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, 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 an examination of the relatedness of populations, and so has become important in anthropology and biogeography.
Contents
- 1 Origin
- 2 Genome structure and diversity
- 3 Replication
- 4 Genes on the mtDNA and their transcription
- 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, 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 an examination of the relatedness of populations, and so has become important in anthropology and biogeography.
Contents
- 1 Origin
- 2 Genome structure and diversity
- 3 Replication
- 4 Genes on the mtDNA and their transcription
- 5 Mitochondrial inheritance
- 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 an examination of the relatedness of populations, and so has become important in anthropology and biogeography.
Nuclear and mitochondrial DNA are thought to be of separate evolutionary origin, with the mtDNA being derived from the circular genomes of the bacteria that were engulfed by the early ancestors of today's eukaryotic cells. This theory is called the endosymbiotic theory. In the cells of extant organisms, the vast majority of the proteins present in the mitochondria (numbering approximately 1500 different types in mammals) are coded for by nuclear DNA, but the genes for some, if not most, of them are thought to have originally been of bacterial origin, having since been transferred to the eukaryotic nucleus during evolution.[8]
The reasons why 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 genome types found in mitochondrial genomes, classified by their structure (e.g. 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 found as linearly organized 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]
Animals
Most animals, specifically bilaterian animals, have a circular mitochondrial genome. Medusozoa and calcarea clades however have species with linear mitochondrial chromosomes. [15]
In terms of base pairs, the anemone Isarachnanthus nocturnus has the largest mitochondrial genome of any animal at 80,923 bp.[16]
In February 2020, a jellyfish-related parasite – Henneguya salminicola – was discovered that lacks mitochondrial genome but retains structures deemed mitochondrion-related organelles. Moreover, nuclear DNA genes involved in aerobic respiration and in mitochondrial DNA replication and transcription were either absent or present only as pseudogenes. This is the first multicellular organism known to have this absence of aerobic respiration and lives completely free of oxygen dependency.[17][18]
Plants and fungi
There are three different mitochondrial genome types found in plants and fungi. The first type is a circular gen
The reasons why 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]
Across all organisms, there are six main genome types found in mitochondrial genomes, classified by their structure (e.g. 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 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 found as linearly organized 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 animals, specifically bilaterian animals, have a circular mitochondrial genome. Medusozoa and calcarea clades however have species with linear mitochondrial chromosomes. [15]
In terms of base pairs, the anemone Isarachnanthus nocturnus has the largest mitochondrial genome of any animal at 80,923 bp.[16]
In February 2020, a jellyfish-related parasite – [16]
In February 2020, a jellyfish-related parasite – Henneguya salminicola – was discovered that lacks mitochondrial genome but retains structures deemed mitochondrion-related organelles. Moreover, nuclear DNA genes involved in aerobic respiration and in mitochondrial DNA replication and transcription were either absent or present only as pseudogenes. This is the first multicellular organism known to have this absence of aerobic respiration and lives completely free of oxygen dependency.[17][18]
There are three different mitochondrial genome types found in plants and fungi. The first type is a circular genome that has introns (type 2) and may range from 19 to 1000 kbp in length. The second genome type is a circular genome (about 20–1000 kbp) that also has a plasmid-like structure (1 kb) (type 3). The final genome type that can be found in plant and fungi is a linear genome made up of homogeneous DNA molecules (type 5).
Great variation in mtDNA gene content and size exists among fungi and plants, although there appears to be a core subset of genes that are present in all eukaryotes (except for the few that have no mitochondria at all).[8] Some plant species have enormous mitochondrial genomes, with Silene conica mtDNA containing as many as 11,300,000 base pairs.[19] Surprisingly, even those huge mtDNAs contain the same number and kinds of genes as related plants with much smaller mtDNAs.[20] 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.[21]
Protists contain the most diverse mitochondrial genomes, with five different types found in this kingdom. Type 2, type 3 and type 5 mentioned in the plant and fungal genomes also exist in some protists, as do two unique genome types. One of these unique types is a heterogeneous collection of circular DNA molecules (type 4) while the other is a heterogeneous collection of linear molecules (type 6). Genome types 4 and 6 each range from 1–200 kbp in size.
The smallest mitochondrial genome sequenced to date is the 5,967 bp mtDNA of the parasite Plasmodium falciparum.[22]The smallest mitochondrial genome sequenced to date is the 5,967 bp mtDNA of the parasite Plasmodium falciparum.[22][23]
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.
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.[24] 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.[25] 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.[26] 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.[27] According to Justin St. John and colleagues, "At the blastocyst stage, the onset of mtDNA replication is specific to the cells of the trophectoderm.[26] In contrast, the cells of the inner cell mass restrict mtDNA replication until they receive the signals to differentiate to specific cell types."embryogenesis, replication of mtDNA is strictly down-regulated from the fertilized oocyte through the preimplantation embryo.[26] 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.[27] According to Justin St. John and colleagues, "At the blastocyst stage, the onset of mtDNA replication is specific to the cells of the trophectoderm.[26] In contrast, the cells of the inner cell mass restrict mtDNA replication until they receive the signals to differentiate to specific cell types."[26]
The two strands of the human mitochondrial DNA are distinguished as the heavy strand and the light strand. The heavy strand is rich in guanine and encodes 12 subunits of the oxidative phosphorylation system, two ribosomal RNAs (12S and 16S), and 14 tRNAs. The light strand encodes one subunit, and 8 tRNAs. So, altogether mtDNA encodes for two rRNAs, 22 tRNAs, and 13 proteins subunits, all of which are involved in the oxidative phosphorylation process.[28][29]
The 37 genes of the Cambridge Reference Sequence for human mitochondrial DNA and their locations[30] Gene Type Product Positions
in the mitogenomeStrand 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) 05,904–07,445 <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.[31] Folded tRNAs therefore act as secondary structure punctuations.[32]
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.[28] 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.[28]
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.[33] Among the 12 tissues examined the highest level of expression was observed in heart, followed by brain and steroidogenic tissue samples.[33]
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.[33] Interestingly, while the expression of protein-encoding genes was stimulated by ACTH, the levels of the mitochondrial 16S rRNA showed no significant change.[33]
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),[34][35] degradation of sperm mtDNA in the male genital tract and in the fertilized egg; and, at least in a few organisms, failure of sperm mtDNA to enter the egg. Whatever the mechanism, this single parent (uniparental inheritance) pattern of mtDNA inheritance is found in most animals, most plants and also in fungi.
In exceptional cases, human babies sometimes inherit mtDNA from both their fathers and their mothers resulting in mtDNA heteroplasmy.[36]
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.[37] Some in vitro fertilization techniques, particularly injecting a sperm into an oocyte, may interfere with this.
The fact that mitochondrial DNA is 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.[38] 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.[39] 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,[40][41][42][43] with a recent mathematical and experimental metastudy providing evidence for a combination of random partitioning of mtDNAs at cell divisions and random turnover of mtDNA molecules within the cell.[27]
Male inheritance
Main article: [28] 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.[28]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.[33] Among the 12 tissues examined the highest level of
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.[33] Among the 12 tissues examined the highest level of expression was observed in heart, followed by brain and steroidogenic tissue samples.[33]
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.[33] Interestingly, while the expression of protein-encoding genes was stimulated by ACTH, the levels of the mitochondrial 16S rRNA showed no significant change.[33]
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),[34][35] degradation of sperm mtDNA in the male genital tract and in the fertilized egg; and, at least in a few organisms, failure of sperm mtDNA to enter the egg. Whatever the mechanism, this single parent (uniparental inheritance) pattern of mtDNA inheritance is found in most animals, most plants and also in fungi.
In exceptional cases, human babies sometimes inherit mtDNA from both their fathers and their mothers resulting in mtDNA heteroplasmy.[36]
Female inheritanceIn exceptional cases, human babies sometimes inherit mtDNA from both their fathers and their mothers resulting in mtDNA heteroplasmy.[36]
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.[37] Some in vitro fertilization techniques, particularly injecting a sperm into an oocyte, may interfere with this.
The fact that mitochondrial DNA is maternally inherited enables genealogical researchers to trace maternal lineage far back in time. (Y-chromosomal DNA, paterna
The fact that mitochondrial DNA is 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.[38] 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.[39] 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.
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,[40][41][42][43] with a recent mathematical and experimental metastudy providing evidence for a combination of random partitioning of mtDNAs at cell divisions and random turnover of mtDNA molecules within the cell.[27]
Male inheritance
Plymouth Rock chickens.[44] Evidence supports rare instances of male mitochondrial inheritance in some mammals as well. Specifically, documented occurrences exist for mice,[45][46] where the male-inherited mitochondria were subsequently rejected. It has also been found in sheep,[47] and in cloned cattle.[48] Rare cases of male mitochondrial inheritance have been documented in humans.[49][50][51][52] 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.[53] Paternally inherited mitochondria have additionally been reported in some insects such as 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.[53] Paternally inherited mitochondria have additionally been reported in some insects such as fruit flies,[54][55] honeybees,[56] and periodical cicadas.[57]
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.[58] 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.[59]
Mutations and disease
reactive oxygen species generated by the respiratory chain due to its proximity remains controversial.[60] mtDNA does not accumulate any more oxidative base damage than nuclear DNA.[61] 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.[62] mtDNA is packaged with proteins which appear to be as protective as proteins of the nuclear chromatin.[63] 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.[64] The outcome of mutation in mtDNA may be an alteration in the coding instructions for some proteins,[65] 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.[66] 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[67] and are influenced by complicated stochastic processes within the cell and during development.[27][68]
Mutations in mitochondrial tRNAs can be responsible for severe diseases like the MELAS and MERRF syndromes.[69]
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.[70]
Use
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.[66] 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[67] and are influenced by complicated stochastic processes within the cell and during development.[27][68]
Mutations in mitochondrial tRNAs can be responsible for severe diseases like the MELAS and MERRF syndromes.[69]
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.
Mutations in mitochondrial tRNAs can be responsible for severe diseases like the MELAS and MERRF syndromes.[69]
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.[70]
Recently a mutation in mtDNA has been used to help diagnose prostate cancer in patients with negative prostate biopsy.[71][72] mtDNA alterations can be detected in the bio-fluids of patients with cancer.[73]
Relationship with aging
Though the idea is controversial, some evidence suggests a link between aging and mitochondrial genome dysfunction.[74] 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.[60] 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.[75] 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.[76] 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.[77] 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.[78] Extensive research is being conducted to further investigate this link and methods to combat aging. Presently, gene therapy and nutraceutical supplementation are popular areas of ongoing research.[79][80] 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.[81]
Neurodegenerative diseasesIncreased 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 approxi
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.[82] It has been proposed that aged mitochondria is the critical factor in the origin of neurodegeneration in Alzheimer’s disease.[83]
In Huntington’s disease, mutant huntingtin protein causes mitochondria dysfunction involving inhibition of mitochondrial electron transport, higher levels of reactive oxygen species and increased oxidative stress.[84] Mutant huntingtin protein promotes oxidative damage to mtDNA, as well as nuclear DNA, that may contribute to Huntington’s disease pathology.[85]
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.[86] Thus oxidative damage to mtDNA of motor neurons may be a significant factor in the etiology of ALS.
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.[87][88][89] 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).[88] To support the scientific community in carrying out comparative analyses between mtDNA features and longevity across animals, a dedicated database was built named MitoAge.[90]
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.[91] 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.[92]
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 pare
Deletion breakpoints frequently occur within or near regions showing non-canonical (non-B) conformations, namely hairpins, cruciforms and cloverleaf-like elements.[91] 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.[92]
Use in forensics
- 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.
reactive oxygen species
