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Mitochondrial DNA (mtDNA or mDNA) is the
DNA Deoxyribonucleic acid (; DNA) is a molecule File:Pentacene on Ni(111) STM.jpg, A scanning tunneling microscopy image of pentacene molecules, which consist of linear chains of five carbon rings. A molecule is an electrically neutral gro ...

DNA
located in
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
, cellular
organelle In cell biology Cell biology (also cellular biology or cytology) is a branch of biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, M ...
s within
eukaryotic Eukaryotes () are organism In biology, an organism () is any organic, life, living system that functions as an individual entity. All organisms are composed of cells (cell theory). Organisms are classified by taxonomy (biology), tax ...
cells that convert chemical energy from food into a form that cells can use, such as
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). Mitochondrial DNA is only a small portion of the DNA in a eukaryotic cell; most of the DNA can be found in the
cell nucleus In , the nucleus (pl. ''nuclei''; from or , meaning ''kernel'' or ''seed'') is a found in . Eukaryotes usually have a single nucleus, but a few cell types, such as mammalian s, have , and a few others including s have . The main structure ...

cell nucleus
and, in plants and algae, also in
plastid The plastid (Greek: πλαστός; plastós: formed, molded – plural plastids) is a membrane-bound organelle found in the cell Cell most often refers to: * Cell (biology), the functional basic unit of life Cell may also refer to: Closed spa ...
s such as
chloroplast A chloroplast is a type of membrane-bound organelle known as a plastid that conducts photosynthesis mostly in plant cell, plant and algae, algal cells. The photosynthetic pigment chlorophyll captures the energy from sunlight, converts it, and ...

chloroplast
s.
Human mitochondrial DNA Human mitochondrial genetics is the study of the genetics Genetics is a branch of biology concerned with the study of genes, genetic variation, and heredity in organisms.Hartl D, Jones E (2005) Though heredity had been observed for millennia ...
was the first significant part of the
human genome The human genome is a complete set of nucleic acid sequences for humans, encoded as DNA within the 23 chromosome pairs in cell nuclei and in a small DNA molecule found within individual Mitochondrial DNA, mitochondria. These are usually treated se ...

human genome
to be sequenced. This sequencing revealed that the human mtDNA includes 16,569 base pairs and encodes 13
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 1958, for which they received a No ...

protein
s. Since animal mtDNA evolves faster than nuclear genetic markers, it represents a mainstay of
phylogenetics 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 mechanisms ...

phylogenetics
and
evolutionary biology Evolutionary biology is the subfield of biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, molecular interacti ...
. It also permits an examination of the relatedness of populations, and so has become important in
anthropology Anthropology is the of ity, concerned with , , , and , in both the present and past, including . studies patterns of behaviour, while studies cultural meaning, including norms and values. studies how language influences social life. studi ...
and
biogeography Biogeography is the study of the distribution of species In biology, a species is the basic unit of biological classification, classification and a taxonomic rank of an organism, as well as a unit of biodiversity. A species is often defin ...

biogeography
.


Origin

Nuclear and mitochondrial DNA are thought to be of separate
evolution Evolution is change in the heritable Heredity, also called inheritance or biological inheritance, is the passing on of Phenotypic trait, traits from parents to their offspring; either through asexual reproduction or sexual reproduction, ...

evolution
ary origin, with the mtDNA being derived from the circular genomes of
bacteria Bacteria (; common noun bacteria, singular bacterium) are a type of biological cell The cell (from Latin ''cella'', meaning "small room") is the basic structural, functional, and biological unit of all known organisms. Cells are the sm ...

bacteria
engulfed by the early ancestors of today's eukaryotic cells. This theory is called the
endosymbiotic theory Symbiogenesis, endosymbiotic theory, or serial endosymbiotic theory, is the leading evolutionary theory of the origin of eukaryotic Eukaryotes () are organism In biology, an organism () is any organic, life, living system that fun ...

endosymbiotic theory
. In the cells of extant organisms, the vast majority of the proteins present in the mitochondria (numbering approximately 1500 different types in
mammal Mammals (from Latin Latin (, or , ) is a classical language belonging to the Italic branch of the Indo-European languages. Latin was originally spoken in the area around Rome, known as Latium. Through the power of the Roman Republ ...
s) are coded for by
nuclear DNA Nuclear DNA (nDNA), or nuclear deoxyribonucleic acid, is the DNA contained within each cell nucleus of a eukaryotic organism. It encodes for the majority of the genome in eukaryotes, with mitochondrial DNA Electron microscopy reveals mitoch ...
, but the genes for some, if not most, of them are thought to have originally been of bacterial origin, having since been transferred to the
eukaryotic Eukaryotes () are organism In biology, an organism () is any organic, life, living system that functions as an individual entity. All organisms are composed of cells (cell theory). Organisms are classified by taxonomy (biology), tax ...
nucleus during
evolution Evolution is change in the heritable Heredity, also called inheritance or biological inheritance, is the passing on of Phenotypic trait, traits from parents to their offspring; either through asexual reproduction or sexual reproduction, ...

evolution
. The reasons why mitochondria have retained some genes are debated. The existence in some species of mitochondrion-derived organelles lacking a genome suggests that complete gene loss is possible, and transferring mitochondrial genes to the nucleus has several advantages. The difficulty of targeting remotely-produced hydrophobic protein products to the mitochondrion is one hypothesis for why some genes are retained in mtDNA; colocalisation for redox regulation is another, citing the desirability of localised control over mitochondrial machinery. Recent analysis of a wide range of mtDNA genomes suggests that both these features may dictate mitochondrial gene retention.


Genome structure and diversity

Across all organisms, there are six main genome types found in mitochondrial genomes, classified by their structure (i.e. circular versus linear), size, presence of
intron An intron (for ''intragenic region'') is any nucleotide sequence A nucleic acid sequence is a succession of bases signified by a series of a set of five different letters that indicate the order of nucleotides Nucleotides are organic molecul ...

intron
s or plasmid like structures, and whether the genetic material is a singular molecule or collection of
homogeneous Homogeneity and heterogeneity are concepts often used in the sciences Science (from the Latin Latin (, or , ) is a classical language belonging to the Italic languages, Italic branch of the Indo-European languages. Latin was originall ...
or
heterogeneous Homogeneity and heterogeneity are concepts often used in the sciences Science (from the Latin Latin (, or , ) is a classical language belonging to the Italic languages, Italic branch of the Indo-European languages. Latin was originally ...
molecules. In many unicellular organisms (e.g., the
ciliate The ciliates are a group of protozoan Protozoa (singular protozoon or protozoan, plural protozoa or protozoans) is an informal term for a group of single-celled eukaryote Eukaryotes () are organisms whose Cell (biology), cells have a c ...

ciliate
''
Tetrahymena ''Tetrahymena'', a unicellular 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 contiguous system t ...

Tetrahymena
'' and the green alga ''
Chlamydomonas reinhardtii ''Chlamydomonas reinhardtii'' is a single-cell green alga about 10 micrometre The micrometre ( international spelling as used by the International Bureau of Weights and Measures The International Bureau of Weights and Measures (fre ...
''), and in rare cases also in multicellular organisms (e.g. in some species of
Cnidaria Pacific sea nettles, ''Chrysaora fuscescens'' Cnidaria () is a phylum In biology, a phylum (; plural The plural (sometimes list of glossing abbreviations, abbreviated ), in many languages, is one of the values of the grammatical number, ...

Cnidaria
), the mtDNA is found as linearly organized
DNA Deoxyribonucleic acid (; DNA) is a molecule File:Pentacene on Ni(111) STM.jpg, A scanning tunneling microscopy image of pentacene molecules, which consist of linear chains of five carbon rings. A molecule is an electrically neutral gro ...

DNA
. Most of these linear mtDNAs possess
telomerase A conceptual diagram showing the protein component of telomerase (TERT) in grey and the RNA component (TR) in yellow Telomerase, also called terminal transferase, is a ribonucleoprotein Nucleoproteins are any protein Proteins are large biomo ...

telomerase
-independent
telomere A telomere ( or , from and ) is a region of repetitive nucleotide Nucleotides are organic molecules , CH4; is among the simplest organic compounds. In chemistry, organic compounds are generally any chemical compounds that contain carbon-h ...

telomere
s (i.e., the ends of the linear
DNA Deoxyribonucleic acid (; DNA) is a molecule File:Pentacene on Ni(111) STM.jpg, A scanning tunneling microscopy image of pentacene molecules, which consist of linear chains of five carbon rings. A molecule is an electrically neutral gro ...

DNA
) with different modes of replication, which have made them interesting objects of research because many of these unicellular organisms with linear mtDNA are known
pathogen In biology, a pathogen ( el, πάθος, "suffering", "passion" and , "producer of") in the oldest and broadest sense, is any organism that can produce disease. A pathogen may also be referred to as an infectious agent, or simply a Germ theory ...
s.


Animals

Most animals, specifically bilaterian animals, have a circular mitochondrial genome.
Medusozoa Medusozoa is a clade A clade (; from grc, , ''klados'', "branch"), also known as a monophyletic group or natural group, is a group of organisms that are monophyly, monophyletic—that is, composed of a common ancestor and all its lineage (e ...

Medusozoa
and calcarea clades however have species with linear mitochondrial chromosomes. In terms of base pairs, the anemone ''Isarachnanthus nocturnus'' has the largest mitochondrial genome of any animal at 80,923 bp. In February 2020, a jellyfish-related parasite – '' Henneguya salminicola'' – was discovered that lacks mitochondrial genome but retains structures deemed mitochondrion-related organelles. Moreover, nuclear DNA genes involved in aerobic respiration and in mitochondrial DNA replication and transcription were either absent or present only as pseudogenes. This is the first multicellular organism known to have this absence of aerobic respiration and lives completely free of oxygen dependency.


Plants and fungi

There are three different mitochondrial genome types found in plants and fungi. The first type is a circular genome that has introns (type 2) and may range from 19 to 1000 kbp in length. The second genome type is a circular genome (about 20–1000 kbp) that also has a plasmid-like structure (1 kb) (type 3). The final genome type that can be found in plants and fungi is a linear genome made up of homogeneous DNA molecules (type 5). Great variation in mtDNA gene content and size exists among fungi and plants, although there appears to be a core subset of genes that are present in all eukaryotes (except for the few that have no mitochondria at all).In Fungi, however, there is no single gene shared among all mitogenomes. Some plant species have enormous mitochondrial genomes, with '''' mtDNA containing as many as 11,300,000 base pairs. Surprisingly, even those huge mtDNAs contain the same number and kinds of genes as related plants with much smaller mtDNAs. The genome of the mitochondrion of the cucumber (''
Cucumis sativus Cucumber (''Cucumis sativus'') is a widely-cultivated creeping vine plant in the ''Cucurbitaceae'' gourd family that bears wikt:Special:Search/cucumiform, cucumiform Fruit, fruits, which are used as vegetables.
'') consists of three circular chromosomes (lengths 1556, 84 and 45 kilobases), which are entirely or largely autonomous with regard to their .


Protists

Protists contain the most diverse mitochondrial genomes, with five different types found in this kingdom. Type 2, type 3 and type 5 mentioned in the plant and fungal genomes also exist in some protists, as do two unique genome types. One of these unique types is a heterogeneous collection of circular DNA molecules (type 4) while the other is a heterogeneous collection of linear molecules (type 6). Genome types 4 and 6 each range from 1–200 kbp in size. The smallest mitochondrial genome sequenced to date is the 5,967 bp mtDNA of the parasite ''
Plasmodium falciparum ''Plasmodium falciparum'' is a unicellular 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 ...

Plasmodium falciparum
''. Endosymbiotic gene transfer, the process by which genes that were coded in the mitochondrial genome are transferred to the cell's main genome, likely explains why more complex organisms such as humans have smaller mitochondrial genomes than simpler organisms such as protists.


Replication

Mitochondrial DNA is replicated by the
DNA polymerase A DNA polymerase is a member of a family of enzyme Enzymes () are s that act as s (biocatalysts). Catalysts accelerate . The molecules upon which enzymes may act are called , and the enzyme converts the substrates into different molecules ...

DNA polymerase
gamma complex which is composed of a 140 kDa catalytic DNA polymerase encoded by the ''
POLG DNA polymerase subunit gamma (POLG or POLG1) is an enzyme Enzymes () are protein Proteins are large s and s that comprise one or more long chains of . Proteins perform a vast array of functions within organisms, including , , , provi ...
'' gene and two 55 kDa accessory subunits encoded by the ''
POLG2 DNA polymerase subunit gamma-2, mitochondrial is a protein that in humans is encoded by the ''POLG2'' gene. The ''POLG2'' gene encodes a 55 kDa accessory subunit protein that imparts high processivity and salt tolerance to the catalytic subunit of ...
'' gene. The replisome machinery is formed by DNA polymerase,
TWINKLE Twinkle may refer to: * Twinkling Twinkling, also called scintillation, is a generic term for variations in apparent brightness, colour Color (American English American English (AmE, AE, AmEng, USEng, en-US), sometimes called U ...
and mitochondrial SSB proteins.
TWINKLE Twinkle may refer to: * Twinkling Twinkling, also called scintillation, is a generic term for variations in apparent brightness, colour Color (American English American English (AmE, AE, AmEng, USEng, en-US), sometimes called U ...
is a
helicase Helicases are a class of enzyme Enzymes () are s that act as s (biocatalysts). Catalysts accelerate . The molecules upon which enzymes may act are called , and the enzyme converts the substrates into different molecules known as . Almost ...

helicase
, which unwinds short stretches of dsDNA in the 5' to 3' direction. All these polypeptides are encoded in the nuclear genome. During
embryogenesis An embryo is the early stage of development of a . In general, in s that , embryonic development is the part of the life cycle that begins just after and continues through the formation of body structures, such as tissues and organs. Each embr ...

embryogenesis
, replication of mtDNA is strictly down-regulated from the fertilized oocyte through the preimplantation embryo. The resulting reduction in per-cell copy number of mtDNA plays a role in the mitochondrial bottleneck, exploiting cell-to-cell variability to ameliorate the inheritance of damaging mutations. According to Justin St. John and colleagues, "At the
blastocyst The blastocyst is a structure formed in the early development of mammal Mammals (from Latin Latin (, or , ) is a classical language belonging to the Italic branch of the Indo-European languages. Latin was originally spoken in th ...

blastocyst
stage, the onset of mtDNA replication is specific to the cells of the
trophectoderm Trophoblasts (from Greek Greek may refer to: Greece Anything of, from, or related to Greece Greece ( el, Ελλάδα, , ), officially the Hellenic Republic, is a country located in Southeast Europe. Its population is approximately 10.7 mil ...
. In contrast, the cells of the
inner cell mass In early embryogenesis of most eutherian mammals, the inner cell mass (ICM; also known as the embryoblast or pluriblast) is the mass of cells inside the primordial embryo that will eventually give rise to the definitive structures of the fetus. T ...
restrict mtDNA replication until they receive the signals to differentiate to specific cell types."


Genes on the human mtDNA and their transcription

The two strands of the human mitochondrial DNA are distinguished as the heavy strand and the light strand. The heavy strand is rich in guanine and encodes 12 subunits of the oxidative phosphorylation system, two ribosomal RNAs (12S and 16S), and 14 tRNAs. The light strand encodes one subunit, and 8 tRNAs. So, altogether mtDNA encodes for two rRNAs, 22 tRNAs, and 13 proteins subunits, all of which are involved in the oxidative phosphorylation process.
The complete sequence of the human mitochondrial DNA in graphic form
Between most (but not all) protein-coding regions, tRNAs are present (see the human mitochondrial genome map). During transcription, the tRNAs acquire their characteristic L-shape that gets recognized and cleaved by specific enzymes. With the mitochondrial RNA processing, individual mRNA, rRNA, and tRNA sequences are released from the primary transcript. Folded tRNAs therefore act as secondary structure punctuations.


Regulation of transcription

The promoters for the initiation of the transcription of the heavy and light strands are located in the main non-coding region of the mtDNA called the displacement loop, the D-loop. There is evidence that the transcription of the mitochondrial rRNAs is regulated by the heavy-strand promoter 1 (HSP1), and the transcription of the polycistronic transcripts coding for the protein subunits are regulated by HSP2. Measurement of the levels of the mtDNA-encoded RNAs in bovine tissues has shown that there are major differences in the expression of the mitochondrial RNAs relative to total tissue RNA. Among the 12 tissues examined the highest level of expression was observed in heart, followed by brain and steroidogenic tissue samples. As demonstrated by the effect of the trophic hormone
ACTH Adrenocorticotropic hormone (ACTH; also adrenocorticotropin, corticotropin) is a polypeptide Peptides (from Greek language Greek (modern , romanized: ''Elliniká'', Ancient Greek, ancient , ''Hellēnikḗ'') is an independent branch of the ...
on adrenal cortex cells, the expression of the mitochondrial genes may be strongly regulated by external factors, apparently to enhance the synthesis of mitochondrial proteins necessary for energy production. Interestingly, while the expression of protein-encoding genes was stimulated by ACTH, the levels of the mitochondrial 16S rRNA showed no significant change.


Mitochondrial inheritance

In most
multicellular organisms Multicellular organisms 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 "Out ...
, mtDNA is inherited from the mother (maternally inherited). Mechanisms for this include simple dilution (an egg contains on average 200,000 mtDNA molecules, whereas a healthy human
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 ...

sperm
has been reported to contain on average 5 molecules), degradation of sperm mtDNA in the male genital tract and in the fertilized egg; and, at least in a few organisms, failure of sperm mtDNA to enter the egg. Whatever the mechanism, this single parent ( uniparental inheritance) pattern of mtDNA inheritance is found in most animals, most plants and also in fungi. In a study published in 2018, human babies were reported to inherit mtDNA from both their fathers and their mothers resulting in mtDNA
heteroplasmy Heteroplasmy is the presence of more than one type of organellar genome ( mitochondrial DNA or plastid DNA) within a cell or individual. It is an important factor in considering the severity of mitochondrial diseases. Because most eukaryotic ce ...
.


Female inheritance

In
sexual reproduction Sexual reproduction is a type of reproduction Reproduction (or procreation or breeding) is the biological process Biological processes are those processes that are vital for an organism In biology, an organism (from Ancient Greek, ...
, mitochondria are normally inherited exclusively from the mother; the mitochondria in mammalian sperm are usually destroyed by the egg cell after fertilization. Also, mitochondria are only in the sperm tail, which is used for propelling the sperm cells and sometimes the tail is lost during fertilization. In 1999 it was reported that paternal sperm mitochondria (containing mtDNA) are marked with
ubiquitin Ubiquitin is a small (8.6 ) found in most tissues of organisms, i.e., it is found . It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 1980s. Four genes in the code for ubiquitin: , , and . ...
to select them for later destruction inside the
embryo An embryo is the early stage of development of a multicellular organism A multicellular organism is an organism In biology, an organism () is any organic, life, living system that functions as an individual entity. All organisms ar ...

embryo
. Some ''
in vitro ''In vitro'' (meaning in glass, or ''in the glass'') studies Study or studies may refer to: General * Education **Higher education * Clinical trial * Experiment * Observational study * Research * Study skills, abilities and approaches applie ...

in vitro
'' fertilization techniques, particularly injecting a sperm into an
oocyte An oocyte (, ), oöcyte, ovocyte, or rarely ocyte, is a female gametocyte A gametocyte is a eukaryotic Eukaryotes () are organism In biology, an organism (from Ancient Greek, Greek: ὀργανισμός, ''organismos'') is any indiv ...
, may interfere with this. The fact that mitochondrial DNA is mostly maternally inherited enables
genealogical Genealogy (from el, γενεαλογία ' "the making of a pedigree") is the study of families, family history, and the tracing of their lineages. Genealogists use oral interviews, historical records, genetic analysis, and other records to ob ...
researchers to trace maternal lineage far back in time. ( Y-chromosomal DNA, paternally inherited, is used in an analogous way to determine the
patrilineal Patrilineality, also known as the male line, the spear side or agnatic kinship, is a common kinship In , kinship is the web of social relationships that form an important part of the lives of all humans in all societies, although its exact ...
history.) This is usually accomplished on
human mitochondrial DNA Human mitochondrial genetics is the study of the genetics Genetics is a branch of biology concerned with the study of genes, genetic variation, and heredity in organisms.Hartl D, Jones E (2005) Though heredity had been observed for millennia ...
by sequencing the hypervariable control regions (HVR1 or HVR2), and sometimes the complete molecule of the mitochondrial DNA, as a
genealogical DNA test A genealogical DNA test is a DNA The structure of part of a DNA double helix Deoxyribonucleic acid (; DNA) is a molecule File:Pentacene on Ni(111) STM.jpg, A scanning tunneling microscopy image of pentacene molecules, which consist o ...
. HVR1, for example, consists of about 440 base pairs. These 440 base pairs are compared to the same regions of other individuals (either specific people or subjects in a database) to determine maternal lineage. Most often, the comparison is made with the revised
Cambridge Reference Sequence The Cambridge Reference Sequence (CRS) for human Humans (''Homo sapiens'') are the most populous and widespread species of primates, characterized by bipedality, opposable thumbs, hairlessness, and intelligence allowing the use of culture, ...
. Vilà ''et al.'' have published studies tracing the matrilineal descent of domestic dogs from wolves. The concept of the
Mitochondrial Eve In human genetics Human genetics is the study of inheritance as it occurs in human beings. Human genetics encompasses a variety of overlapping fields including: classical genetics, cytogenetics, molecular genetics Molecular genetics is ...
is based on the same type of analysis, attempting to discover the origin of
human Humans (''Homo sapiens'') are the most abundant and widespread species In biology, a species is the basic unit of biological classification, classification and a taxonomic rank of an organism, as well as a unit of biodiversity. A speci ...

human
ity by tracking the lineage back in time.


The mitochondrial bottleneck

Entities subject to uniparental inheritance and with little to no recombination may be expected to be subject to
Muller's ratchet In evolution Evolution is change in the Heredity, heritable Phenotypic trait, characteristics of biological populations over successive generations. These characteristics are the Gene expression, expressions of genes that are passed on from pa ...
, the accumulation of deleterious mutations until functionality is lost. Animal populations of mitochondria avoid this through a developmental process known as the . The bottleneck exploits random 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 in which different cells have different mutant loads. Cell-level selection may then act to remove those cells with more mutant mtDNA, leading to a stabilisation 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 the random partitioning of mtDNAs at cell divisions and the random turnover of mtDNA molecules within the cell.


Male inheritance

Male mitochondrial DNA inheritance has been discovered in
Plymouth Rock chicken The Plymouth Rock is an American list of chicken breeds, breed of domestic chicken. It was first seen in Massachusetts in the nineteenth century, and for much of the early twentieth century was the most popular chicken breed in the United State ...

Plymouth Rock chicken
s. Evidence supports rare instances of male mitochondrial inheritance in some mammals as well. Specifically, documented occurrences exist for mice, where the male-inherited mitochondria were subsequently rejected. It has also been found in sheep, and in cloned cattle. Rare cases of male mitochondrial inheritance have been documented in humans. Although many of these cases involve cloned embryos or subsequent rejection of the paternal mitochondria, others document ''
in vivo Studies Study or studies may refer to: General * Education **Higher education * Clinical trial * Experiment * Observational study * Research * Study skills, abilities and approaches applied to learning Other * Study (art), a drawing or series ...
'' inheritance and persistence under lab conditions. Doubly uniparental inheritance of mtDNA is observed in bivalve mollusks. In those species, females have only one type of mtDNA (F), whereas males have F type mtDNA in their somatic cells, but M type of mtDNA (which can be as much as 30% divergent) in
germline 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 mechanisms ...
cells. Paternally inherited mitochondria have additionally been reported in some insects such as
fruit flies Fruit fly may refer to: Organisms * Drosophilidae, a family of smaller flies, including: ** ''Drosophila'', the genus of small fruit flies and vinegar flies ** ''Drosophila melanogaster'' or common fruit fly, an important model organism in modern b ...

fruit flies
,
honeybee A honey bee (also spelled honeybee) is a eusocial flying insect within the genus Genus (plural genera) is a taxonomic rank Taxonomy (general) is the practice and science of classification of things or concepts, including the principles t ...

honeybee
s, and
periodical cicadas ''Magicicada'' is the genus of the 13-year and 17-year periodical cicadas of eastern North America, consisting of seven species. Although they are sometimes called "locusts", this is a misnomer, as cicadas belong to the taxonomic order Hemiptera ...
.


Mitochondrial donation

An IVF technique known as mitochondrial donation or mitochondrial replacement therapy (MRT) results in offspring containing mtDNA from a donor female, and nuclear DNA from the mother and father. In the spindle transfer procedure, the nucleus of an egg is inserted into the cytoplasm of an egg from a donor female which has had its nucleus removed, but still contains the donor female's mtDNA. The composite egg is then fertilized with the male's sperm. The procedure is used when a woman with genetically defective mitochondria wishes to procreate and produce offspring with healthy mitochondria. The first known child to be born as a result of mitochondrial donation was a boy born to a Jordanian couple in Mexico on 6 April 2016.


Mutations and disease


Susceptibility

The concept that mtDNA is particularly susceptible to
reactive oxygen species Reactive oxygen species (ROS) are highly Reactivity (chemistry), reactive chemicals formed from O2. Examples of ROS include peroxides, superoxide, hydroxyl radical, singlet oxygen, and alpha-oxygen. The reduction of molecular oxygen (O2) produce ...
generated by the respiratory chain due to its proximity remains controversial. mtDNA does not accumulate any more oxidative base damage than nuclear DNA. It has been reported that at least some types of oxidative DNA damage are repaired more efficiently in mitochondria than they are in the nucleus. mtDNA is packaged with proteins which appear to be as protective as proteins of the nuclear chromatin. Moreover, mitochondria evolved a unique mechanism which maintains mtDNA integrity through degradation of excessively damaged genomes followed by replication of intact/repaired mtDNA. This mechanism is not present in the nucleus and is enabled by multiple copies of mtDNA present in mitochondria. The outcome of mutation in mtDNA may be an alteration in the coding instructions for some proteins, which may have an effect on organism metabolism and/or fitness.


Genetic illness

Mutations of mitochondrial DNA can lead to a number of illnesses including
exercise intolerance Exercise intolerance is a condition of inability or decreased ability to perform physical exercise Exercise is any bodily activity that enhances or maintains physical fitness Physical fitness is a state of health Health is a state of ...
and
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 ...
(KSS), which causes a person to lose full function of heart, eye, and muscle movements. Some evidence suggests that they might be major contributors to the aging process and age-associated pathologies. Particularly in the context of disease, the proportion of mutant mtDNA molecules in a cell is termed
heteroplasmy Heteroplasmy is the presence of more than one type of organellar genome ( mitochondrial DNA or plastid DNA) within a cell or individual. It is an important factor in considering the severity of mitochondrial diseases. Because most eukaryotic ce ...
. The within-cell and between-cell distributions of heteroplasmy dictate the onset and severity of disease and are influenced by complicated
stochastic processes In probability theory Probability theory is the branch of mathematics Mathematics (from Greek: ) includes the study of such topics as numbers (arithmetic and number theory), formulas and related structures (algebra), shapes and spaces ...
within the cell and during development. Mutations in mitochondrial tRNAs can be responsible for severe diseases like the MELAS and MERRF syndromes. Mutations in nuclear genes that encode proteins that mitochondria use can also contribute to mitochondrial diseases. These diseases do not follow mitochondrial inheritance patterns, but instead follow Mendelian inheritance patterns.


Use in disease diagnosis

Recently a mutation in mtDNA has been used to help diagnose prostate cancer in patients with negative prostate biopsy. mtDNA alterations can be detected in the bio-fluids of patients with cancer.


Relationship with aging

Though the idea is controversial, some evidence suggests a link between aging and mitochondrial genome dysfunction. In essence, mutations in mtDNA upset a careful balance of
reactive oxygen species Reactive oxygen species (ROS) are highly Reactivity (chemistry), reactive chemicals formed from O2. Examples of ROS include peroxides, superoxide, hydroxyl radical, singlet oxygen, and alpha-oxygen. The reduction of molecular oxygen (O2) produce ...
(ROS) production and enzymatic ROS scavenging (by enzymes like
superoxide dismutase Superoxide dismutase (SOD, ) is an enzyme that alternately catalyzes the dismutation (or partitioning) of the superoxide () radical (chemistry), radical into ordinary molecular oxygen (O2) and hydrogen peroxide (). Superoxide is produced as a by-p ...
,
catalase Catalase is a common enzyme found in nearly all living organisms exposed to oxygen (such as bacteria, plants, and animals) which catalyst, catalyzes the decomposition of hydrogen peroxide to water and oxygen. It is a very important enzyme in prote ...

catalase
,
glutathione peroxidase Glutathione (GSH) is an antioxidant in plants, animals, fungi, and some bacteria and archaea. Glutathione is capable of preventing damage to important Cell (biology), cellular components caused by reactive oxygen species such as free radicals, pe ...
and others). However, some mutations that increase ROS production (e.g., by reducing antioxidant defenses) in worms increase, rather than decrease, their longevity. Also, naked mole rats,
rodent Rodents (from Latin Latin (, or , ) is a classical language belonging to the Italic branch of the Indo-European languages. Latin was originally spoken in the area around Rome, known as Latium. Through the power of the Roman Republi ...

rodent
s about the size of
mice A mouse, plural mice, is a small mammal Mammals (from Latin Latin (, or , ) is a classical language A classical language is a language A language is a structured system of communication Communication (from Latin ...

mice
, live about eight times longer than mice despite having reduced, compared to mice, antioxidant defenses and increased oxidative damage to biomolecules. Once, there was thought to be a positive feedback loop at work (a 'Vicious Cycle'); as mitochondrial DNA accumulates genetic damage caused by free radicals, the mitochondria lose function and leak free radicals into the
cytosol The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells Cell most often refers to: * Cell (biology), the functional basic unit of life Cell may also refer to: Closed spaces * Monastic cell, a s ...
. A decrease in mitochondrial function reduces overall metabolic efficiency. However, this concept was conclusively disproved when it was demonstrated that mice, which were genetically altered to accumulate mtDNA mutations at accelerated rate do age prematurely, but their tissues do not produce more ROS as predicted by the 'Vicious Cycle' hypothesis. Supporting a link between longevity and mitochondrial DNA, some studies have found correlations between biochemical properties of the mitochondrial DNA and the longevity of species. Extensive research is being conducted to further investigate this link and methods to combat aging. Presently,
gene therapy Gene therapy is a medical Medicine is the science Science () is a systematic enterprise that builds and organizes knowledge Knowledge is a familiarity, awareness, or understanding of someone or something, such as facts ( descri ...

gene therapy
and
nutraceutical A nutraceutical or 'bioceutical' is a pharmaceutical alternative which claims physiological benefits. In the US, "nutraceuticals" are largely unregulated, as they exist in the same category as dietary supplement A dietary supplement is a ...
supplementation are popular areas of ongoing research. Bjelakovic et al. analyzed the results of 78 studies between 1977 and 2012, involving a total of 296,707 participants, and concluded that antioxidant supplements do not reduce all-cause mortality nor extend lifespan, while some of them, such as beta carotene, vitamin E, and higher doses of vitamin A, may actually increase mortality.


Neurodegenerative diseases

Increased mt
DNA damage DNA repair is a collection of processes by which a identifies and corrects damage to the molecules that encode its . In human cells, both normal activities and environmental factors such as can cause DNA damage, resulting in tens of thousan ...
is a feature of several
neurodegenerative diseases A neurodegenerative disease is caused by the progressive loss of structure or function of neurons, in the process known as neurodegeneration. Such neuronal damage may ultimately involve cell death. Neurodegenerative diseases include amyotrophic l ...
. The brains of individuals with
Alzheimer’s disease Alzheimer's disease (AD), also referred to simply as Alzheimer's, is a neurodegenerative disease Neurodegeneration is the progressive loss of structure or function of neurons, including their death. Many neurodegenerative diseases—inc ...
have elevated levels of oxidative DNA damage in both
nuclear DNA Nuclear DNA (nDNA), or nuclear deoxyribonucleic acid, is the DNA contained within each cell nucleus of a eukaryotic organism. It encodes for the majority of the genome in eukaryotes, with mitochondrial DNA Electron microscopy reveals mitoch ...
and mtDNA, but the mtDNA has approximately 10-fold higher levels than nuclear DNA. It has been proposed that aged
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
is the critical factor in the origin of neurodegeneration in Alzheimer’s disease. In
Huntington’s disease Huntington's disease (HD), also known as Huntington's chorea, is a neurodegenerative disease that is mostly Genetic disorder#Autosomal dominant, inherited. The earliest symptoms are often subtle problems with mood or mental abilities. A gener ...
, mutant
huntingtin protein Huntingtin (Htt), is the protein Proteins are large biomolecules or macromolecules that are comprised of one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, includ ...
causes mitochondrial dysfunction involving inhibition of
mitochondrial A mitochondrion (, plural mitochondria) is a double 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 ide ...

mitochondrial
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 ...

electron transport
, higher levels of
reactive oxygen species Reactive oxygen species (ROS) are highly Reactivity (chemistry), reactive chemicals formed from O2. Examples of ROS include peroxides, superoxide, hydroxyl radical, singlet oxygen, and alpha-oxygen. The reduction of molecular oxygen (O2) produce ...
and increased
oxidative stress Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species Reactive oxygen species (ROS) are highly chemicals formed from O2. Examples of ROS include s, , , , and . The reduction of molecular oxygen ...
. Mutant huntingtin protein promotes oxidative damage to mtDNA, as well as nuclear DNA, that may contribute to Huntington’s disease
pathology Pathology is the study of the causesCauses, or causality, is the relationship between one event and another. It may also refer to: * Causes (band), an indie band based in the Netherlands * Causes (company), an online company See also * Cau ...
. The
DNA oxidation DNA oxidation is the process of oxidative damage of deoxyribonucleic acid File:DNA animation.gif, The structure of part of a DNA double helix Deoxyribonucleic acid (; DNA) is a molecule composed of two polynucleotide chains that coil aroun ...
product (8-oxoG) is a well-established marker of oxidative DNA damage. In persons with
amyotrophic lateral sclerosis Amyotrophic lateral sclerosis (ALS; also known as Lou Gehrig's disease in Canada Canada is a country in the northern part of North America. Its Provinces and territories of Canada, ten provinces and three territories extend from the A ...
(ALS), the enzymes that normally repair 8-oxoG DNA damages in the mtDNA of spinal
motor neuron A motor neuron (or motoneuron or efferent neuron) is a neuron A neuron or nerve cell is an electrically excitable cell Cell most often refers to: * Cell (biology), the functional basic unit of life Cell may also refer to: Closed spaces * ...
s are impaired. Thus oxidative damage to mtDNA of motor neurons may be a significant factor in the
etiology Etiology (pronounced ; alternatively: aetiology or ætiology) is the study of causation or origination. The word is derived from the Greek#REDIRECT Greek Greek may refer to: Greece Anything of, from, or related to Greece Greece ( el, Ε ...
of ALS.


Correlation of the mtDNA base composition with animal life spans

Over the past decade, an Israeli research group led by Professor Vadim Fraifeld has shown that strong and significant
correlations In statistics Statistics is the discipline that concerns the collection, organization, analysis, interpretation, and presentation of data. In applying statistics to a scientific, industrial, or social problem, it is conventional to begin wi ...
exist between the mtDNA base composition and animal species-specific maximum life spans. As demonstrated in their work, higher mtDNA
guanine Guanine () (symbol A symbol is a mark, sign, or word In linguistics, a word of a spoken language can be defined as the smallest sequence of phonemes that can be uttered in isolation with semantic, objective or pragmatics, practical me ...

guanine
+
cytosine Cytosine () (symbol A symbol is a mark, sign, or word In linguistics, a word of a spoken language can be defined as the smallest sequence of phonemes that can be uttered in isolation with semantic, objective or pragmatics, practical ...

cytosine
content ( GC%) strongly associates with longer
maximum life span Maximum life span (or, for humans Humans (''Homo sapiens'') are the most populous and widespread species In biology, a species is the basic unit of biological classification, classification and a taxonomic rank of an organism, as well as ...
s across animal species. An additional observation is that the mtDNA GC% correlation with the maximum life spans is independent of the well-known correlation between animal species metabolic rate and maximum life spans. The mtDNA GC% and resting metabolic rate explain the differences in animal species maximum life spans in a multiplicative manner (i.e., species maximum life span = their mtDNA GC% * metabolic rate). To support the scientific community in carrying out comparative analyses between mtDNA features and longevity across animals, a dedicated database was built name
MitoAge


Relationship with non-B (non-canonical) DNA structures

Deletion breakpoints frequently occur within or near regions showing non-canonical (non-B) conformations, namely hairpins, cruciforms and cloverleaf-like elements. Moreover, there is data supporting the involvement of helix-distorting intrinsically curved regions and long G-tetrads in eliciting instability events. In addition, higher breakpoint densities were consistently observed within GC-skewed regions and in the close vicinity of the degenerate sequence motif YMMYMNNMMHM.


Use in forensics

Unlike nuclear DNA, which is inherited from both parents and in which genes are rearranged in the process of recombination, there is usually no change in mtDNA from parent to offspring. Although mtDNA also recombines, it does so with copies of itself within the same mitochondrion. Because of this and because the
mutation rate In genetics Genetics is a branch of biology concerned with the study of genes, genetic variation, and heredity in organisms.Hartl D, Jones E (2005) Though heredity had been observed for millennia, Gregor Mendel, Moravia, Moravian scientist an ...
of animal mtDNA is higher than that of nuclear DNA, mtDNA is a powerful tool for tracking ancestry through females (
matrilineage Matrilineality is the tracing of kinship In anthropology, kinship is the web of social relationships that form an important part of the lives of all humans in all societies, although its exact meanings even within this discipline are often d ...
) and has been used in this role to track the ancestry of many species back hundreds of generations. The rapid mutation rate (in animals) makes mtDNA useful for assessing genetic relationships of individuals or groups within a species and also for identifying and quantifying the phylogeny (evolutionary relationships; see
phylogenetics 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 mechanisms ...

phylogenetics
) among different species. To do this, biologists determine and then compare the mtDNA sequences from different individuals or species. Data from the comparisons is used to construct a network of relationships among the sequences, which provides an estimate of the relationships among the individuals or species from which the mtDNAs were taken. mtDNA can be used to estimate the relationship between both closely related and distantly related species. Due to the high mutation rate of mtDNA in animals, the 3rd positions of the codons change relatively rapidly, and thus provide information about the genetic distances among closely related individuals or species. On the other hand, the substitution rate of mt-proteins is very low, thus amino acid changes accumulate slowly (with corresponding slow changes at 1st and 2nd codon positions) and thus they provide information about the genetic distances of distantly related species. Statistical models that treat substitution rates among codon positions separately, can thus be used to simultaneously estimate phylogenies that contain both closely and distantly related species Mitochondrial DNA was admitted into evidence for the first time ever in a United States courtroom in 1996 during ''State of Tennessee v. Paul Ware''. In the 1998 United States court case of Commonwealth of Pennsylvania v. Patricia Lynne Rorrer, mitochondrial DNA was admitted into evidence in the State of Pennsylvania for the first time. The case was featured in episode 55 of season 5 of the true crime drama series Forensic Files (season 5). Mitochondrial DNA was first admitted into evidence in California, United States, in the successful prosecution of David Westerfield for the 2002 kidnapping and murder of 7-year-old Murder of Danielle van Dam, Danielle van Dam in San Diego: it was used for both human and dog identification. This was the first trial in the U.S. to admit canine DNA. The remains of Richard III of England, King Richard III, who died in 1485, were identified by comparing his mtDNA with that of two matrilineal descendants of his sister who were alive in 2013, 527 years after he died.


Use in evolutionary biology and systematic biology

mtDNA is conserved across eukaryotic organism given the critical role of mitochondria in cellular respiration. However, due to less efficient DNA repair (compared to nuclear DNA) it has a relatively high mutation rate (but slow compared to other DNA regions such as microsatellites) which makes it useful for studying the evolutionary relationships—phylogeny—of organisms. Biologists can determine and then compare mtDNA sequences among different species and use the comparisons to build an evolutionary tree for the species examined. For instance, while most nuclear genes are nearly identical between humans and chimpanzees, their mitochondrial genomes are 9.8% different. Human and Western gorilla, gorilla mitochondrial genomes are 11.8% different, suggesting that we may be more similar to chimps than gorillas.


History

Mitochondrial DNA was discovered in the 1960s by Margit M. K. Nass and Sylvan Nass by Electron microscope, electron microscopy as DNase-sensitive threads inside mitochondria, and by Ellen Haslbrunner, Hans Tuppy and Gottfried Schatz by biochemical assays on highly purified mitochondrial fractions.


Mitochondrial sequence databases

Several specialized databases have been founded to collect mitochondrial genome sequences and other information. Although most of them focus on sequence data, some of them include phylogenetic or functional information. * AmtDB: a database of ancient human mitochondrial genomes. * InterMitoBase: an annotated database and analysis platform of protein-protein interactions for human mitochondria. (apparently last updated in 2010, but still available) * MitoBreak: the mitochondrial DNA breakpoints database. * MitoFish and MitoAnnotator: a mitochondrial genome database of fish. See also Cawthorn et al. * Mitome: a database for comparative mitochondrial genomics in metazoan animals (no longer available) * MitoRes: a resource of nuclear-encoded mitochondrial genes and their products in metazoa (apparently no longer being updated) * MitoSatPlant: Mitochondrial microsatellites database of viridiplantae. * MitoZoa 2.0: a database for comparative and evolutionary analyses of mitochondrial genomes in Metazoa. (no longer available)


MtDNA-phenotype association databases

Genome-wide association study, Genome-wide association studies can reveal associations of mtDNA genes and their mutations with phenotypes including Longevity, lifespan and disease risks. In 2021, the largest, UK Biobank-based, genome-wide association study of mitochondrial DNA unveiled 260 new associations with phenotypes including Longevity, lifespan and disease risks for e.g. type 2 diabetes.


Mitochondrial mutation databases

Several specialized databases exist that report polymorphisms and mutations in the human mitochondrial DNA, together with the assessment of their pathogenicity. * MitImpact: A collection of pre-computed pathogenicity predictions for all nucleotide changes that cause non-synonymous substitutions in human mitochondrial protein coding gene

* MITOMAP: A compendium of polymorphisms and mutations in human mitochondrial DN


See also


References


External links

* {{Portal bar, Biology, Evolutionary biology DNA Mitochondrial genetics Senescence