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Mitochondrial DNA (mtDNA and mDNA) is the
DNA Deoxyribonucleic acid (; DNA) is a polymer composed of two polynucleotide chains that coil around each other to form a double helix. The polymer carries genetic instructions for the development, functioning, growth and reproduction of al ...
located in the
mitochondria A mitochondrion () is an organelle found in the cells of most eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is us ...
organelle In cell biology, an organelle is a specialized subunit, usually within a cell (biology), cell, that has a specific function. The name ''organelle'' comes from the idea that these structures are parts of cells, as Organ (anatomy), organs are to th ...
s in a
eukaryotic The eukaryotes ( ) constitute the Domain (biology), domain of Eukaryota or Eukarya, organisms whose Cell (biology), cells have a membrane-bound cell nucleus, nucleus. All animals, plants, Fungus, fungi, seaweeds, and many unicellular organisms ...
cell that converts chemical energy from food into
adenosine triphosphate Adenosine triphosphate (ATP) is a nucleoside triphosphate that provides energy to drive and support many processes in living cell (biology), cells, such as muscle contraction, nerve impulse propagation, and chemical synthesis. Found in all known ...
(ATP). Mitochondrial DNA is a small portion of the DNA contained in a eukaryotic cell; most of the DNA is in the
cell nucleus The cell nucleus (; : nuclei) is a membrane-bound organelle found in eukaryote, eukaryotic cell (biology), cells. Eukaryotic cells usually have a single nucleus, but a few cell types, such as mammalian red blood cells, have #Anucleated_cells, ...
, and, in plants and algae, the DNA also is found in
plastid A plastid is a membrane-bound organelle found in the Cell (biology), cells of plants, algae, and some other eukaryotic organisms. Plastids are considered to be intracellular endosymbiotic cyanobacteria. Examples of plastids include chloroplasts ...
s, such as
chloroplast A chloroplast () is a type of membrane-bound organelle, organelle known as a plastid that conducts photosynthesis mostly in plant cell, plant and algae, algal cells. Chloroplasts have a high concentration of chlorophyll pigments which captur ...
s. Mitochondrial DNA is responsible for coding of 13 essential subunits of the complex
oxidative phosphorylation Oxidative phosphorylation(UK , US : or electron transport-linked phosphorylation or terminal oxidation, is the metabolic pathway in which Cell (biology), cells use enzymes to Redox, oxidize nutrients, thereby releasing chemical energy in order ...
(OXPHOS) system which has a role in cellular energy conversion.
Human mitochondrial DNA Human mitochondrial genetics is the study of the genetics of human mitochondrial DNA (the DNA contained in human mitochondria). The human mitochondrial genome is the entirety of hereditary information contained in human mitochondria. Mitochondr ...
was the first significant part of the
human genome The human genome is a complete set of nucleic acid sequences for humans, encoded as the DNA within each of the 23 distinct chromosomes in the cell nucleus. A small DNA molecule is found within individual Mitochondrial DNA, mitochondria. These ar ...
to be sequenced. This sequencing revealed that human mtDNA has 16,569
base pair A base pair (bp) is a fundamental unit of double-stranded nucleic acids consisting of two nucleobases bound to each other by hydrogen bonds. They form the building blocks of the DNA double helix and contribute to the folded structure of both DNA ...
s and encodes 13
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
s. As in other vertebrates, the human mitochondrial
genetic code Genetic code is a set of rules used by living cell (biology), cells to Translation (biology), translate information encoded within genetic material (DNA or RNA sequences of nucleotide triplets or codons) into proteins. Translation is accomplished ...
differs slightly from nuclear DNA. Since animal mtDNA evolves faster than nuclear genetic markers, it represents a mainstay of
phylogenetics In biology, phylogenetics () is the study of the evolutionary history of life using observable characteristics of organisms (or genes), which is known as phylogenetic inference. It infers the relationship among organisms based on empirical dat ...
and
evolutionary biology Evolutionary biology is the subfield of biology that studies the evolutionary processes such as natural selection, common descent, and speciation that produced the diversity of life on Earth. In the 1930s, the discipline of evolutionary biolo ...
. It also permits tracing the relationships of populations, and so has become important in
anthropology Anthropology is the scientific study of humanity, concerned with human behavior, human biology, cultures, society, societies, and linguistics, in both the present and past, including archaic humans. Social anthropology studies patterns of behav ...
and
biogeography Biogeography is the study of the species distribution, distribution of species and ecosystems in geography, geographic space and through evolutionary history of life, geological time. Organisms and biological community (ecology), communities o ...
.


Origin

Nuclear and mitochondrial DNA are thought to have separate
evolution Evolution is the change in the heritable Phenotypic trait, characteristics of biological populations over successive generations. It occurs when evolutionary processes such as natural selection and genetic drift act on genetic variation, re ...
ary origins, with the mtDNA derived from the circular genomes of
bacteria Bacteria (; : bacterium) are ubiquitous, mostly free-living organisms often consisting of one Cell (biology), biological cell. They constitute a large domain (biology), domain of Prokaryote, prokaryotic microorganisms. Typically a few micr ...
engulfed by the ancestors of modern 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 cells from prokaryotic organisms. The theory holds that mitochondria, plastids such as chloroplasts, and possibl ...
. In the cells of extant organisms, the vast majority of the proteins in the mitochondria (numbering approximately 1500 different types in
mammal A mammal () is a vertebrate animal of the Class (biology), class Mammalia (). Mammals are characterised by the presence of milk-producing mammary glands for feeding their young, a broad neocortex region of the brain, fur or hair, and three ...
s) are coded 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 and plastid DNA coding for the rest. ...
, but the genes for some, if not most, of them are thought to be of bacterial origin, having been transferred to the
eukaryotic The eukaryotes ( ) constitute the Domain (biology), domain of Eukaryota or Eukarya, organisms whose Cell (biology), cells have a membrane-bound cell nucleus, nucleus. All animals, plants, Fungus, fungi, seaweeds, and many unicellular organisms ...
nucleus during
evolution Evolution is the change in the heritable Phenotypic trait, characteristics of biological populations over successive generations. It occurs when evolutionary processes such as natural selection and genetic drift act on genetic variation, re ...
. The reasons 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 mitochondrial genome types, classified by structure (i.e. circular versus linear), size, presence of
intron An intron is any nucleotide sequence within a gene that is not expressed or operative in the final RNA product. The word ''intron'' is derived from the term ''intragenic region'', i.e., a region inside a gene."The notion of the cistron .e., gen ...
s or plasmid like structures, and whether the genetic material is a singular molecule or collection of
homogeneous Homogeneity and heterogeneity are concepts relating to the uniformity of a substance, process or image. A homogeneous feature is uniform in composition or character (i.e., color, shape, size, weight, height, distribution, texture, language, i ...
or
heterogeneous Homogeneity and heterogeneity are concepts relating to the uniformity of a substance, process or image. A homogeneous feature is uniform in composition or character (i.e., color, shape, size, weight, height, distribution, texture, language, i ...
molecules. In many unicellular organisms (e.g., the
ciliate The ciliates are a group of alveolates characterized by the presence of hair-like organelles called cilia, which are identical in structure to flagellum, eukaryotic flagella, but are in general shorter and present in much larger numbers, with a ...
'' Tetrahymena'' and the
green alga The green algae (: green alga) are a group of chlorophyll-containing autotrophic eukaryotes consisting of the phylum Prasinodermophyta and its unnamed sister group that contains the Chlorophyta and Charophyta/ Streptophyta. The land plants ( ...
'' Chlamydomonas reinhardtii''), and in rare cases also in multicellular organisms (e.g. in some species of
Cnidaria Cnidaria ( ) is a phylum under kingdom Animalia containing over 11,000 species of aquatic invertebrates found both in fresh water, freshwater and marine environments (predominantly the latter), including jellyfish, hydroid (zoology), hydroids, ...
), the mtDNA is linear
DNA Deoxyribonucleic acid (; DNA) is a polymer composed of two polynucleotide chains that coil around each other to form a double helix. The polymer carries genetic instructions for the development, functioning, growth and reproduction of al ...
. Most of these linear mtDNAs possess
telomerase Telomerase, also called terminal transferase, is a ribonucleoprotein that adds a species-dependent telomere repeat sequence to the 3' end of telomeres. A telomere is a region of repetitive sequences at each end of the chromosomes of most euka ...
-independent
telomere A telomere (; ) is a region of repetitive nucleotide sequences associated with specialized proteins at the ends of linear chromosomes (see #Sequences, Sequences). Telomeres are a widespread genetic feature most commonly found in eukaryotes. In ...
s (i.e., the ends of the linear
DNA Deoxyribonucleic acid (; DNA) is a polymer composed of two polynucleotide chains that coil around each other to form a double helix. The polymer carries genetic instructions for the development, functioning, growth and reproduction of al ...
) 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 (, "suffering", "passion" and , "producer of"), in the oldest and broadest sense, is any organism or agent that can produce disease. A pathogen may also be referred to as an infectious agent, or simply a Germ theory of d ...
s.


Animals

Most (
bilateria Bilateria () is a large clade of animals characterised by bilateral symmetry during embryonic development. This means their body plans are laid around a longitudinal axis with a front (or "head") and a rear (or "tail") end, as well as a left� ...
n) animals have a circular mitochondrial genome.
Medusozoa Medusozoa is a clade in the phylum Cnidaria, and is often considered a subphylum. It includes the classes Hydrozoa, Scyphozoa, Staurozoa and Box jellyfish, Cubozoa, and possibly the parasitic Polypodium (animal), Polypodiozoa. Medusozoans are dis ...
and calcarea
clade In biology, a clade (), also known as a Monophyly, monophyletic group or natural group, is a group of organisms that is composed of a common ancestor and all of its descendants. Clades are the fundamental unit of cladistics, a modern approach t ...
s however include species with linear mitochondrial chromosomes. With a few exceptions, animals have 37 genes in their mitochondrial DNA: 13 for
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
s, 22 for tRNAs, and 2 for rRNAs. Mitochondrial genomes for animals average about 16,000 base pairs in length. The anemone ''Isarachnanthus nocturnus'' has the largest mitochondrial genome of any animal at 80,923 bp. The smallest known mitochondrial genome in animals belongs to the comb jelly '' Vallicula multiformis'', which consist of 9,961 bp. In February 2020, a jellyfish-related parasite – '' Henneguya salminicola'' – was discovered that lacks a mitochondrial genome but retains structures deemed mitochondrion-related organelles. Moreover, nuclear DNA genes involved in aerobic respiration and mitochondrial DNA replication and transcription were either absent or present only as
pseudogene Pseudogenes are nonfunctional segments of DNA that resemble functional genes. Pseudogenes can be formed from both protein-coding genes and non-coding genes. In the case of protein-coding genes, most pseudogenes arise as superfluous copies of fun ...
s. This is the first multicellular organism known to have this absence of aerobic respiration and live completely free of oxygen dependency.


Plants and fungi

There are three different mitochondrial genome types 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 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 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 '' Silene conica'' 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'') consists of three circular chromosomes (lengths 1556, 84 and 45 kilobases), which are entirely or largely autonomous with regard to their replication.


Protists

Protist A protist ( ) or protoctist is any eukaryotic organism that is not an animal, land plant, or fungus. Protists do not form a natural group, or clade, but are a paraphyletic grouping of all descendants of the last eukaryotic common ancest ...
s contain the most diverse mitochondrial genomes, with five different types found in this kingdom. Type 2, type 3, and type 5 of 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 organism, unicellular protozoan parasite of humans and is the deadliest species of ''Plasmodium'' that causes malaria in humans. The parasite is transmitted through the bite of a female ''Anopheles'' mos ...
''.
Endosymbiotic An endosymbiont or endobiont is an organism that lives within the body or cells of another organism. Typically the two organisms are in a mutualistic relationship. Examples are nitrogen-fixing bacteria (called rhizobia), which live in the root ...
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

The two strands of the human mitochondrial DNA are distinguished as the heavy strand and the light strand. The regulation of mitochondrial DNA replication and transcription initiation is located in a single intergenic noncoding region (NCR). In human, the 1,100 base pairs NCR region contains three promoters of two L-strand promoters (LSP and LSP2) and one H-strand promoter (HSP). Unlike bidirectional and specific origin initiation of nuclear DNA replication, mitochondrial DNA has two strand-specific, unidirectional origins of replication of the leading H strand (OH) which located in NCR and the lagging L strand (OL) which located in the tRNA gene cluster. Mitochondrial DNA is replicated by the
DNA polymerase A DNA polymerase is a member of a family of enzymes that catalyze the synthesis of DNA molecules from nucleoside triphosphates, the molecular precursors of DNA. These enzymes are essential for DNA replication and usually work in groups to create t ...
gamma complex which is composed of a 140 kDa catalytic DNA polymerase encoded by the '' POLG'' gene and two 55 kDa accessory subunits encoded by the '' POLG2'' gene. The replisome machinery is formed by DNA polymerase,
TWINKLE Twinkle may refer to: * Twinkling, the variation of brightness of distant objects People * Twinkle (singer) (1948–2015), born Lynn Annette Ripley, English singer-songwriter * Twinkle Bajpai, Indian singer, television and film actress * Twinkl ...
and mitochondrial SSB proteins. TWINKLE is a
helicase Helicases are a class of enzymes that are vital to all organisms. Their main function is to unpack an organism's genetic material. Helicases are motor proteins that move directionally along a nucleic double helix, separating the two hybridized ...
, 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 initial stage of development for a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male ...
, 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 embryonic development of mammals. It possesses an inner cell mass (ICM) also known as the ''embryoblast'' which subsequently forms the embryo, and an outer layer of trophoblast cells called the ...
stage, the onset of mtDNA replication is specific to the cells of the
trophectoderm The trophoblast (from Greek : to feed; and : germinator) is the outer layer of cells of the blastocyst. Trophoblasts are present four days after fertilization in humans. They provide nutrients to the embryo and develop into a large part of the pl ...
. In contrast, the cells of the
inner cell mass The inner cell mass (ICM) or embryoblast (known as the pluriblast in marsupials) is a structure in the early development of an embryo. It is the mass of cells inside the blastocyst that will eventually give rise to the definitive structures of t ...
restrict mtDNA replication until they receive the
signals A signal is both the process and the result of Signal transmission, transmission of data over some transmission media, media accomplished by embedding some variation. Signals are important in multiple subject fields including signal processin ...
to differentiate to specific cell types."


DNA repair

Although several DNA repair pathways have been reported to occur in the mitochondria, currently the base excision repair pathway is the pathway most comprehensively described. Proteins that are employed in the maintenance of mitochondrial DNA are encoded by nuclear genes and translocated to the mitochondria. The
mitochondria A mitochondrion () is an organelle found in the cells of most eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is us ...
of human cells are capable of repairing
DNA Deoxyribonucleic acid (; DNA) is a polymer composed of two polynucleotide chains that coil around each other to form a double helix. The polymer carries genetic instructions for the development, functioning, growth and reproduction of al ...
base pair mismatches by a pathway that is distinct from the DNA mismatch repair pathway of the nucleus.deSouza-Pinto NC, Mason PA, Hashiguchi K, Weissman L, Tian J, Guay D, Lebel M, Stevnsner TV, Rasmussen LJ, Bohr VA. Novel DNA mismatch-repair activity involving YB-1 in human mitochondria. DNA Repair (Amst). 2009 Jun 4;8(6):704-19. doi: 10.1016/j.dnarep.2009.01.021. Epub 2009 Mar 9. PMID: 19272840; PMCID: PMC2693314. This distinct mitochondrial pathway includes the activity of the Y box binding protein 1 (designated YB-1 or YBX1), that likely acts in the mismatch binding and recognition steps of mismatch repair. DNA repair mechanisms specific to the mitochondria may reflect the proximity of the mitochondrial DNA to the oxidative phosphorylation system and consequently to the DNA-damaging reactive oxygen species formed during ATP production.


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 Guanine () (symbol G or Gua) is one of the four main nucleotide bases found in the nucleic acids DNA and RNA, the others being adenine, cytosine, and thymine ( uracil in RNA). In DNA, guanine is paired with cytosine. The guanine nucleoside ...
and encodes 12 subunits of the
oxidative phosphorylation Oxidative phosphorylation(UK , US : or electron transport-linked phosphorylation or terminal oxidation, is the metabolic pathway in which Cell (biology), cells use enzymes to Redox, oxidize nutrients, thereby releasing chemical energy in order ...
system, two
ribosomal RNA Ribosomal ribonucleic acid (rRNA) is a type of non-coding RNA which is the primary component of ribosomes, essential to all cells. rRNA is a ribozyme which carries out protein synthesis in ribosomes. Ribosomal RNA is transcribed from ribosomal ...
s (12S and 16S), and 14
transfer RNA Transfer ribonucleic acid (tRNA), formerly referred to as soluble ribonucleic acid (sRNA), is an adaptor molecule composed of RNA, typically 76 to 90 nucleotides in length (in eukaryotes). In a cell, it provides the physical link between the gene ...
s (tRNAs). The light strand encodes one subunit and 8 tRNAs. So, altogether mtDNA encodes for two rRNAs, 22 tRNAs, and 13
protein subunit In structural biology, a protein subunit is a polypeptide chain or single protein molecule that assembles (or "''coassembles''") with others to form a protein complex. Large assemblies of proteins such as viruses often use a small number of t ...
s, 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. Transcription is done by the single-subunit mitochondrial RNA polymerase (POLRMT). In association with two of accessory factors, mitochondrial transcription factor A (TFAM) and mitochondrial transcription factor B2 (TFB2M), the POLRMT complex recognizes promoters and initiates transcription. Transcription resulted in polycistronic transcripts that are processed in discrete mitochondrial RNA granules into individual mRNAs, tRNAs, and rRNAs.


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 the heart, followed by brain and steroidogenic tissue samples. As demonstrated by the effect of the trophic hormone ACTH 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 A multicellular organism is an organism that consists of more than one cell, unlike unicellular organisms. All species of animals, land plants and most fungi are multicellular, as are many algae, whereas a few organisms are partially uni- and pa ...
, 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 (: sperm or sperms) 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 ...
has been reported to contain on average 5 molecules), degradation of sperm mtDNA in the male genital tract and 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, a finding that has been rejected by other scientists.


Female inheritance

In
sexual reproduction Sexual reproduction is a type of reproduction that involves a complex life cycle in which a gamete ( haploid reproductive cells, such as a sperm or egg cell) with a single set of chromosomes combines with another gamete to produce a zygote tha ...
, 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 present solely in the midpiece, which is used for propelling the sperm cells, and sometimes the midpiece, along with 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  kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ''ubiquitously''. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 19 ...
to select them for later destruction inside the
embryo An embryo ( ) is the initial stage of development for a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male sp ...
. Some ''
in vitro ''In vitro'' (meaning ''in glass'', or ''in the glass'') Research, studies are performed with Cell (biology), cells or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in ...
'' fertilization techniques, particularly injecting a sperm into an
oocyte An oocyte (, oöcyte, or ovocyte) is a female gametocyte or germ cell involved in reproduction. In other words, it is an immature ovum, or egg cell. An oocyte is produced in a female fetus in the ovary during female gametogenesis. The female ger ...
, may interfere with this. The fact that mitochondrial DNA is mostly maternally inherited enables
genealogical Genealogy () 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 obtain information about a family and to demonstrate kin ...
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 system in which an individual's family membership derives from and is recorded through their father's lineage. It generally involves the inheritanc ...
history.) This is usually accomplished on
human mitochondrial DNA Human mitochondrial genetics is the study of the genetics of human mitochondrial DNA (the DNA contained in human mitochondria). The human mitochondrial genome is the entirety of hereditary information contained in human mitochondria. Mitochondr ...
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-based Genetic testing, genetic test used in genetic genealogy that looks at specific locations of a person's genome in order to find or verify ancestral genealogical relationships, or (with lower reliability) to ...
. 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. Vilà ''et al.'' have published studies tracing the matrilineal descent of domestic dogs from wolves. The concept of the
Mitochondrial Eve In human genetics, the Mitochondrial Eve (more technically known as the Mitochondrial-Most Recent Common Ancestor, shortened to mt-Eve or mt-MRCA) is the matrilineal most recent common ancestor (MRCA) of all living humans. In other words, she ...
is based on the same type of analysis, attempting to discover the origin of
human Humans (''Homo sapiens'') or modern humans are the most common and widespread species of primate, and the last surviving species of the genus ''Homo''. They are Hominidae, great apes characterized by their Prehistory of nakedness and clothing ...
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, the accumulation of deleterious mutations until functionality is lost. Animal populations of mitochondria avoid this through a developmental process known as the mtDNA bottleneck. 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 chickens. 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 that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, an ...
'' 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 mtDNA (which can be as much as 30% divergent) in
germline In biology and genetics, the germline is the population of a multicellular organism's cells that develop into germ cells. In other words, they are the cells that form gametes ( eggs and sperm), which can come together to form a zygote. They dif ...
cells. Paternally inherited mitochondria have additionally been reported in some insects such as fruit flies, honeybees, and periodical cicadas.


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 In chemistry and biology, reactive oxygen species (ROS) are highly Reactivity (chemistry), reactive chemicals formed from diatomic oxygen (), water, and hydrogen peroxide. Some prominent ROS are hydroperoxide (H2O2), superoxide (O2−), hydroxyl ...
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 at the normally expected level or duration for people of that age, size, sex, and muscle mass. It also includes experiences of unusually severe pos ...
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 chr ...
(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. 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 and related fields, a stochastic () or random process is a mathematical object usually defined as a family of random variables in a probability space, where the index of the family often has the interpretation of time. Stoc ...
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. mtDNA is characterized by the high rate of polymorphisms and mutations. Some of these are increasingly recognized as an important cause of human pathology such as oxidative phosphorylation (OXPHOS) disorders, maternally inherited diabetes and deafness (MIDD), Type 2 diabetes mellitus,
Neurodegenerative disease A neurodegenerative disease is caused by the progressive loss of neurons, in the process known as neurodegeneration. Neuronal damage may also ultimately result in their death. Neurodegenerative diseases include amyotrophic lateral sclerosis, mul ...
, heart failure, and cancer.


Relationship with ageing

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 In chemistry and biology, reactive oxygen species (ROS) are highly Reactivity (chemistry), reactive chemicals formed from diatomic oxygen (), water, and hydrogen peroxide. Some prominent ROS are hydroperoxide (H2O2), superoxide (O2−), hydroxyl ...
(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 () anion radical into normal molecular oxygen (O2) and hydrogen peroxide (). Superoxide is produced as a by-product of oxy ...
,
catalase Catalase is a common enzyme found in nearly all living organisms exposed to oxygen (such as bacteria, plants, and animals) which catalyzes the decomposition of hydrogen peroxide to water and oxygen. It is a very important enzyme in protecting ...
,
glutathione peroxidase Glutathione peroxidase (GPx) () is the general name of an enzyme family with peroxidase activity whose main biological role is to protect the organism from oxidative damage. The biochemical function of glutathione peroxidase is to reduce lipid ...
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 , 'to gnaw') are mammals of the Order (biology), order Rodentia ( ), which are characterized by a single pair of continuously growing incisors in each of the upper and Mandible, lower jaws. About 40% of all mammal specie ...
s about the size of
mice A mouse (: mice) is a small rodent. Characteristically, mice are known to have a pointed snout, small rounded ears, a body-length scaly tail, and a high breeding rate. The best known mouse species is the common house mouse (''Mus musculus' ...
, 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 ( intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondri ...
. 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 an accelerated rate to 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. The application of a mitochondrial-specific ROS scavenger, which lead to a significant longevity of the mice studied, suggests that mitochondria may still be well-implicated in ageing. Extensive research is being conducted to further investigate this link and methods to combat ageing. Presently,
gene therapy Gene therapy is Health technology, medical technology that aims to produce a therapeutic effect through the manipulation of gene expression or through altering the biological properties of living cells. The first attempt at modifying human DNA ...
and
nutraceutical Nutraceutical is a terminology evolved scientifically & also through marketing which is used to imply a pharmaceutical effect from plant extracts, compounds, food products which have efficacy and therapeutic influence on clinical outcomes and patien ...
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. In a recent study, it was shown that dietary restriction can reverse ageing alterations by affecting the accumulation of mtDNA damage in several organs of rats. For example, dietary restriction prevented age-related accumulation of mtDNA damage in the cortex and decreased it in the lung and testis.


Neurodegenerative diseases

Increased mt DNA damage is a feature of several
neurodegenerative diseases A neurodegenerative disease is caused by the progressive loss of neurons, in the process known as neurodegeneration. Neuronal damage may also ultimately result in their death. Neurodegenerative diseases include amyotrophic lateral sclerosis, mul ...
. The brains of individuals with
Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...
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 and plastid DNA coding for the rest. ...
and mtDNA, but the mtDNA has approximately 10-fold higher levels than nuclear DNA. It has been proposed that aged
mitochondria A mitochondrion () is an organelle found in the cells of most eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is us ...
is the critical factor in the origin of neurodegeneration in Alzheimer's disease. Analysis of the brains of AD patients suggested an impaired function of the
DNA repair DNA repair is a collection of processes by which a cell (biology), cell identifies and corrects damage to the DNA molecules that encode its genome. A weakened capacity for DNA repair is a risk factor for the development of cancer. DNA is cons ...
pathway, which would cause reduce the overall quality of mtDNA. In
Huntington's disease Huntington's disease (HD), also known as Huntington's chorea, is an incurable neurodegenerative disease that is mostly Genetic disorder#Autosomal dominant, inherited. It typically presents as a triad of progressive psychiatric, cognitive, and ...
, mutant huntingtin protein causes mitochondrial dysfunction involving inhibition of
mitochondrial A mitochondrion () is an organelle found in the cells of most eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is used ...
electron transport, higher levels of
reactive oxygen species In chemistry and biology, reactive oxygen species (ROS) are highly Reactivity (chemistry), reactive chemicals formed from diatomic oxygen (), water, and hydrogen peroxide. Some prominent ROS are hydroperoxide (H2O2), superoxide (O2−), hydroxyl ...
and increased
oxidative stress Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. Disturbances in the normal ...
. 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 disease. The word ''pathology'' also refers to the study of disease in general, incorporating a wide range of biology research fields and medical practices. However, when used in the context of modern medical treatme ...
. The
DNA oxidation DNA oxidation is the process of oxidative damage of Deoxyribonucleic Acid, deoxyribonucleic acid. As described in detail by Burrows et al., 8-oxo-2'-deoxyguanosine (8-oxo-dG) is the most common oxidative lesion observed in duplex DNA because guan ...
product 8-oxoguanine (8-oxoG) is a well-established marker of oxidative DNA damage. In persons with
amyotrophic lateral sclerosis Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND) or—in the United States—Lou Gehrig's disease (LGD), is a rare, Terminal illness, terminal neurodegenerative disease, neurodegenerative disorder that results i ...
(ALS), the enzymes that normally repair 8-oxoG DNA damages in the mtDNA of spinal
motor neuron A motor neuron (or motoneuron), also known as efferent neuron is a neuron whose cell body is located in the motor cortex, brainstem or the spinal cord, and whose axon (fiber) projects to the spinal cord or outside of the spinal cord to directly o ...
s are impaired. Thus oxidative damage to mtDNA of motor neurons may be a significant factor in the
etiology Etiology (; alternatively spelled aetiology or ætiology) is the study of causation or origination. The word is derived from the Greek word ''()'', meaning "giving a reason for" (). More completely, etiology is the study of the causes, origins ...
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 exist between the mtDNA base composition and animal species-specific maximum life spans. As demonstrated in their work, higher mtDNA
guanine Guanine () (symbol G or Gua) is one of the four main nucleotide bases found in the nucleic acids DNA and RNA, the others being adenine, cytosine, and thymine ( uracil in RNA). In DNA, guanine is paired with cytosine. The guanine nucleoside ...
+
cytosine Cytosine () (symbol C or Cyt) is one of the four nucleotide bases found in DNA and RNA, along with adenine, guanine, and thymine ( uracil in RNA). It is a pyrimidine derivative, with a heterocyclic aromatic ring and two substituents attac ...
content ( GC%) strongly associates with longer maximum life spans 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


mtDNA mutational spectrum is sensitive to species-specific life-history traits

De novo mutations arise either due to mistakes during DNA replication or due to unrepaired damage caused in turn by endogenous and exogenous mutagens. It has been long believed that mtDNA can be particularly sensitive to damage caused by reactive oxygen species (ROS), however, G>T substitutions, the hallmark of the oxidative damage in the nuclear genome, are very rare in mtDNA and do not increase with age. Comparing the mtDNA mutational spectra of hundreds of mammalian species, it has been recently demonstrated that species with extended lifespans have an increased rate of A>G substitutions on single-stranded heavy chains. This discovery led to the hypothesis that A>G is a mitochondria-specific marker of age-associated oxidative damage. This finding provides a mutational (contrary to the selective one) explanation for the observation that long-lived species have GC-rich mtDNA: long-lived species become GC-rich simply because of their biased process of mutagenesis. An association between mtDNA mutational spectrum and species-specific life-history traits in mammals opens a possibility to link these factors together discovering new life-history-specific mutagens in different groups of organisms.


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, data supports 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, the mutation rate is the frequency of new mutations in a single gene, nucleotide sequence, or organism over time. Mutation rates are not constant and are not limited to a single type of mutation; there are many different types of mu ...
of animal mtDNA is higher than that of nuclear DNA, mtDNA is a powerful tool for tracking ancestry through females ( matrilineage) and has been used in this role to track the ancestry of many species back hundreds of generations. mtDNA testing can be used by forensic scientists in cases where nuclear DNA is severely degraded. Autosomal cells only have two copies of nuclear DNA but can have hundreds of copies of mtDNA due to the multiple mitochondria present in each cell. This means highly degraded evidence that would not be beneficial for STR analysis could be used in mtDNA analysis. mtDNA may be present in bones, teeth, or hair, which could be the only remains left in the case of severe degradation. In contrast to STR analysis, mtDNA sequencing uses
Sanger sequencing Sanger sequencing is a method of DNA sequencing that involves electrophoresis and is based on the random incorporation of chain-terminating dideoxynucleotides by DNA polymerase during in vitro DNA replication. After first being developed by Fred ...
. The known sequence and questioned sequence are both compared to the Revised Cambridge Reference Sequence to generate their respective haplotypes. If the known sample sequence and questioned sequence originated from the same matriline, one would expect to see identical sequences and identical differences from the rCRS. Cases arise where there are no known samples to collect and the unknown sequence can be searched in a database such as EMPOP. The Scientific Working Group on DNA Analysis Methods recommends three conclusions for describing the differences between a known mtDNA sequence and a questioned mtDNA sequence: exclusion for two or more differences between the sequences, inconclusive if there is one nucleotide difference, or inability to exclude if there are no nucleotide differences between the two sequences. The rapid mutation rate (in animals) makes mtDNA useful for assessing the genetic relationships of individuals or groups within a species and also for identifying and quantifying the phylogeny (evolutionary relationships; see
phylogenetics In biology, phylogenetics () is the study of the evolutionary history of life using observable characteristics of organisms (or genes), which is known as phylogenetic inference. It infers the relationship among organisms based on empirical dat ...
) 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 California () is a U.S. state, state in the Western United States that lies on the West Coast of the United States, Pacific Coast. It borders Oregon to the north, Nevada and Arizona to the east, and shares Mexico–United States border, an ...
, United States, in the successful prosecution of David Westerfield for the 2002 kidnapping and murder of 7-year-old Danielle van Dam in
San Diego San Diego ( , ) is a city on the Pacific coast of Southern California, adjacent to the Mexico–United States border. With a population of over 1.4 million, it is the List of United States cities by population, eighth-most populous city in t ...
: 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
King Richard III Richard III (2 October 1452 – 22 August 1485) was King of England from 26 June 1483 until his death in 1485. He was the last king of the Plantagenet dynasty and its cadet branch the House of York. His defeat and death at the Battle of Boswor ...
, 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 organisms given the critical role of mitochondria in
cellular respiration Cellular respiration is the process of oxidizing biological fuels using an inorganic electron acceptor, such as oxygen, to drive production of adenosine triphosphate (ATP), which stores chemical energy in a biologically accessible form. Cell ...
. 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
microsatellite A microsatellite is a tract of repetitive DNA in which certain Sequence motif, DNA motifs (ranging in length from one to six or more base pairs) are repeated, typically 5–50 times. Microsatellites occur at thousands of locations within an organ ...
s) which makes it useful for studying the evolutionary relationships—
phylogeny A phylogenetic tree or phylogeny is a graphical representation which shows the evolutionary history between a set of species or Taxon, taxa during a specific time.Felsenstein J. (2004). ''Inferring Phylogenies'' Sinauer Associates: Sunderland, M ...
—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
chimpanzee The chimpanzee (; ''Pan troglodytes''), also simply known as the chimp, is a species of Hominidae, great ape native to the forests and savannahs of tropical Africa. It has four confirmed subspecies and a fifth proposed one. When its close rel ...
s, their mitochondrial genomes are 9.8% different. Human and
gorilla Gorillas are primarily herbivorous, terrestrial great apes that inhabit the tropical forests of equatorial Africa. The genus ''Gorilla'' is divided into two species: the eastern gorilla and the western gorilla, and either four or five su ...
mitochondrial genomes are 11.8% different, suggesting that humans may be more closely related to chimpanzees than gorillas.


mtDNA in nuclear DNA

Whole genome sequences of more than 66,000 people revealed that most of them had some mitochondrial DNA inserted into their
nuclear Nuclear may refer to: Physics Relating to the nucleus of the atom: *Nuclear engineering *Nuclear physics *Nuclear power *Nuclear reactor *Nuclear weapon *Nuclear medicine *Radiation therapy *Nuclear warfare Mathematics * Nuclear space *Nuclear ...
genome A genome is all the genetic information of an organism. It consists of nucleotide sequences of DNA (or RNA in RNA viruses). The nuclear genome includes protein-coding genes and non-coding genes, other functional regions of the genome such as ...
s. More than 90% of these nuclear-mitochondrial segments ( NUMTs) were inserted after humans diverged from the other apes. Results indicate such transfers currently occur as frequently as once in every ≈4,000 human births. It appears that organellar DNA is much more often transferred to nuclear DNA than previously thought. This observation also supports the idea of the endosymbiont theory that
eukaryote The eukaryotes ( ) constitute the Domain (biology), domain of Eukaryota or Eukarya, organisms whose Cell (biology), cells have a membrane-bound cell nucleus, nucleus. All animals, plants, Fungus, fungi, seaweeds, and many unicellular organisms ...
s have evolved from
endosymbiont An endosymbiont or endobiont is an organism that lives within the body or cells of another organism. Typically the two organisms are in a mutualism (biology), mutualistic relationship. Examples are nitrogen-fixing bacteria (called rhizobia), whi ...
s which turned into organelles while transferring most of their DNA to the nucleus so that the organellar genome shrunk in the process.


History

Mitochondrial DNA was discovered in the 1960s by Margit M. K. Nass and Sylvan Nass by
electron microscopy An electron microscope is a microscope that uses a beam of electrons as a source of illumination. It uses electron optics that are analogous to the glass lenses of an optical light microscope to control the electron beam, for instance focusing i ...
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 studies can reveal associations of mtDNA genes and their mutations with
phenotype In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology (physical form and structure), its developmental processes, its biochemical and physiological propert ...
s including lifespan and disease risks. In 2021, the largest,
UK Biobank UK Biobank is a long-term prospective biobank study in the United Kingdom (UK) that houses the de-identified biological samples and health-related data of half a million people. The volunteer participants aged 40-69 were recruited between 2006 ...
-based, genome-wide association study of mitochondrial DNA unveiled 260 new associations with phenotypes including 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
MitImpact 3D - IRCCS-CSS Bioinformatics lab
* MITOMAP: A compendium of polymorphisms and mutations in human mitochondrial DN
WebHome < MITOMAP < Foswiki


See also


References


External links

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