractionation method was further developed, improving the quality of the mitochondria isolated, and other elements of cell respiration were determined to occur in the mitochondria. The first high-resolution electron micrographs appeared in 1952, replacing the Janus Green stains as the preferred way to visualize mitochondria. This led to a more detailed analysis of the structure of the mitochondria, including confirmation that they were surrounded by a membrane. It also showed a second membrane inside the mitochondria that folded up in ridges dividing up the inner chamber and that the size and shape of the mitochondria varied from cell to cell. The popular term "powerhouse of the cell" was coined by
Philip Siekevitz Philip Siekevitz (February 25, 1918 – December 5, 2009) was an American cell biologist who spent most of his career at Rockefeller University. He was involved in early studies of protein synthesis and protein trafficking, trafficking, established ...
in 1957. In 1967, it was discovered that mitochondria contained
ribosomes Ribosomes ( ) are macromolecular machines, found within all cells, that perform biological protein synthesis (mRNA translation). Ribosomes link amino acids Amino acids are organic compounds that contain both amino and carboxylic acid f ...
. In 1968, methods were developed for mapping the mitochondrial genes, with the genetic and physical map of yeast mitochondrial DNA completed in 1976.

* Anti-mitochondrial antibodies * Mitochondrial metabolic rates * Mitochondrial permeability transition pore *
Mitophagy Mitophagy is the selective degradation of mitochondria A mitochondrion (; ) is an organelle found in the cells of most Eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respira ...
* Nebenkern * Oncocyte *
Oncocytoma An oncocytoma is a tumor made up of oncocytes, epithelial cell (biology), cells characterized by an excessive amount of mitochondria, resulting in an abundant acidophilic, granular cytoplasm. The cells and the tumor that they compose are often ben ...
*
Paternal mtDNA transmission In genetics Genetics is the study of genes, genetic variation, and heredity in organisms.Hartl D, Jones E (2005) It is an important branch in biology because heredity is vital to organisms' evolution. Gregor Mendel, a Moravian Augustinians, Au ...
*
Plastid The plastid (Greek: πλαστός; plastós: formed, molded – plural plastids) is a membrane-bound organelle found in the cells of plants Plants are predominantly Photosynthesis, photosynthetic eukaryotes of the Kingdom (biology), kingd ...
* Submitochondrial particle

References

General *

*
Powering the Cell Mitochondria
– XVIVO Scientific Animation
Mitodb.com
– The mitochondrial disease database.

at
University of Mainz The Johannes Gutenberg University Mainz (german: Johannes Gutenberg-Universität Mainz) is a public university, public research university in Mainz, Rhineland Palatinate, Germany, named after the printer Johannes Gutenberg since 1946. With approx ...

Mitochondria Research Portal
at mitochondrial.net

at cytochemistry.net

at
University of Alabama The University of Alabama (informally known as Alabama, UA, or Bama) is a public research university in Tuscaloosa, Alabama. Established in 1820 and opened to students in 1831, the University of Alabama is the oldest and largest of the pub ...

MIP
Mitochondrial Physiology Society
3D structures of proteins from inner mitochondrial membrane
at
University of Michigan The University of Michigan (U-M, UMich, or Michigan) is a public university, public research university in Ann Arbor, Michigan. Founded in 1817 by an act of the old Michigan Territory as the History of the University of Michigan#The Catholepistemi ...

3D structures of proteins associated with outer mitochondrial membrane
at
University of Michigan The University of Michigan (U-M, UMich, or Michigan) is a public university, public research university in Ann Arbor, Michigan. Founded in 1817 by an act of the old Michigan Territory as the History of the University of Michigan#The Catholepistemi ...

Mitochondrial Protein Partnership
at
University of Wisconsin A university () is an educational institution, institution of higher education, higher (or Tertiary education, tertiary) education and research which awards academic degrees in several Discipline (academia), academic disciplines. Universities ty ...

MitoMiner – A mitochondrial proteomics database
at MRC Mitochondrial Biology Unit
Mitochondrion – Cell Centered Database

at
San Diego State University San Diego State University (SDSU) is a Public university, public research university in San Diego, San Diego, California. Founded in 1897 as San Diego Normal School, it is the third-oldest university and southernmost in the 23-member California ...

Video Clip of Rat-liver Mitochondrion from Cryo-electron Tomography
{{Authority control Cellular respiration Endosymbiotic events