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Oxidative phosphorylation (UK , US ) or electron transport-linked phosphorylation or terminal oxidation is the
metabolic pathway In biochemistry, a metabolic pathway is a linked series of chemical reactions occurring within a cell (biology), cell. The reactants, products, and intermediates of an enzymatic reaction are known as metabolites, which are modified by a sequence ...
in which cells use
enzyme Enzymes () are proteins that act as biological catalysts (biocatalysts). Catalysts accelerate chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates in ...

enzyme
s to
oxidize (mild reducing agent) are added to powdered potassium permanganate (strong oxidizing agent), a violent redox reaction accompanied by self-ignition starts. Redox (reduction–oxidation, pronunciation: or ) is a type of chemical reaction in w ...

oxidize
nutrient A nutrient is a substance Substance may refer to: * Substance (Jainism), a term in Jain ontology to denote the base or owner of attributes * Chemical substance, a material with a definite chemical composition * Matter, anything that has mass and t ...
s, thereby releasing chemical energy in order to produce
adenosine triphosphate Adenosine triphosphate (ATP) is an organic compound In , organic compounds are generally any s that contain - . Due to carbon's ability to (form chains with other carbon s), millions of organic compounds are known. The study of the properti ...

adenosine triphosphate
(ATP). In
eukaryotes Eukaryotes () are organism In biology, an organism (from Ancient Greek, Greek: ὀργανισμός, ''organismos'') is any individual contiguous system that embodies the Life#Biology, properties of life. It is a synonym for "Outline ...
, this takes place inside
mitochondria A mitochondrion (; ) is a double-membrane Image:Schematic size.jpg, up150px, Schematic of size-based membrane exclusion A membrane is a selective barrier; it allows some things to pass through but stops others. Such things may be molecules, i ...

mitochondria
. Almost all
aerobic organism 300px, Aerobic and anaerobic bacteria can be identified by growing them in test tubes of thioglycollate broth: 1: Obligate aerobe 300px, Aerobic and anaerobic bacteria can be identified by growing them in test tubes of thioglycollate broth: 1 ...
s carry out oxidative phosphorylation. This pathway is so pervasive because it releases more energy (provided by
oxygen Oxygen is the chemical element Image:Simple Periodic Table Chart-blocks.svg, 400px, Periodic table, The periodic table of the chemical elements In chemistry, an element is a pure substance consisting only of atoms that all have the same ...
) than alternative
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 ...
processes such as
anaerobic Anaerobic means "living, active, occurring, or existing in the absence of free oxygen", as opposed to aerobic which means "living, active, or occurring only in the presence of oxygen." Anaerobic may also refer to: *Anaerobic adhesive, a bonding ag ...
glycolysis Glycolysis is the metabolic pathway In biochemistry, a metabolic pathway is a linked series of chemical reaction A chemical reaction is a process that leads to the IUPAC nomenclature for organic transformations, chemical transformation of on ...

glycolysis
. The energy stored in the chemical bonds of
glucose Glucose is a simple with the . Glucose is the most abundant , a subcategory of s. Glucose is mainly made by and most during from water and carbon dioxide, using energy from sunlight, where it is used to make in s, the most abundant carbohydr ...

glucose
is released by the cell in the
citric acid cycle The citric acid cycle (CAC) – also known as the TCA cycle (tricarboxylic acid cycle) or the Krebs cycle – is a series of chemical reactions to release stored energy through the redox, oxidation of acetyl-CoA derived from carbohydra ...

citric acid cycle
producing carbon dioxide, and the energetic
electron donorsAn electron donor is a chemical entity that donates electrons to another compound. It is a reducing agent that, by virtue of its donating electrons, is itself oxidized in the process. Typical reducing agents undergo permanent chemical alteration thr ...
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 phosphate ...
and
FADH In biochemistry Biochemistry or biological chemistry, is the study of es within and relating to living s. A sub-discipline of both and , biochemistry may be divided into three fields: , and . Over the last decades of the 20th century, b ...

FADH
. Oxidative phosphorylation uses these molecules and O2 to
produce ATP
produce ATP
, which is used throughout the cell whenever energy is needed. During oxidative phosphorylation, electrons are transferred from the electron donors to a series of
electron acceptors Image:DOT hazmat class 5.1.svg, 125px, Dangerous goods label for oxidizing agents In chemistry, an oxidizing agent (oxidant, oxidizer), or oxidising agent (oxidiser) is a substance that has the ability to oxidize other substances — in other ...

electron acceptors
in a series of
redox reaction (mild reducing agent) are added to powdered potassium permanganate (strong oxidizing agent), a violent redox reaction accompanied by self-ignition starts. Redox (reduction–oxidation, pronunciation: or ) is a type of chemical reaction in whi ...

redox reaction
s ending in oxygen, whose reaction releases half of the total energy.Voet, D.; Voet, J. G. (2004). "Biochemistry", 3rd ed., p. 804, Wiley.ISBN 0-471-19350-X. In
eukaryote Eukaryotes () are organism In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, molecular interact ...

eukaryote
s, these redox reactions are catalyzed by a series of
protein complex A protein complex or multiprotein complex is a group of two or more associated polypeptide chain Peptides (from Greek language Greek (modern , romanized: ''Elliniká'', Ancient Greek, ancient , ''Hellēnikḗ'') is an independent branch of ...
es within the inner membrane of the cell's mitochondria, whereas, in
prokaryote A prokaryote () is a single-celled organism A unicellular organism, also known as a single-celled organism, is an organism In biology, an organism (from Ancient Greek, Greek: ὀργανισμός, ''organismos'') is any individual contig ...
s, these proteins are located in the cell's outer membrane. These linked sets of proteins are called the
electron transport chain An electron transport chain (ETC) is a series of protein complex A protein complex or multiprotein complex is a group of two or more associated polypeptide chain Peptides (from Greek language Greek (modern , romanized: ''Elliniká'', Anc ...

electron transport chain
. In eukaryotes, five main protein complexes are involved, whereas in prokaryotes many different enzymes are present, using a variety of electron donors and acceptors. The energy transferred by electrons flowing through this electron transport chain is used to transport
proton A proton is a subatomic particle, symbol or , with a positive electric charge of +1''e'' elementary charge and a mass slightly less than that of a neutron. Protons and neutrons, each with masses of approximately one atomic mass unit, are collecti ...

proton
s across the
inner mitochondrial membrane The inner mitochondrial membrane (IMM) is the mitochondria A mitochondrion (; ) is a double-membrane Image:Schematic size.jpg, up150px, Schematic of size-based membrane exclusion A membrane is a selective barrier; it allows some things to pa ...
, in a process called ''
electron transport is the site of oxidative phosphorylation Oxidative phosphorylation (UK , US or electron transport-linked phosphorylation or terminal oxidation) is the metabolic pathway In biochemistry Biochemistry or biological chemistry, is the study of c ...
''. This generates
potential energy In physics, potential energy is the energy held by an object because of its position relative to other objects, stresses within itself, its electric charge, or other factors. Common types of potential energy include the gravitational potentia ...

potential energy
in the form of a
pH
pH
gradient and an
electrical potential The electric potential (also called the ''electric field potential'', potential drop, the electrostatic potential) is the amount of work energy needed to move a unit of electric charge Electric charge is the physical property of matter that c ...

electrical potential
across this membrane. This store of energy is tapped when protons flow back across the membrane and down the potential energy gradient, through a large enzyme called
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 of ...

ATP synthase
in a process called
chemiosmosis Chemiosmosis is the movement of ions across a semipermeable membrane bound structure, down their electrochemical gradient. An example of this would be the formation of adenosine triphosphate, adenosine triphosphate (ATP) by the movement of hydrogen ...

chemiosmosis
. The ATP synthase uses the energy to transform
adenosine diphosphate Adenosine diphosphate (ADP), also known as adenosine pyrophosphate (APP), is an important organic compound , CH4; is among the simplest organic compounds. In chemistry Chemistry is the scientific discipline involved with Chemical element, ele ...

adenosine diphosphate
(ADP) into adenosine triphosphate, in a
phosphorylation In chemistry Chemistry is the study of the properties and behavior of . It is a that covers the that make up matter to the composed of s, s and s: their composition, structure, properties, behavior and the changes they undergo during ...

phosphorylation
reaction. The reaction is driven by the proton flow, which forces the
rotation A rotation is a circular movement of an object around a center (or point) of rotation. The plane (geometry), geometric plane along which the rotation occurs is called the ''rotation plane'', and the imaginary line extending from the center an ...

rotation
of a part of the enzyme. The ATP synthase is a rotary mechanical motor. Although oxidative phosphorylation is a vital part of metabolism, it produces
reactive oxygen species Reactive oxygen species (ROS) are highly chemicals formed from O2. Examples of ROS include s, , , , and . The reduction of molecular oxygen (O2) produces (•), which is the to most other reactive oxygen species: :O2 + e− → • of super ...
such as
superoxide A superoxide is a compound that contains the superoxide ion, which has the chemical formula . The systematic name of the anion is dioxide(1−). The reactive oxygen ion superoxide is particularly important as the product of the one-electron ...

superoxide
and
hydrogen peroxide Hydrogen peroxide is a chemical compound A chemical compound is a chemical substance A chemical substance is a form of matter In classical physics and general chemistry, matter is any substance that has mass and takes up space by hav ...

hydrogen peroxide
, which lead to propagation of
free radicals In chemistry Chemistry is the scientific discipline involved with Chemical element, elements and chemical compound, compounds composed of atoms, molecules and ions: their composition, structure, properties, behavior and the changes they un ...
, damaging cells and contributing to
disease A disease is a particular abnormal condition that negatively affects the structure A structure is an arrangement and organization of interrelated elements in a material object or system A system is a group of Interaction, interactin ...
and, possibly,
aging Ageing or aging (see spelling differences Despite the various English dialects Dialect The term dialect (from Latin , , from the Ancient Greek word , , "discourse", from , , "through" and , , "I speak") is used in two distinct ways ...

aging
and
senescence Ann Pouder American supercentenarians are citizens or residents of the United States who have attained or surpassed 110 years of age. , the Gerontology Research Group The Gerontology Research Group (GRG) is a global group of researchers in v ...

senescence
. The enzymes carrying out this metabolic pathway are also the target of many drugs and poisons that
inhibit Inhibitor or inhibition may refer to: In biology * Enzyme inhibitor 400px, An enzyme binding site that would normally bind substrate can alternatively bind a competitive inhibitor, preventing substrate access. Dihydrofolate reductase is inhibi ...
their activities.


Chemiosmosis

Oxidative phosphorylation works by using
energy In physics Physics is the that studies , its , its and behavior through , and the related entities of and . "Physical science is that department of knowledge which relates to the order of nature, or, in other words, to the regula ...

energy
-releasing chemical reactions to drive energy-requiring reactions. The two sets of reactions are said to be ''coupled''. This means one cannot occur without the other. The chain of redox reactions driving the flow of electrons through the electron transport chain, from electron donors such as
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 phosphate ...
to
electron acceptor An electron acceptor is a chemical entity that accepts electron The electron is a subatomic particle (denoted by the symbol or ) whose electric charge is negative one elementary charge. Electrons belong to the first generation (particle phy ...
s such as
oxygen Oxygen is the chemical element Image:Simple Periodic Table Chart-blocks.svg, 400px, Periodic table, The periodic table of the chemical elements In chemistry, an element is a pure substance consisting only of atoms that all have the same ...

oxygen
and hydrogen (protons), is an
exergonic An exergonic process is one which there is a positive flow of energy from the system to the surroundings. This is in contrast with an endergonic In chemical thermodynamics Chemical thermodynamics is the study of the interrelation of heat ...

exergonic
process – it releases energy, whereas the synthesis of ATP is an
endergonic In chemical thermodynamics Chemical thermodynamics is the study of the interrelation of heat In thermodynamics, heat is energy in transfer to or from a thermodynamic system, by mechanisms other than thermodynamic work or transfer of ma ...

endergonic
process, which requires an input of energy. Both the electron transport chain and the ATP synthase are embedded in a membrane, and energy is transferred from the electron transport chain to the ATP synthase by movements of protons across this membrane, in a process called ''
chemiosmosis Chemiosmosis is the movement of ions across a semipermeable membrane bound structure, down their electrochemical gradient. An example of this would be the formation of adenosine triphosphate, adenosine triphosphate (ATP) by the movement of hydrogen ...

chemiosmosis
''. A current of protons is driven from the negative N-side of the membrane to the positive P-side through the proton-pumping enzymes of the electron transport chain. The movement of protons creates an
electrochemical gradient An electrochemical gradient is a of , usually for an that can move across a . The gradient consists of two parts, the chemical gradient, or difference in across a membrane, and the electrical gradient, or difference in across a membrane. When ...
across the membrane, which is often called the ''proton-motive force''. It has two components: a difference in proton concentration (a H+ gradient, Δ) and a difference in
electric potential The electric potential (also called the ''electric field potential'', potential drop, the electrostatic potential) is defined as the amount of work Work may refer to: * Work (human activity), intentional activity people perform to support the ...

electric potential
, with the N-side having a negative charge. ATP synthase releases this stored energy by completing the circuit and allowing protons to flow down the electrochemical gradient, back to the N-side of the membrane. The electrochemical gradient drives the rotation of part of the enzyme's structure and couples this motion to the synthesis of ATP. The two components of the proton-motive force are
thermodynamic Thermodynamics is a branch of physics Physics is the natural science that studies matter, its Elementary particle, fundamental constituents, its Motion (physics), motion and behavior through Spacetime, space and time, and the related ent ...
ally equivalent: In mitochondria, the largest part of energy is provided by the potential; in
alkaliphileAlkaliphiles are a class of extremophilic microbes capable of survival in alkaline ( pH roughly 8.5–11) environments, growing optimally around a pH of 10. These bacteria can be further categorized as obligate alkaliphiles (those that require high ...
bacteria the electrical energy even has to compensate for a counteracting inverse pH difference. Inversely,
chloroplast A chloroplast is a type of membrane-bound 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 structure ...

chloroplast
s operate mainly on ΔpH. However, they also require a small membrane potential for the kinetics of ATP synthesis. In the case of the
fusobacterium ''Fusobacterium'' is a genus of Anaerobic organism, anaerobic, Gram-negative, non-sporeforming bacteria, similar to ''Bacteroides''. Individual Cell (biology), cells are slender, rod-shaped Bacillus (shape), bacilli with pointed ends. Strains of ' ...
'' Propionigenium modestum'' it drives the counter-rotation of subunits a and c of the FO motor of ATP synthase. The amount of energy released by oxidative phosphorylation is high, compared with the amount produced by
anaerobic fermentation Fermentation is a metabolic Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life Life is a characteristic that distinguishes physical entities that have biological processes, such as signaling ...
, due to the high energy of O2.
Glycolysis Glycolysis is the metabolic pathway In biochemistry, a metabolic pathway is a linked series of chemical reaction A chemical reaction is a process that leads to the IUPAC nomenclature for organic transformations, chemical transformation of on ...

Glycolysis
produces only 2 ATP molecules, but somewhere between 30 and 36 ATPs are produced by the oxidative phosphorylation of the 10 NADH and 2 succinate molecules made by converting one molecule of
glucose Glucose is a simple with the . Glucose is the most abundant , a subcategory of s. Glucose is mainly made by and most during from water and carbon dioxide, using energy from sunlight, where it is used to make in s, the most abundant carbohydr ...

glucose
to carbon dioxide and water, while each cycle of
beta oxidation In biochemistry Biochemistry or biological chemistry, is the study of chemical process In a scientific Science () is a systematic enterprise that Scientific method, builds and organizes knowledge in the form of Testability, testable ...
of a
fatty acid In chemistry Chemistry is the study of the properties and behavior of . It is a that covers the that make up matter to the composed of s, s and s: their composition, structure, properties, behavior and the changes they undergo during ...
yields about 14 ATPs. These ATP yields are theoretical maximum values; in practice, some protons leak across the membrane, lowering the yield of ATP.


Electron and proton transfer molecules

The electron transport chain carries both protons and electrons, passing electrons from donors to acceptors, and transporting protons across a membrane. These processes use both soluble and protein-bound transfer molecules. In mitochondria, electrons are transferred within the intermembrane space by the water-
soluble In chemistry Chemistry is the scientific Science () is a systematic enterprise that builds and organizes knowledge Knowledge is a familiarity or awareness, of someone or something, such as facts A fact is an occurrence i ...
electron transfer protein
cytochrome c The cytochrome complex, or cyt ''c'', is a small hemeprotein found loosely associated with the inner membrane of the mitochondrion A mitochondrion (; ) is a double-membrane Image:Schematic size.jpg, up150px, Schematic of size-based membra ...

cytochrome c
. This carries only electrons, and these are transferred by the reduction and oxidation of an
iron Iron () is a chemical element In chemistry Chemistry is the study of the properties and behavior of . It is a that covers the that make up matter to the composed of s, s and s: their composition, structure, properties, behav ...

iron
atom that the protein holds within a
heme Heme, or haem, is a precursor Precursor or Precursors may refer to: *Precursor (religion), a forerunner, predecessor ** The Precursor, John the Baptist Science and technology * Precursor (bird), a hypothesized genus of fossil birds that was comp ...

heme
group in its structure. Cytochrome c is also found in some bacteria, where it is located within the
periplasmic space 400px, cell_wall.html"_;"title="Gram-negative_cell_wall">Gram-negative_cell_wall_ The_periplasm_is_a_concentrated_gel-like_matrix_(biology).html" ;"title="cell_wall_.html" ;"title="cell_wall.html" ;"title="Gram-negative cell wall">Gram-negative ce ...
. Within the inner mitochondrial membrane, the
lipid In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, molecular interactions, Physiology, physiological mechanis ...
-soluble electron carrier
coenzyme Q10 Coenzyme Q, also known as ubiquinone, is a coenzyme A cofactor is a non-protein Proteins are large biomolecules or macromolecules that are comprised of one or more long chains of amino acid residue (biochemistry), residues. Proteins perfor ...
(Q) carries both electrons and protons by a
redox Redox (reduction–oxidation, pronunciation: or ) is a type of chemical reaction A chemical reaction is a process that leads to the chemical transformation of one set of chemical substance A chemical substance is a form of matter ...

redox
cycle. This small
benzoquinoneBenzoquinone (C6H4O2) is a quinone with a single benzene ring, of which there are only two: * 1,4-Benzoquinone, most commonly (also ''para''-benzoquinone, ''p''-benzoquinone, ''para''-quinone, or just quinone) * 1,2-Benzoquinone, less commonly (also ...
molecule is very
hydrophobic In chemistry Chemistry is the scientific Science () is a systematic enterprise that builds and organizes knowledge Knowledge is a familiarity or awareness, of someone or something, such as facts A fact is an occurrence ...
, so it diffuses freely within the membrane. When Q accepts two electrons and two protons, it becomes reduced to the ''
ubiquinol Ubiquinol is an electron-rich (reduced) form of coenzyme Q10, coenzyme Q10. The natural ubiquinol form of coenzyme Q10 is 2,3-dimethoxy-5-methyl-6-poly prenyl-1,4-benzoquinol, where the polyprenylated side-chain is 9-10 units long in mammals. Co ...

ubiquinol
'' form (QH2); when QH2 releases two electrons and two protons, it becomes oxidized back to the ''ubiquinone'' (Q) form. As a result, if two enzymes are arranged so that Q is reduced on one side of the membrane and QH2 oxidized on the other, ubiquinone will couple these reactions and shuttle protons across the membrane. Some bacterial electron transport chains use different quinones, such as
menaquinone Vitamin K2 or menaquinone () is one of three types of vitamin K, the other two being vitamin K1 (phylloquinone Phytomenadione, also known as vitamin K1 or phylloquinone, is a vitamin A vitamin is an organic molecule (or a set of molecules ...
, in addition to ubiquinone. Within proteins, electrons are transferred between cofactors,
iron–sulfur cluster Iron–sulfur clusters (or iron–sulphur clusters in British spelling Despite the various English dialects spoken from country to country and within different regions of the same country, there are only slight regional variations in Eng ...
s and cytochromes. There are several types of iron–sulfur cluster. The simplest kind found in the electron transfer chain consists of two iron atoms joined by two atoms of inorganic
sulfur Sulfur (in nontechnical British English: sulphur) is a chemical element In chemistry Chemistry is the study of the properties and behavior of . It is a that covers the that make up matter to the composed of s, s and s: th ...

sulfur
; these are called Fe–2Sclusters. The second kind, called Fe–4S contains a cube of four iron atoms and four sulfur atoms. Each iron atom in these clusters is coordinated by an additional
amino acid Amino acids are organic compound In , organic compounds are generally any s that contain - . Due to carbon's ability to (form chains with other carbon s), millions of organic compounds are known. The study of the properties, reactions, a ...

amino acid
, usually by the sulfur atom of
cysteine Cysteine (symbol Cys or C; ) is a semiessential proteinogenic amino acid with the chemical formula, formula HOOC-CH-(NH2)-CH2-SH. The thiol side chain in cysteine often participates in enzymatic reactions as a nucleophile. The thiol is suscepti ...

cysteine
. Metal ion cofactors undergo redox reactions without binding or releasing protons, so in the electron transport chain they serve solely to transport electrons through proteins. Electrons move quite long distances through proteins by hopping along chains of these cofactors. This occurs by
quantum tunnelling Quantum tunnelling or tunneling (US) is the quantum mechanical Quantum mechanics is a fundamental theory A theory is a reason, rational type of abstraction, abstract thinking about a phenomenon, or the results of such thinking. The proce ...
, which is rapid over distances of less than 1.4 m.


Eukaryotic electron transport chains

Many
catabolic Catabolism () is the set of metabolic Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main purposes of metabolism are: the conversion of the ener ...
biochemical processes, such as
glycolysis Glycolysis is the metabolic pathway In biochemistry, a metabolic pathway is a linked series of chemical reaction A chemical reaction is a process that leads to the IUPAC nomenclature for organic transformations, chemical transformation of on ...

glycolysis
, the
citric acid cycle The citric acid cycle (CAC) – also known as the TCA cycle (tricarboxylic acid cycle) or the Krebs cycle – is a series of chemical reactions to release stored energy through the redox, oxidation of acetyl-CoA derived from carbohydra ...

citric acid cycle
, and
beta oxidation In biochemistry Biochemistry or biological chemistry, is the study of chemical process In a scientific Science () is a systematic enterprise that Scientific method, builds and organizes knowledge in the form of Testability, testable ...
, produce the reduced
coenzyme A cofactor is a non-protein Proteins are large biomolecule , showing alpha helices, represented by ribbons. This poten was the first to have its suckture solved by X-ray crystallography by Max Perutz and Sir John Cowdery Kendrew in 195 ...
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 phosphate ...
. This coenzyme contains electrons that have a high transfer potential; in other words, they will release a large amount of energy upon oxidation. However, the cell does not release this energy all at once, as this would be an uncontrollable reaction. Instead, the electrons are removed from NADH and passed to oxygen through a series of enzymes that each release a small amount of the energy. This set of enzymes, consisting of complexes I through IV, is called the electron transport chain and is found in the inner membrane of the mitochondrion.
Succinate Succinic acid () is a dicarboxylic acidA dicarboxylic acid is an organic compound , CH4; is among the simplest organic compounds. In chemistry Chemistry is the scientific discipline involved with Chemical element, elements and chemical co ...

Succinate
is also oxidized by the electron transport chain, but feeds into the pathway at a different point. In
eukaryote Eukaryotes () are organism In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, molecular interact ...

eukaryote
s, the enzymes in this electron transport system use the energy released from O2 by NADH to pump
proton A proton is a subatomic particle, symbol or , with a positive electric charge of +1''e'' elementary charge and a mass slightly less than that of a neutron. Protons and neutrons, each with masses of approximately one atomic mass unit, are collecti ...

proton
s across the inner membrane of the mitochondrion. This causes protons to build up in the
intermembrane space #REDIRECT Intermembrane space #REDIRECT Intermembrane space#REDIRECT Intermembrane space The intermembrane space (IMS) is the space occurring between or involving two or more membranes. In cell biology, it is most commonly described as the region be ...
, and generates an
electrochemical gradient An electrochemical gradient is a of , usually for an that can move across a . The gradient consists of two parts, the chemical gradient, or difference in across a membrane, and the electrical gradient, or difference in across a membrane. When ...
across the membrane. The energy stored in this potential is then used by ATP synthase to produce ATP. Oxidative phosphorylation in the eukaryotic mitochondrion is the best-understood example of this process. The mitochondrion is present in almost all eukaryotes, with the exception of anaerobic protozoa such as ''
Trichomonas vaginalis ''Trichomonas vaginalis'' is an Anaerobic organism, anaerobic, flagellated protozoan parasite and the causative agent of trichomoniasis. It is the most common pathogenic protozoan infection of humans in industrialized countries. Infection rates i ...

Trichomonas vaginalis
'' that instead reduce protons to hydrogen in a remnant mitochondrion called a
hydrogenosome A hydrogenosome is a membrane-enclosed 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 par ...

hydrogenosome
.


NADH-coenzyme Q oxidoreductase (complex I)

NADH-coenzyme Q oxidoreductase, also known as ''NADH dehydrogenase'' or ''complex I'', is the first protein in the electron transport chain. Complex I is a giant
enzyme Enzymes () are proteins that act as biological catalysts (biocatalysts). Catalysts accelerate chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates in ...

enzyme
with the mammalian complex I having 46 subunits and a molecular mass of about 1,000 kilodaltons (kDa). The structure is known in detail only from a bacterium; in most organisms the complex resembles a boot with a large "ball" poking out from the membrane into the mitochondrion. The genes that encode the individual proteins are contained in both the
cell nucleus In cell biology, the nucleus (pl. ''nuclei''; from Latin or , meaning ''kernel'' or ''seed'') is a biological membrane#Function, membrane-bound organelle found in eukaryote, eukaryotic cell (biology), cells. Eukaryotes usually have a single n ...

cell 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). Mi ...
, as is the case for many enzymes present in the mitochondrion. The reaction that is catalyzed by this enzyme is the two electron oxidation 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 phosphate ...
by
coenzyme Q10 Coenzyme Q, also known as ubiquinone, is a coenzyme A cofactor is a non-protein Proteins are large biomolecules or macromolecules that are comprised of one or more long chains of amino acid residue (biochemistry), residues. Proteins perfor ...
or ''ubiquinone'' (represented as Q in the equation below), a lipid-soluble
quinone The quinones are a class of organic compound In chemistry Chemistry is the study of the properties and behavior of . It is a that covers the that make up matter to the composed of s, s and s: their composition, structure, properties ...

quinone
that is found in the mitochondrion membrane: The start of the reaction, and indeed of the entire electron chain, is the binding of a NADH molecule to complex I and the donation of two electrons. The electrons enter complex I via a
prosthetic group A prosthetic group is the non-amino acid component that is part of the structure of the heteroproteins or conjugated proteins, being covalently linked to the apoprotein. Not to be confused with the cofactor that binds to the enzyme apoenzyme (ei ...
attached to the complex,
flavin mononucleotide Flavin mononucleotide (FMN), or riboflavin-5′-phosphate, is a biomolecule produced from riboflavin (vitamin B2) by the enzyme riboflavin kinase and functions as the prosthetic group of various oxidoreductases, including NADH dehydrogenase, as ...

flavin mononucleotide
(FMN). The addition of electrons to FMN converts it to its reduced form, FMNH2. The electrons are then transferred through a series of iron–sulfur clusters: the second kind of prosthetic group present in the complex. There are both Fe–2Sand Fe–4Siron–sulfur clusters in complex I. As the electrons pass through this complex, four protons are pumped from the matrix into the intermembrane space. Exactly how this occurs is unclear, but it seems to involve
conformational change In biochemistry Biochemistry or biological chemistry, is the study of es within and relating to living s. A sub-discipline of both and , biochemistry may be divided into three fields: , and . Over the last decades of the 20th century, bi ...

conformational change
s in complex I that cause the protein to bind protons on the N-side of the membrane and release them on the P-side of the membrane. Finally, the electrons are transferred from the chain of iron–sulfur clusters to a ubiquinone molecule in the membrane. Reduction of ubiquinone also contributes to the generation of a proton gradient, as two protons are taken up from the matrix as it is reduced to
ubiquinol Ubiquinol is an electron-rich (reduced) form of coenzyme Q10, coenzyme Q10. The natural ubiquinol form of coenzyme Q10 is 2,3-dimethoxy-5-methyl-6-poly prenyl-1,4-benzoquinol, where the polyprenylated side-chain is 9-10 units long in mammals. Co ...

ubiquinol
(QH2).


Succinate-Q oxidoreductase (complex II)

Succinate-Q oxidoreductase, also known as ''complex II'' or ''succinate dehydrogenase'', is a second entry point to the electron transport chain. It is unusual because it is the only enzyme that is part of both the citric acid cycle and the electron transport chain. Complex II consists of four protein subunits and contains a bound
flavin adenine dinucleotide In biochemistry Biochemistry or biological chemistry, is the study of chemical process In a scientific Science () is a systematic enterprise that Scientific method, builds and organizes knowledge in the form of Testability, testable ...

flavin adenine dinucleotide
(FAD) cofactor, iron–sulfur clusters, and a
heme Heme, or haem, is a precursor Precursor or Precursors may refer to: *Precursor (religion), a forerunner, predecessor ** The Precursor, John the Baptist Science and technology * Precursor (bird), a hypothesized genus of fossil birds that was comp ...

heme
group that does not participate in electron transfer to coenzyme Q, but is believed to be important in decreasing production of reactive oxygen species. It oxidizes
succinate Succinic acid () is a dicarboxylic acidA dicarboxylic acid is an organic compound , CH4; is among the simplest organic compounds. In chemistry Chemistry is the scientific discipline involved with Chemical element, elements and chemical co ...

succinate
to
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 salts and esters are known as ...

fumarate
and reduces ubiquinone. As this reaction releases less energy than the oxidation of NADH, complex II does not transport protons across the membrane and does not contribute to the proton gradient. In some eukaryotes, such as the
parasitic worm Parasitic worms, also known as helminths, are large macroparasites; adults can generally be seen with the naked eye. Many are intestinal worms An intestinal parasite infection is a condition in which a parasite Parasitism is a symbi ...
''
Ascaris suum ''Ascaris suum'', also known as the large roundworm of pig, is a parasitic Parasitism is a Symbiosis, symbiotic biological interactions, relationship between species, where one organism, the parasite, lives on or inside another organism, th ...
'', an enzyme similar to complex II, fumarate reductase (menaquinol:fumarate oxidoreductase, or QFR), operates in reverse to oxidize ubiquinol and reduce fumarate. This allows the worm to survive in the anaerobic environment of the large intestine, carrying out anaerobic oxidative phosphorylation with fumarate as the electron acceptor. Another unconventional function of complex II is seen in the malaria parasite ''Plasmodium falciparum''. Here, the reversed action of complex II as an oxidase is important in regenerating ubiquinol, which the parasite uses in an unusual form of pyrimidine biosynthesis.


Electron transfer flavoprotein-Q oxidoreductase

Electron-transferring-flavoprotein dehydrogenase, Electron transfer flavoprotein-ubiquinone oxidoreductase (ETF-Q oxidoreductase), also known as ''electron transferring-flavoprotein dehydrogenase'', is a third entry point to the electron transport chain. It is an enzyme that accepts electrons from electron-transferring flavoprotein in the mitochondrial matrix, and uses these electrons to reduce ubiquinone. This enzyme contains a and a Fe–4Scluster, but, unlike the other respiratory complexes, it attaches to the surface of the membrane and does not cross the lipid bilayer. In mammals, this metabolic pathway is important in
beta oxidation In biochemistry Biochemistry or biological chemistry, is the study of chemical process In a scientific Science () is a systematic enterprise that Scientific method, builds and organizes knowledge in the form of Testability, testable ...
of
fatty acid In chemistry Chemistry is the study of the properties and behavior of . It is a that covers the that make up matter to the composed of s, s and s: their composition, structure, properties, behavior and the changes they undergo during ...
s and catabolism of
amino acid Amino acids are organic compound In , organic compounds are generally any s that contain - . Due to carbon's ability to (form chains with other carbon s), millions of organic compounds are known. The study of the properties, reactions, a ...

amino acid
s and choline, as it accepts electrons from multiple acetyl-CoA dehydrogenases. In plants, ETF-Q oxidoreductase is also important in the metabolic responses that allow survival in extended periods of darkness.


Q-cytochrome c oxidoreductase (complex III)

Coenzyme Q - cytochrome c reductase, Q-cytochrome c oxidoreductase is also known as ''cytochrome c reductase'', ''cytochrome bc1 complex'', or simply ''complex III''. In mammals, this enzyme is a protein dimer, dimer, with each subunit complex containing 11 protein subunits, an [2Fe-2S] iron–sulfur cluster and three cytochromes: one cytochrome c1 and two b cytochromes. A cytochrome is a kind of electron-transferring protein that contains at least one
heme Heme, or haem, is a precursor Precursor or Precursors may refer to: *Precursor (religion), a forerunner, predecessor ** The Precursor, John the Baptist Science and technology * Precursor (bird), a hypothesized genus of fossil birds that was comp ...

heme
group. The iron atoms inside complex III's heme groups alternate between a reduced ferrous (+2) and oxidized ferric (+3) state as the electrons are transferred through the protein. The reaction catalyzed by complex III is the oxidation of one molecule of
ubiquinol Ubiquinol is an electron-rich (reduced) form of coenzyme Q10, coenzyme Q10. The natural ubiquinol form of coenzyme Q10 is 2,3-dimethoxy-5-methyl-6-poly prenyl-1,4-benzoquinol, where the polyprenylated side-chain is 9-10 units long in mammals. Co ...

ubiquinol
and the reduction of two molecules of
cytochrome c The cytochrome complex, or cyt ''c'', is a small hemeprotein found loosely associated with the inner membrane of the mitochondrion A mitochondrion (; ) is a double-membrane Image:Schematic size.jpg, up150px, Schematic of size-based membra ...

cytochrome c
, a heme protein loosely associated with the mitochondrion. Unlike coenzyme Q, which carries two electrons, cytochrome c carries only one electron. As only one of the electrons can be transferred from the QH2 donor to a cytochrome c acceptor at a time, the reaction mechanism of complex III is more elaborate than those of the other respiratory complexes, and occurs in two steps called the Q cycle. In the first step, the enzyme binds three substrates, first, QH2, which is then oxidized, with one electron being passed to the second substrate, cytochrome c. The two protons released from QH2 pass into the intermembrane space. The third substrate is Q, which accepts the second electron from the QH2 and is reduced to Q.−, which is the semiquinone, ubisemiquinone free radical. The first two substrates are released, but this ubisemiquinone intermediate remains bound. In the second step, a second molecule of QH2 is bound and again passes its first electron to a cytochrome c acceptor. The second electron is passed to the bound ubisemiquinone, reducing it to QH2 as it gains two protons from the mitochondrial matrix. This QH2 is then released from the enzyme. As coenzyme Q is reduced to ubiquinol on the inner side of the membrane and oxidized to ubiquinone on the other, a net transfer of protons across the membrane occurs, adding to the proton gradient. The rather complex two-step mechanism by which this occurs is important, as it increases the efficiency of proton transfer. If, instead of the Q cycle, one molecule of QH2 were used to directly reduce two molecules of cytochrome c, the efficiency would be halved, with only one proton transferred per cytochrome c reduced.


Cytochrome c oxidase (complex IV)

Cytochrome c oxidase, also known as ''complex IV'', is the final protein complex in the electron transport chain. The mammalian enzyme has an extremely complicated structure and contains 13 subunits, two heme groups, as well as multiple metal ion cofactors – in all, three atoms of copper, one of magnesium and one of zinc. This enzyme mediates the final reaction in the electron transport chain and transfers electrons to oxygen and hydrogen (protons), while pumping protons across the membrane. The final
electron acceptor An electron acceptor is a chemical entity that accepts electron The electron is a subatomic particle (denoted by the symbol or ) whose electric charge is negative one elementary charge. Electrons belong to the first generation (particle phy ...
oxygen, which provides most of the energy released in the electron transfer chain and is also called the ''terminal electron acceptor'', is reduced to water in this step, which releases half of all the energy in aerobic respiration. Both the direct pumping of protons and the consumption of matrix protons in the reduction of oxygen contribute to the proton gradient. The reaction catalyzed is the oxidation of cytochrome c and the reduction of oxygen:


Alternative reductases and oxidases

Many eukaryotic organisms have electron transport chains that differ from the much-studied mammalian enzymes described above. For example, plants have alternative NADH oxidases, which oxidize NADH in the cytosol rather than in the mitochondrial matrix, and pass these electrons to the ubiquinone pool. These enzymes do not transport protons, and, therefore, reduce ubiquinone without altering the electrochemical gradient across the inner membrane. Another example of a divergent electron transport chain is the ''alternative oxidase'', which is found in plants, as well as some fungus, fungi, protists, and possibly some animals. This enzyme transfers electrons directly from ubiquinol to oxygen. The electron transport pathways produced by these alternative NADH and ubiquinone oxidases have lower adenosine triphosphate, ATP yields than the full pathway. The advantages produced by a shortened pathway are not entirely clear. However, the alternative oxidase is produced in response to stresses such as cold,
reactive oxygen species Reactive oxygen species (ROS) are highly chemicals formed from O2. Examples of ROS include s, , , , and . The reduction of molecular oxygen (O2) produces (•), which is the to most other reactive oxygen species: :O2 + e− → • of super ...
, and infection by pathogens, as well as other factors that inhibit the full electron transport chain. Alternative pathways might, therefore, enhance an organisms' resistance to injury, by reducing oxidative stress.


Organization of complexes

The original model for how the respiratory chain complexes are organized was that they diffuse freely and independently in the mitochondrial membrane. However, recent data suggest that the complexes might form higher-order structures called supercomplexes or "respirasomes". In this model, the various complexes exist as organized sets of interacting enzymes. These associations might allow channeling of substrates between the various enzyme complexes, increasing the rate and efficiency of electron transfer. Within such mammalian supercomplexes, some components would be present in higher amounts than others, with some data suggesting a ratio between complexes I/II/III/IV and the ATP synthase of approximately 1:1:3:7:4. However, the debate over this supercomplex hypothesis is not completely resolved, as some data do not appear to fit with this model.


Prokaryotic electron transport chains

In contrast to the general similarity in structure and function of the electron transport chains in eukaryotes, bacteria and archaea possess a large variety of electron-transfer enzymes. These use an equally wide set of chemicals as substrates. In common with eukaryotes, prokaryotic electron transport uses the energy released from the oxidation of a substrate to pump ions across a membrane and generate an electrochemical gradient. In the bacteria, oxidative phosphorylation in ''Escherichia coli'' is understood in most detail, while archaeal systems are at present poorly understood. The main difference between eukaryotic and prokaryotic oxidative phosphorylation is that bacteria and archaea use many different substances to donate or accept electrons. This allows prokaryotes to grow under a wide variety of environmental conditions. In ''E. coli'', for example, oxidative phosphorylation can be driven by a large number of pairs of reducing agents and oxidizing agents, which are listed below. The Standard electrode potential#Non-standard condition, midpoint potential of a chemical measures how much energy is released when it is oxidized or reduced, with reducing agents having negative potentials and oxidizing agents positive potentials. As shown above, ''E. coli'' can grow with reducing agents such as formate, hydrogen, or lactate as electron donors, and nitrate, DMSO, or oxygen as acceptors. The larger the difference in midpoint potential between an oxidizing and reducing agent, the more energy is released when they react. Out of these compounds, the succinate/fumarate pair is unusual, as its midpoint potential is close to zero. Succinate can therefore be oxidized to fumarate if a strong oxidizing agent such as oxygen is available, or fumarate can be reduced to succinate using a strong reducing agent such as formate. These alternative reactions are catalyzed by Succinate - coenzyme Q reductase, succinate dehydrogenase and fumarate reductase, respectively. Some prokaryotes use redox pairs that have only a small difference in midpoint potential. For example, nitrification, nitrifying bacteria such as ''Nitrobacter'' oxidize nitrite to nitrate, donating the electrons to oxygen. The small amount of energy released in this reaction is enough to pump protons and generate ATP, but not enough to produce NADH or NADPH directly for use in anabolism. This problem is solved by using a nitrite oxidoreductase to produce enough proton-motive force to run part of the electron transport chain in reverse, causing complex I to generate NADH. Prokaryotes control their use of these electron donors and acceptors by varying which enzymes are produced, in response to environmental conditions. This flexibility is possible because different oxidases and reductases use the same ubiquinone pool. This allows many combinations of enzymes to function together, linked by the common ubiquinol intermediate. These respiratory chains therefore have a modular design, with easily interchangeable sets of enzyme systems. In addition to this metabolic diversity, prokaryotes also possess a range of isozymes – different enzymes that catalyze the same reaction. For example, in ''E. coli'', there are two different types of ubiquinol oxidase using oxygen as an electron acceptor. Under highly aerobic conditions, the cell uses an oxidase with a low affinity for oxygen that can transport two protons per electron. However, if levels of oxygen fall, they switch to an oxidase that transfers only one proton per electron, but has a high affinity for oxygen.


ATP synthase (complex V)

ATP synthase, also called ''complex V'', is the final enzyme in the oxidative phosphorylation pathway. This enzyme is found in all forms of life and functions in the same way in both prokaryotes and eukaryotes. The enzyme uses the energy stored in a proton gradient across a membrane to drive the synthesis of ATP from ADP and phosphate (Pi). Estimates of the number of protons required to synthesize one ATP have ranged from three to four, with some suggesting cells can vary this ratio, to suit different conditions. This
phosphorylation In chemistry Chemistry is the study of the properties and behavior of . It is a that covers the that make up matter to the composed of s, s and s: their composition, structure, properties, behavior and the changes they undergo during ...

phosphorylation
reaction is an chemical equilibrium, equilibrium, which can be shifted by altering the proton-motive force. In the absence of a proton-motive force, the ATP synthase reaction will run from right to left, hydrolyzing ATP and pumping protons out of the matrix across the membrane. However, when the proton-motive force is high, the reaction is forced to run in the opposite direction; it proceeds from left to right, allowing protons to flow down their concentration gradient and turning ADP into ATP. Indeed, in the closely related V-ATPase, vacuolar type H+-ATPases, the hydrolysis reaction is used to acidify cellular compartments, by pumping protons and hydrolysing ATP. ATP synthase is a massive protein complex with a mushroom-like shape. The mammalian enzyme complex contains 16 subunits and has a mass of approximately 600 kilodaltons. The portion embedded within the membrane is called FO and contains a ring of c subunits and the proton channel. The stalk and the ball-shaped headpiece is called F1 and is the site of ATP synthesis. The ball-shaped complex at the end of the F1 portion contains six proteins of two different kinds (three α subunits and three β subunits), whereas the "stalk" consists of one protein: the γ subunit, with the tip of the stalk extending into the ball of α and β subunits. Both the α and β subunits bind nucleotides, but only the β subunits catalyze the ATP synthesis reaction. Reaching along the side of the F1 portion and back into the membrane is a long rod-like subunit that anchors the α and β subunits into the base of the enzyme. As protons cross the membrane through the channel in the base of ATP synthase, the FO proton-driven motor rotates. Rotation might be caused by changes in the ionization of amino acids in the ring of c subunits causing electrostatic interactions that propel the ring of c subunits past the proton channel. This rotating ring in turn drives the rotation of the central axle (the γ subunit stalk) within the α and β subunits. The α and β subunits are prevented from rotating themselves by the side-arm, which acts as a stator. This movement of the tip of the γ subunit within the ball of α and β subunits provides the energy for the active sites in the β subunits to undergo a cycle of movements that produces and then releases ATP. This ATP synthesis reaction is called the ''binding change mechanism'' and involves the active site of a β subunit cycling between three states. In the "open" state, ADP and phosphate enter the active site (shown in brown in the diagram). The protein then closes up around the molecules and binds them loosely – the "loose" state (shown in red). The enzyme then changes shape again and forces these molecules together, with the active site in the resulting "tight" state (shown in pink) binding the newly produced ATP molecule with very high Dissociation constant, affinity. Finally, the active site cycles back to the open state, releasing ATP and binding more ADP and phosphate, ready for the next cycle. In some bacteria and archaea, ATP synthesis is driven by the movement of sodium ions through the cell membrane, rather than the movement of protons. Archaea such as ''Methanococcus'' also contain the A1Ao synthase, a form of the enzyme that contains additional proteins with little similarity in sequence to other bacterial and eukaryotic ATP synthase subunits. It is possible that, in some species, the A1Ao form of the enzyme is a specialized sodium-driven ATP synthase, but this might not be true in all cases.


Oxidative phosphorylation - energetics

The energy released in oxidative phosphorylation can mostly be attributed to O2 with its relatively weak double bond. The transport of electrons from redox pair NAD+/ NADH to the final redox pair 1/2 O2/ H2O can be summarized as 1/2 O2 + NADH + H+ → H2O + NAD+ The potential difference between these two redox pairs is 1.14 volt, which is equivalent to -52 kcal/mol or -2600 kJ per 6 mol of O2. When one NADH is oxidized through the electron transfer chain, three ATPs are produced, which is equivalent to 7.3 kcal/mol x 3 = 21.9 kcal/mol. The conservation of the energy can be calculated by the following formula Efficiency = (21.9 x 100%) / 52 = 42% So we can conclude that when NADH is oxidized, about 42% of energy is conserved in the form of three ATPs and the remaining (58%) energy is lost as heat (unless the chemical energy of ATP under physiological conditions was underestimated).


Reactive oxygen species

Molecular oxygen is an ideal terminal
electron acceptor An electron acceptor is a chemical entity that accepts electron The electron is a subatomic particle (denoted by the symbol or ) whose electric charge is negative one elementary charge. Electrons belong to the first generation (particle phy ...
because it is a strong oxidizing agent. The reduction of oxygen does involve potentially harmful intermediates. Although the transfer of four electrons and four protons reduces oxygen to water, which is harmless, transfer of one or two electrons produces
superoxide A superoxide is a compound that contains the superoxide ion, which has the chemical formula . The systematic name of the anion is dioxide(1−). The reactive oxygen ion superoxide is particularly important as the product of the one-electron ...

superoxide
or peroxide anions, which are dangerously reactive. These
reactive oxygen species Reactive oxygen species (ROS) are highly chemicals formed from O2. Examples of ROS include s, , , , and . The reduction of molecular oxygen (O2) produces (•), which is the to most other reactive oxygen species: :O2 + e− → • of super ...
and their reaction products, such as the hydroxyl radical, are very harmful to cells, as they oxidize proteins and cause mutations in DNA. This cellular damage might contribute to
disease A disease is a particular abnormal condition that negatively affects the structure A structure is an arrangement and organization of interrelated elements in a material object or system A system is a group of Interaction, interactin ...
and is proposed as one cause of free-radical theory of aging, aging. The cytochrome c oxidase complex is highly efficient at reducing oxygen to water, and it releases very few partly reduced intermediates; however small amounts of superoxide anion and peroxide are produced by the electron transport chain. Particularly important is the reduction of coenzyme Q in complex III, as a highly reactive ubisemiquinone free radical is formed as an intermediate in the Q cycle. This unstable species can lead to electron "leakage" when electrons transfer directly to oxygen, forming superoxide. As the production of reactive oxygen species by these proton-pumping complexes is greatest at high membrane potentials, it has been proposed that mitochondria regulate their activity to maintain the membrane potential within a narrow range that balances ATP production against oxidant generation. For instance, oxidants can activate uncoupling proteins that reduce membrane potential. To counteract these reactive oxygen species, cells contain numerous antioxidant systems, including antioxidant vitamins such as vitamin C and vitamin E, and antioxidant enzymes such as superoxide dismutase, catalase, and peroxidases, which detoxify the reactive species, limiting damage to the cell.


Oxidative phosphorylation in hypoxic conditions

As
oxygen Oxygen is the chemical element Image:Simple Periodic Table Chart-blocks.svg, 400px, Periodic table, The periodic table of the chemical elements In chemistry, an element is a pure substance consisting only of atoms that all have the same ...

oxygen
is fundamental for oxidative phosphorylation, a shortage in O2 level likely alters ATP production rates. However, proton motive force and ATP production can be maintained by intracellular acidosis. Cytosolic protons that have accumulated with ATP hydrolysis and lactic acidosis can freely diffuse across the mitochondrial outer-membrane and acidify the inter-membrane space, hence directly contributing to the proton motive force and ATP production.


Inhibitors

There are several well-known drugs and toxins that inhibit oxidative phosphorylation. Although any one of these toxins inhibits only one enzyme in the electron transport chain, inhibition of any step in this process will halt the rest of the process. For example, if oligomycin inhibits ATP synthase, protons cannot pass back into the mitochondrion. As a result, the proton pumps are unable to operate, as the gradient becomes too strong for them to overcome. NADH is then no longer oxidized and the citric acid cycle ceases to operate because the concentration of NAD+ falls below the concentration that these enzymes can use. Many site-specific inhibitors of the electron transport chain have contributed to the present knowledge of mitochondrial respiration. Synthesis of ATP is also dependent on the electron transport chain, so all site-specific inhibitors also inhibit ATP formation. The fish poison rotenone, the barbiturate drug amobarbital, amytal, and the antibiotic piericidin A inhibit NADH and coenzyme Q. Carbon monoxide, cyanide, hydrogen sulphide and azide effectively inhibit cytochrome oxidase. Carbon monoxide reacts with the reduced form of the cytochrome while cyanide and azide react with the oxidised form. An antibiotic, antimycin A, and dimercaprol, British anti-Lewisite, an antidote used against chemical weapons, are the two important inhibitors of the site between cytochrome B and C1. Not all inhibitors of oxidative phosphorylation are toxins. In brown adipose tissue, regulated proton channels called uncoupling proteins can uncouple respiration from ATP synthesis. This rapid respiration produces heat, and is particularly important as a way of maintaining body temperature for hibernation, hibernating animals, although these proteins may also have a more general function in cells' responses to stress.


History

The field of oxidative phosphorylation began with the report in 1906 by Arthur Harden of a vital role for phosphate in cellular
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 ...
, but initially only sugar phosphates were known to be involved. However, in the early 1940s, the link between the oxidation of sugars and the generation of ATP was firmly established by Herman Kalckar, confirming the central role of ATP in energy transfer that had been proposed by Fritz Albert Lipmann in 1941. Later, in 1949, Morris Friedkin and Albert L. Lehninger proved that the coenzyme NADH linked metabolic pathways such as the citric acid cycle and the synthesis of ATP. The term ''oxidative phosphorylation'' was coined by in 1939. For another twenty years, the mechanism by which ATP is generated remained mysterious, with scientists searching for an elusive "high-energy intermediate" that would link oxidation and phosphorylation reactions. This puzzle was solved by Peter D. Mitchell with the publication of the chemiosmotic theory in 1961. At first, this proposal was highly controversial, but it was slowly accepted and Mitchell was awarded a Nobel Prize, Nobel prize in 1978. Subsequent research concentrated on purifying and characterizing the enzymes involved, with major contributions being made by David E. Green on the complexes of the electron-transport chain, as well as Efraim Racker on the ATP synthase. A critical step towards solving the mechanism of the ATP synthase was provided by Paul D. Boyer, by his development in 1973 of the "binding change" mechanism, followed by his radical proposal of rotational catalysis in 1982. More recent work has included x-ray crystallography, structural studies on the enzymes involved in oxidative phosphorylation by John E. Walker, with Walker and Boyer being awarded a Nobel Prize in 1997.


See also

*Respirometry *TIM/TOM Complex


Notes


References


Further reading


Introductory

* * *


Advanced

* * * *


General resources


Animated diagrams illustrating oxidative phosphorylation
John Wiley & Sons, Wiley and Co ''Concepts in Biochemistry''
On-line biophysics lectures
Antony Crofts, University of Illinois at Urbana–Champaign
ATP Synthase
Graham Johnson


Structural resources

*Protein Data Bank, PDB molecule of the month:
ATP synthase




*Interactive molecular models at Universidade Fernando Pessoa:
NADH dehydrogenase






{{DEFAULTSORT:Oxidative Phosphorylation Cellular respiration Integral membrane proteins Metabolism