Mitochondrial DNA

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Mitochondrial DNA is the small circular chromosome found inside mitochondria. These organelles, found in all eukaryotic cells, are the powerhouse of the cell. The mitochondria, and thus mitochondrial DNA, are passed exclusively from mother to offspring through the egg cell. Mitochondrial DNA lg.jpg
Mitochondrial DNA is the small circular chromosome found inside mitochondria. These organelles, found in all eukaryotic cells, are the powerhouse of the cell. The mitochondria, and thus mitochondrial DNA, are passed exclusively from mother to offspring through the egg cell.
Illustration of the location of mitochondrial DNA in human cells
Electron microscopy reveals mitochondrial DNA in discrete foci. Bars: 200 nm. (A) Cytoplasmic section after immunogold labelling with anti-DNA; gold particles marking mtDNA are found near the mitochondrial membrane (black dots in upper right). (B) Whole mount view of cytoplasm after extraction with CSK buffer and immunogold labelling with anti-DNA; mtDNA (marked by gold particles) resists extraction. From Iborra et al., 2004. Electron microscopy reveals mitochondrial DNA in discrete foci.jpg
Electron microscopy reveals mitochondrial DNA in discrete foci. Bars: 200 nm. (A) Cytoplasmic section after immunogold labelling with anti-DNA; gold particles marking mtDNA are found near the mitochondrial membrane (black dots in upper right). (B) Whole mount view of cytoplasm after extraction with CSK buffer and immunogold labelling with anti-DNA; mtDNA (marked by gold particles) resists extraction. From Iborra et al., 2004.

Mitochondrial DNA (mtDNA or mDNA) [3] is the DNA located in mitochondria, cellular organelles within eukaryotic cells that convert chemical energy from food into a form that cells can use, such as adenosine triphosphate (ATP). Mitochondrial DNA is only a small portion of the DNA in a eukaryotic cell; most of the DNA can be found in the cell nucleus and, in plants and algae, also in plastids such as chloroplasts.


Human mitochondrial DNA was the first significant part of the human genome to be sequenced. [4] This sequencing revealed that the human mtDNA includes 16,569 base pairs and encodes 13 proteins.

Since animal mtDNA evolves faster than nuclear genetic markers, [5] [6] [7] it represents a mainstay of phylogenetics and evolutionary biology. It also permits tracing the relationships of populations, and so has become important in anthropology and biogeography.


Nuclear and mitochondrial DNA are thought to have separate evolutionary origins, with the mtDNA derived from the circular genomes of bacteria engulfed by the ancestors of modern eukaryotic cells. This theory is called the endosymbiotic theory. In the cells of extant organisms, the vast majority of the proteins in the mitochondria (numbering approximately 1500 different types in mammals) are coded by nuclear DNA, but the genes for some, if not most, of them are thought to be of bacterial origin, having been transferred to the eukaryotic nucleus during evolution. [8]

The reasons mitochondria have retained some genes are debated. The existence in some species of mitochondrion-derived organelles lacking a genome [9] suggests that complete gene loss is possible, and transferring mitochondrial genes to the nucleus has several advantages. [10] The difficulty of targeting remotely-produced hydrophobic protein products to the mitochondrion is one hypothesis for why some genes are retained in mtDNA; [11] colocalisation for redox regulation is another, citing the desirability of localised control over mitochondrial machinery. [12] Recent analysis of a wide range of mtDNA genomes suggests that both these features may dictate mitochondrial gene retention. [8]

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 introns or plasmid like structures, and whether the genetic material is a singular molecule or collection of homogeneous or heterogeneous molecules. [13]

In many unicellular organisms (e.g., the ciliate Tetrahymena and the green alga Chlamydomonas reinhardtii ), and in rare cases also in multicellular organisms (e.g. in some species of Cnidaria), the mtDNA is linear DNA. Most of these linear mtDNAs possess telomerase-independent telomeres (i.e., the ends of the linear 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 pathogens. [14]


Most (bilaterian) animals have a circular mitochondrial genome. Medusozoa and calcarea clades however include species with linear mitochondrial chromosomes. [15] With a few exceptions, animals have 37 genes in their mitochondrial DNA: 13 for proteins, 22 for tRNAs, and 2 for rRNAs. [16]

Mitochondrial genomes for animals average about 16,000 base pairs in length. [16] The anemone Isarachnanthus nocturnus has the largest mitochondrial genome of any animal at 80,923 bp. [17] The smallest known mitochondrial genome in animals belongs to the comb jelly Vallicula multiformis , which consist of 9,961 bp. [18]

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 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. [19] [20]

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). [21] [22] [23]

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). [8] In Fungi, however, there is no single gene shared among all mitogenomes. [24] Some plant species have enormous mitochondrial genomes, with Silene conica mtDNA containing as many as 11,300,000 base pairs. [25] Surprisingly, even those huge mtDNAs contain the same number and kinds of genes as related plants with much smaller mtDNAs. [26] 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. [27]


Protists 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.[ citation needed ]

The smallest mitochondrial genome sequenced to date is the 5,967 bp mtDNA of the parasite Plasmodium falciparum . [28] [29]

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.

Genome Type [13] KingdomIntronsSizeShapeDescription
1AnimalNo11–28 kbpCircularSingle molecule
2Fungi, Plant, ProtistaYes19–1000 kbpCircularSingle molecule
3Fungi, Plant, ProtistaNo20–1000 kbpCircularLarge molecule and small plasmid like structures
4ProtistaNo1–200 kbpCircularHeterogeneous group of molecules
5Fungi, Plant, ProtistaNo1–200 kbpLinearHomogeneous group of molecules
6ProtistaNo1–200 kbpLinearHeterogeneous group of molecules


Mitochondrial DNA is replicated by the DNA polymerase 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. [30] The replisome machinery is formed by DNA polymerase, TWINKLE and mitochondrial SSB proteins. TWINKLE is a helicase, which unwinds short stretches of dsDNA in the 5' to 3' direction. [31] All these polypeptides are encoded in the nuclear genome.

During embryogenesis, replication of mtDNA is strictly down-regulated from the fertilized oocyte through the preimplantation embryo. [32] 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. [33] According to Justin St. John and colleagues, "At the blastocyst stage, the onset of mtDNA replication is specific to the cells of the trophectoderm. [32] In contrast, the cells of the inner cell mass restrict mtDNA replication until they receive the signals to differentiate to specific cell types." [32]

Human mitochondrial DNA with the 37 genes on their respective H- and L-strands Map of the human mitochondrial genome.svg
Human mitochondrial DNA with the 37 genes on their respective H- and L-strands

Genes on the human mtDNA and their transcription

Schematic karyogram showing the human genome, with 23 chromosome pairs as well as the mitochondrial genome (to scale at bottom left, annotated "MT"). Its genome is relatively tiny compared to the rest, and its copy number per human cell varies from 0 (erythrocytes) up to 1,500,000 (oocytes).

Further information: Karyotype Human karyotype with bands and sub-bands.png
Schematic karyogram showing the human genome, with 23 chromosome pairs as well as the mitochondrial genome (to scale at bottom left, annotated "MT"). Its genome is relatively tiny compared to the rest, and its copy number per human cell varies from 0 (erythrocytes) up to 1,500,000 (oocytes).

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 transfer RNAs (tRNAs). The light strand encodes one subunit, and 8 tRNAs. So, altogether mtDNA encodes for two rRNAs, 22 tRNAs, and 13 protein subunits, all of which are involved in the oxidative phosphorylation process. [36] [37]

The 37 genes of the Cambridge Reference Sequence for human mitochondrial DNA and their locations [38]
in the mitogenome
MT-ATP8 protein coding ATP synthase, Fo subunit 8 (complex V)08,366–08,572 (overlap with MT-ATP6)H
MT-ATP6 protein coding ATP synthase, Fo subunit 6 (complex V)08,527–09,207 (overlap with MT-ATP8)H
MT-CO1 protein coding Cytochrome c oxidase, subunit 1 (complex IV)05,904–07,445H
MT-CO2 protein coding Cytochrome c oxidase, subunit 2 (complex IV)07,586–08,269H
MT-CO3 protein coding Cytochrome c oxidase, subunit 3 (complex IV)09,207–09,990H
MT-CYB protein coding Cytochrome b (complex III)14,747–15,887H
MT-ND1 protein coding NADH dehydrogenase, subunit 1 (complex I)03,307–04,262H
MT-ND2 protein coding NADH dehydrogenase, subunit 2 (complex I)04,470–05,511H
MT-ND3 protein coding NADH dehydrogenase, subunit 3 (complex I)10,059–10,404H
MT-ND4L protein coding NADH dehydrogenase, subunit 4L (complex I)10,470–10,766 (overlap with MT-ND4)H
MT-ND4 protein coding NADH dehydrogenase, subunit 4 (complex I)10,760–12,137 (overlap with MT-ND4L)H
MT-ND5 protein coding NADH dehydrogenase, subunit 5 (complex I)12,337–14,148H
MT-ND6 protein coding NADH dehydrogenase, subunit 6 (complex I)14,149–14,673L
MT-RNR2 protein coding Humanin
MT-TA transfer RNAtRNA-Alanine (Ala or A)05,587–05,655L
MT-TR transfer RNAtRNA-Arginine (Arg or R)10,405–10,469H
MT-TN transfer RNAtRNA-Asparagine (Asn or N)05,657–05,729L
MT-TD transfer RNAtRNA-Aspartic acid (Asp or D)07,518–07,585H
MT-TC transfer RNAtRNA-Cysteine (Cys or C)05,761–05,826L
MT-TE transfer RNAtRNA-Glutamic acid (Glu or E)14,674–14,742L
MT-TQ transfer RNAtRNA-Glutamine (Gln or Q)04,329–04,400L
MT-TG transfer RNAtRNA-Glycine (Gly or G)09,991–10,058H
MT-TH transfer RNAtRNA-Histidine (His or H)12,138–12,206H
MT-TI transfer RNAtRNA-Isoleucine (Ile or I)04,263–04,331H
MT-TL1 transfer RNAtRNA-Leucine (Leu-UUR or L)03,230–03,304H
MT-TL2 transfer RNAtRNA-Leucine (Leu-CUN or L)12,266–12,336H
MT-TK transfer RNAtRNA-Lysine (Lys or K)08,295–08,364H
MT-TM transfer RNAtRNA-Methionine (Met or M)04,402–04,469H
MT-TF transfer RNAtRNA-Phenylalanine (Phe or F)00,577–00,647H
MT-TP transfer RNAtRNA-Proline (Pro or P)15,956–16,023L
MT-TS1 transfer RNAtRNA-Serine (Ser-UCN or S)07,446–07,514L
MT-TS2 transfer RNAtRNA-Serine (Ser-AGY or S)12,207–12,265H
MT-TT transfer RNAtRNA-Threonine (Thr or T)15,888–15,953H
MT-TW transfer RNAtRNA-Tryptophan (Trp or W)05,512–05,579H
MT-TY transfer RNAtRNA-Tyrosine (Tyr or Y)05,826–05,891L
MT-TV transfer RNAtRNA-Valine (Val or V)01,602–01,670H
MT-RNR1 ribosomal RNASmall subunit : SSU (12S)00,648–01,601H
MT-RNR2 ribosomal RNALarge subunit : LSU (16S)01,671–03,229H

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. [39] Folded tRNAs therefore act as secondary structure punctuations. [40]

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. [36] 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. [36]

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. [41] Among the 12 tissues examined the highest level of expression was observed in heart, followed by brain and steroidogenic tissue samples. [41]

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. [41] Interestingly, while the expression of protein-encoding genes was stimulated by ACTH, the levels of the mitochondrial 16S rRNA showed no significant change. [41]

Mitochondrial inheritance

In most multicellular organisms, 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 has been reported to contain on average 5 molecules), [42] [43] 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. [44]

In a study published in 2018, human babies were reported to inherit mtDNA from both their fathers and their mothers resulting in mtDNA heteroplasmy, [45] a finding that has been rejected by other scientists. [46] [47] [48]

Female inheritance

In sexual reproduction, 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 to select them for later destruction inside the embryo. [49] Some in vitro fertilization techniques, particularly injecting a sperm into an oocyte, may interfere with this.

The fact that mitochondrial DNA is mostly maternally inherited enables genealogical researchers to trace maternal lineage far back in time. (Y-chromosomal DNA, paternally inherited, is used in an analogous way to determine the patrilineal history.) This is usually accomplished on human mitochondrial DNA by sequencing the hypervariable control regions (HVR1 or HVR2), and sometimes the complete molecule of the mitochondrial DNA, as a genealogical DNA test. [50] 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. [51] The concept of the Mitochondrial Eve is based on the same type of analysis, attempting to discover the origin of humanity 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, [52] [53] [54] [55] 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. [33]

Male inheritance

Male mitochondrial DNA inheritance has been discovered in Plymouth Rock chickens. [56] Evidence supports rare instances of male mitochondrial inheritance in some mammals as well. Specifically, documented occurrences exist for mice, [57] [58] where the male-inherited mitochondria were subsequently rejected. It has also been found in sheep, [59] and in cloned cattle. [60] Rare cases of male mitochondrial inheritance have been documented in humans. [61] [62] [63] [45] Although many of these cases involve cloned embryos or subsequent rejection of the paternal mitochondria, others document in vivo 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 cells. [64] Paternally inherited mitochondria have additionally been reported in some insects such as fruit flies, [65] [66] honeybees, [67] and periodical cicadas. [68]

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. [69] 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. [70]

Mutations and disease

Human mitochondrial DNA with groups of protein-, rRNA- and tRNA-encoding genes Mitochondrial DNA en.svg
Human mitochondrial DNA with groups of protein-, rRNA- and tRNA-encoding genes
The involvement of mitochondrial DNA in several human diseases Mitochondrial DNA and diseases.svg
The involvement of mitochondrial DNA in several human diseases


The concept that mtDNA is particularly susceptible to reactive oxygen species generated by the respiratory chain due to its proximity remains controversial. [71] mtDNA does not accumulate any more oxidative base damage than nuclear DNA. [72] 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. [73] mtDNA is packaged with proteins which appear to be as protective as proteins of the nuclear chromatin. [74] 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. [75] The outcome of mutation in mtDNA may be an alteration in the coding instructions for some proteins, [76] 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 and Kearns–Sayre syndrome (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. [77] 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 [78] and are influenced by complicated stochastic processes within the cell and during development. [33] [79]

Mutations in mitochondrial tRNAs can be responsible for severe diseases like the MELAS and MERRF syndromes. [80]

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. [81]

Use in disease diagnosis

Recently a mutation in mtDNA has been used to help diagnose prostate cancer in patients with negative prostate biopsy. [82] [83] mtDNA alterations can be detected in the bio-fluids of patients with cancer. [84] mtDNA is characterized by the high rate of polymorphisms and mutations. Some of which 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, heart failure and cancer.

Relationship with ageing

Though the idea is controversial, some evidence suggests a link between aging and mitochondrial genome dysfunction. [85] In essence, mutations in mtDNA upset a careful balance of reactive oxygen species (ROS) production and enzymatic ROS scavenging (by enzymes like superoxide dismutase, catalase, glutathione peroxidase and others). However, some mutations that increase ROS production (e.g., by reducing antioxidant defenses) in worms increase, rather than decrease, their longevity. [71] Also, naked mole rats, rodents about the size of mice, live about eight times longer than mice despite having reduced, compared to mice, antioxidant defenses and increased oxidative damage to biomolecules. [86] 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. A decrease in mitochondrial function reduces overall metabolic efficiency. [87] 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. [88] 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. [89] The application of a mitochondrial-specific ROS scavenger, which lead to a significant longevity of the mice studied, [90] 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 and nutraceutical supplementation are popular areas of ongoing research. [91] [92] 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. [93] In a recent study, it was showed 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. [94]

Neurodegenerative diseases

Increased mtDNA damage is a feature of several neurodegenerative diseases.

The brains of individuals with Alzheimer's disease have elevated levels of oxidative DNA damage in both nuclear DNA and mtDNA, but the mtDNA has approximately 10-fold higher levels than nuclear DNA. [95] It has been proposed that aged mitochondria is the critical factor in the origin of neurodegeneration in Alzheimer's disease. [96] Analysis of the brains of AD patients suggested an impaired function of the DNA repair pathway, which would cause reduce the overall quality of mtDNA. [97]

In Huntington's disease, mutant huntingtin protein causes mitochondrial dysfunction involving inhibition of mitochondrial electron transport, higher levels of reactive oxygen species and increased oxidative stress. [98] Mutant huntingtin protein promotes oxidative damage to mtDNA, as well as nuclear DNA, that may contribute to Huntington's disease pathology. [99]

The DNA oxidation product 8-oxoguanine (8-oxoG) is a well-established marker of oxidative DNA damage. In persons with amyotrophic lateral sclerosis (ALS), the enzymes that normally repair 8-oxoG DNA damages in the mtDNA of spinal motor neurons are impaired. [100] Thus oxidative damage to mtDNA of motor neurons may be a significant factor in the etiology of ALS.

Correlation of the mtDNA base composition with animal life spans

Animal species mtDNA base composition was retrieved from the MitoAge database and compared to their maximum life span from AnAge database. Correlation between the mtDNA GC%25 and maximum life span across 387 different mammalian species.png
Animal species mtDNA base composition was retrieved from the MitoAge database and compared to their maximum life span from AnAge database.

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. [101] [102] [103] As demonstrated in their work, higher mtDNA guanine + cytosine 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). [102] To support the scientific community in carrying out comparative analyses between mtDNA features and longevity across animals, a dedicated database was built named MitoAge. [104]

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 chain. [105] 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. [106] 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. [107]

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 of animal mtDNA is higher than that of nuclear DNA, [108] 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. 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. [109] 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 cannot exclude if there are no nucleotide differences between the two sequences. [110]

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) 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 [80]

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. [111]

In the 1998 United States court case of Commonwealth of Pennsylvania v. Patricia Lynne Rorrer, [112] mitochondrial DNA was admitted into evidence in the State of Pennsylvania for the first time. [113] [114] The case was featured in episode 55 of season 5 of the true crime drama series Forensic Files (season 5). [115]

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 Danielle van Dam in San Diego: it was used for both human and dog identification. [116] This was the first trial in the U.S. to admit canine DNA. [117]

The remains of 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. [118]

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 gorilla mitochondrial genomes are 11.8% different, suggesting that humans may be more closely related to chimpanzees than gorillas. [119]

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 genomes. More than 90% of these nuclear-mitochondrial segments (NUMTs) were inserted after humans diverged from apes. Results indicate such transfers currently occur as frequent as once in every ~4,000 human births. [120]

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 eukaryotes have evolved from endosymbionts which turned into organelles while transferring most of their DNA to the nucleus so that the organellar genome shrunk in the process. [121]


Mitochondrial DNA was discovered in the 1960s by Margit M. K. Nass and Sylvan Nass by electron microscopy as DNase-sensitive threads inside mitochondria, [122] and by Ellen Haslbrunner, Hans Tuppy and Gottfried Schatz by biochemical assays on highly purified mitochondrial fractions. [123]

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.

MtDNA-phenotype association databases

Genome-wide association studies can reveal associations of mtDNA genes and their mutations with phenotypes including 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 lifespan and disease risks for e.g. type 2 diabetes. [133] [134]

Mitochondrial mutation databases

Several specialized databases exist that report polymorphisms and mutations in the human mitochondrial DNA, together with the assessment of their pathogenicity.

See also

Related Research Articles

<span class="mw-page-title-main">Mitochondrion</span> Organelle in eukaryotic cells responsible for respiration

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 throughout the cell as a source of chemical energy. They were discovered by Albert von Kölliker in 1857 in the voluntary muscles of insects. The term mitochondrion was coined by Carl Benda in 1898. The mitochondrion is popularly nicknamed the "powerhouse of the cell", a phrase coined by Philip Siekevitz in a 1957 article of the same name.

<span class="mw-page-title-main">Mitochondrial disease</span> Spontaneously occurring or inherited disorder that involves mitochondrial dysfunction

Mitochondrial disease is a group of disorders caused by mitochondrial dysfunction. Mitochondria are the organelles that generate energy for the cell and are found in every cell of the human body except red blood cells. They convert the energy of food molecules into the ATP that powers most cell functions.

<span class="mw-page-title-main">Leigh syndrome</span> Mitochondrial metabolism disease characterized by progressive loss of mental and movement abilities

Leigh syndrome is an inherited neurometabolic disorder that affects the central nervous system. It is named after Archibald Denis Leigh, a British neuropsychiatrist who first described the condition in 1951. Normal levels of thiamine, thiamine monophosphate, and thiamine diphosphate are commonly found, but there is a reduced or absent level of thiamine triphosphate. This is thought to be caused by a blockage in the enzyme thiamine-diphosphate kinase, and therefore treatment in some patients would be to take thiamine triphosphate daily. While the majority of patients typically exhibit symptoms between the ages of 3 and 12 months, instances of adult onset have also been documented.

Heteroplasmy is the presence of more than one type of organellar genome within a cell or individual. It is an important factor in considering the severity of mitochondrial diseases. Because most eukaryotic cells contain many hundreds of mitochondria with hundreds of copies of mitochondrial DNA, it is common for mutations to affect only some mitochondria, leaving most unaffected.

<span class="mw-page-title-main">Human mitochondrial genetics</span> Study of the human mitochondrial genome

Human mitochondrial genetics is the study of the genetics of human mitochondrial DNA. The human mitochondrial genome is the entirety of hereditary information contained in human mitochondria. Mitochondria are small structures in cells that generate energy for the cell to use, and are hence referred to as the "powerhouses" of the cell.

<span class="mw-page-title-main">MELAS syndrome</span> Medical condition

Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is one of the family of mitochondrial diseases, which also include MIDD, MERRF syndrome, and Leber's hereditary optic neuropathy. It was first characterized under this name in 1984. A feature of these diseases is that they are caused by defects in the mitochondrial genome which is inherited purely from the female parent. The most common MELAS mutation is mitochondrial mutation, mtDNA, referred to as m.3243A>G.

<span class="mw-page-title-main">Nuclear gene</span> Gene located in the cell nucleus of a eukaryote

A nuclear gene is a gene that has its DNA nucleotide sequence physically situated within the cell nucleus of a eukaryotic organism. This term is employed to differentiate nuclear genes, which are located in the cell nucleus, from genes that are found in mitochondria or chloroplasts. The vast majority of genes in eukaryotes are nuclear.

Extrachromosomal DNA is any DNA that is found off the chromosomes, either inside or outside the nucleus of a cell. Most DNA in an individual genome is found in chromosomes contained in the nucleus. Multiple forms of extrachromosomal DNA exist, and, while some of these serve important biological functions, they can also play a role in diseases such as cancer.

Extranuclear inheritance or cytoplasmic inheritance is the transmission of genes that occur outside the nucleus. It is found in most eukaryotes and is commonly known to occur in cytoplasmic organelles such as mitochondria and chloroplasts or from cellular parasites like viruses or bacteria.

Nuclear mitochondrial DNA (NUMT) segments or genetic loci describe a transposition of any type of cytoplasmic mitochondrial DNA into the nuclear genome of eukaryotic organisms.

<span class="mw-page-title-main">MT-RNR1</span> SSU rRNA of the mitochondrial ribosome

Mitochondrially encoded 12S ribosomal RNA is the SSU rRNA of the mitochondrial ribosome. In humans, 12S is encoded by the MT-RNR1 gene and is 959 nucleotides long. MT-RNR1 is one of the 37 genes contained in animal mitochondria genomes. Their 2 rRNA, 22 tRNA and 13 mRNA genes are very useful in phylogenetic studies, in particular the 12S and 16S rRNAs. The 12S rRNA is the mitochondrial homologue of the prokaryotic 16S and eukaryotic nuclear 18S ribosomal RNAs. Mutations in the MT-RNR1 gene may be associated with hearing loss. The rRNA gene also encodes a peptide MOTS-c, also known as Mitochondrial-derived peptide MOTS-c or Mitochondrial open reading frame of the 12S rRNA-c.

<span class="mw-page-title-main">MT-ATP8</span> Mitochondrial protein-coding gene whose product is involved in ATP synthesis

MT-ATP8 is a mitochondrial gene with the full name 'mitochondrially encoded ATP synthase membrane subunit 8' that encodes a subunit of mitochondrial ATP synthase, ATP synthase Fo subunit 8. This subunit belongs to the Fo complex of the large, transmembrane F-type ATP synthase. This enzyme, which is also known as complex V, is responsible for the final step of oxidative phosphorylation in the electron transport chain. Specifically, one segment of ATP synthase allows positively charged ions, called protons, to flow across a specialized membrane inside mitochondria. Another segment of the enzyme uses the energy created by this proton flow to convert a molecule called adenosine diphosphate (ADP) to ATP. Subunit 8 differs in sequence between Metazoa, plants and Fungi.

<span class="mw-page-title-main">MT-ATP6</span> Mitochondrial protein-coding gene whose product is involved in ATP synthesis

MT-ATP6 is a mitochondrial gene with the full name 'mitochondrially encoded ATP synthase membrane subunit 6' that encodes the ATP synthase Fo subunit 6. This subunit belongs to the Fo complex of the large, transmembrane F-type ATP synthase. This enzyme, which is also known as complex V, is responsible for the final step of oxidative phosphorylation in the electron transport chain. Specifically, one segment of ATP synthase allows positively charged ions, called protons, to flow across a specialized membrane inside mitochondria. Another segment of the enzyme uses the energy created by this proton flow to convert a molecule called adenosine diphosphate (ADP) to ATP. Mutations in the MT-ATP6 gene have been found in approximately 10 to 20 percent of people with Leigh syndrome.

Mitochondrially encoded tRNA histidine, also known as MT-TH, is a transfer RNA which, in humans, is encoded by the mitochondrial MT-TH gene.

<span class="mw-page-title-main">Cytochrome c oxidase subunit I</span> Enzyme of the respiratory chain encoded by the mitochondrial genome

Cytochrome c oxidase I (COX1) also known as mitochondrially encoded cytochrome c oxidase I (MT-CO1) is a protein that is encoded by the MT-CO1 gene in eukaryotes. The gene is also called COX1, CO1, or COI. Cytochrome c oxidase I is the main subunit of the cytochrome c oxidase complex. In humans, mutations in MT-CO1 have been associated with Leber's hereditary optic neuropathy (LHON), acquired idiopathic sideroblastic anemia, Complex IV deficiency, colorectal cancer, sensorineural deafness, and recurrent myoglobinuria.

Mitochondrially encoded tRNA glutamic acid also known as MT-TE is a transfer RNA which in humans is encoded by the mitochondrial MT-TE gene. MT-TE is a small 69 nucleotide RNA that transfers the amino acid glutamic acid to a growing polypeptide chain at the ribosome site of protein synthesis during translation.

Mitochondrially encoded tRNA lysine also known as MT-TK is a transfer RNA which in humans is encoded by the mitochondrial MT-TK gene.

Mitochondrially encoded tRNA asparagine also known as MT-TN is a transfer RNA which in humans is encoded by the mitochondrial MT-TN gene.

<span class="mw-page-title-main">Mitochondrial ribosome</span> Protein complex

The mitochondrial ribosome, or mitoribosome, is a protein complex that is active in mitochondria and functions as a riboprotein for translating mitochondrial mRNAs encoded in mtDNA. The mitoribosome is attached to the inner mitochondrial membrane. Mitoribosomes, like cytoplasmic ribosomes, consist of two subunits — large (mt-LSU) and small (mt-SSU). Mitoribosomes consist of several specific proteins and fewer rRNAs. While mitochondrial rRNAs are encoded in the mitochondrial genome, the proteins that make up mitoribosomes are encoded in the nucleus and assembled by cytoplasmic ribosomes before being implanted into the mitochondria.

Taosheng Huang is a physician-scientist with substantial academic achievements and professional experience in translational research, specifically, in human mitochondrial genetics. He is a full Professor and Director of the Molecular Diagnostic Laboratory in the Division of Human Genetics at Cincinnati Children’s Hospital Medical Center (CCHMC). Huang has published over 100 manuscripts in many impactful journals.


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