Editing Mitochondrial DNA (section)

== Mutations and disease ==
[[File:Mitochondrial DNA en.svg|thumb|upright=1.35|right|[[Human mitochondrial DNA]] with groups of protein-, rRNA- and tRNA-encoding genes]]
[[File:Mitochondrial DNA and diseases.svg|thumb|upright=1.35|right|The involvement of mitochondrial DNA in several human diseases]]

=== Susceptibility ===
The concept that mtDNA is particularly susceptible to [[reactive oxygen species]] generated by the [[respiratory chain]] due to its proximity remains controversial.<ref name="pmid19796285">{{Cite journal |vauthors=Alexeyev MF |date=October 2009 |title=Is there more to aging than mitochondrial DNA and reactive oxygen species? |journal=The FEBS Journal |volume=276 |issue=20 |pages=5768–5787 |doi=10.1111/j.1742-4658.2009.07269.x |pmc=3097520 |pmid=19796285}}</ref> mtDNA does not accumulate any more oxidative base damage than nuclear DNA.<ref>{{Cite journal |vauthors=Anson RM, Hudson E, Bohr VA |date=February 2000 |title=Mitochondrial endogenous oxidative damage has been overestimated |journal=FASEB Journal |volume=14 |issue=2 |pages=355–360 |doi=10.1096/fasebj.14.2.355 |pmid=10657991 |s2cid=19771110 |doi-access=free}}</ref> 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.<ref>{{Cite journal |vauthors=Thorslund T, Sunesen M, Bohr VA, Stevnsner T |date=April 2002 |title=Repair of 8-oxoG is slower in endogenous nuclear genes than in mitochondrial DNA and is without strand bias |url=https://zenodo.org/record/1260266 |url-status=live |journal=DNA Repair |volume=1 |issue=4 |pages=261–273 |doi=10.1016/S1568-7864(02)00003-4 |pmid=12509245 |archive-url=https://web.archive.org/web/20191231090007/https://zenodo.org/record/1260266 |archive-date=31 December 2019 |access-date=30 June 2019}}</ref> mtDNA is packaged with proteins which appear to be as protective as proteins of the nuclear chromatin.<ref>{{Cite journal |vauthors=Guliaeva NA, Kuznetsova EA, Gaziev AI |year=2006 |title=[Proteins associated with mitochondrial DNA protect it against the action of X-rays and hydrogen peroxide] |trans-title=Proteins associated with mitochondrial DNA protect it against the action of X-rays and hydrogen peroxide |journal=Biofizika |language=ru |volume=51 |issue=4 |pages=692–697 |pmid=16909848}}</ref> 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.<ref>{{Cite journal |vauthors=Alexeyev M, Shokolenko I, Wilson G, LeDoux S |date=May 2013 |title=The maintenance of mitochondrial DNA integrity--critical analysis and update |journal=Cold Spring Harbor Perspectives in Biology |volume=5 |issue=5 |pages=a012641 |doi=10.1101/cshperspect.a012641 |pmc=3632056 |pmid=23637283}}</ref> The outcome of mutation in mtDNA may be an alteration in the coding instructions for some proteins,<ref>{{Cite book |title=Encyclopedia of Earth |vauthors=Hogan CM |publisher=National Council for Science and the Environment |year=2010 |veditors=Monosson E, Cleveland CJ |location=Washington DC |chapter=Mutation |access-date=18 April 2011 |chapter-url=http://www.eoearth.org/article/Mutation?topic=49496 |archive-url=https://web.archive.org/web/20110430051516/http://www.eoearth.org/article/Mutation?topic=49496 |archive-date=30 April 2011 |url-status=live}}</ref> which may have an effect on organism metabolism and/or fitness.

=== Genetic illness ===
{{Further|Mitochondrial disease}}
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 [[Aging-associated diseases|age-associated pathologies]].<ref>{{Cite journal |vauthors=Alexeyev MF, Ledoux SP, Wilson GL |date=October 2004 |title=Mitochondrial DNA and aging |journal=Clinical Science |volume=107 |issue=4 |pages=355–364 |doi=10.1042/CS20040148 |pmid=15279618 |s2cid=5747202}}</ref> 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<ref>{{Cite journal |vauthors=Burgstaller JP, Johnston IG, Poulton J |date=January 2015 |title=Mitochondrial DNA disease and developmental implications for reproductive strategies |journal=Molecular Human Reproduction |volume=21 |issue=1 |pages=11–22 |doi=10.1093/molehr/gau090 |pmc=4275042 |pmid=25425607}}</ref> and are influenced by complicated [[cellular noise|stochastic processes]] within the cell and during development.<ref name=pmid26035426/><ref>{{Cite journal |display-authors=6 |vauthors=Burgstaller JP, Johnston IG, Jones NS, Albrechtová J, Kolbe T, Vogl C, Futschik A, Mayrhofer C, Klein D, Sabitzer S, Blattner M, Gülly C, Poulton J, Rülicke T, Piálek J, Steinborn R, Brem G |date=June 2014 |title=MtDNA segregation in heteroplasmic tissues is common in vivo and modulated by haplotype differences and developmental stage |journal=Cell Reports |volume=7 |issue=6 |pages=2031–2041 |doi=10.1016/j.celrep.2014.05.020 |pmc=4570183 |pmid=24910436}}</ref>

Mutations in mitochondrial tRNAs can be responsible for severe diseases like the [[MELAS syndrome|MELAS]] and [[MERRF syndrome|MERRF]] syndromes.<ref name="nature">{{Cite journal |vauthors=Taylor RW, Turnbull DM |date=May 2005 |title=Mitochondrial DNA mutations in human disease |journal=Nature Reviews. Genetics |volume=6 |issue=5 |pages=389–402 |doi=10.1038/nrg1606 |pmc=1762815 |pmid=15861210}}</ref>

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.<ref>{{Cite journal |vauthors=Angelini C, Bello L, Spinazzi M, Ferrati C |date=July 2009 |title=Mitochondrial disorders of the nuclear genome |journal=Acta Myologica |volume=28 |issue=1 |pages=16–23 |pmc=2859630 |pmid=19772191}}</ref>

=== Use in disease diagnosis ===

Recently a mutation in mtDNA has been used to help diagnose prostate cancer in patients with negative [[prostate biopsy]].<ref name="pmid20944788">{{Cite journal |vauthors=Reguly B, Jakupciak JP, Parr RL |date=October 2010 |title=3.4 kb mitochondrial genome deletion serves as a surrogate predictive biomarker for prostate cancer in histopathologically benign biopsy cores |journal=Canadian Urological Association Journal |volume=4 |issue=5 |pages=E118–E122 |doi=10.5489/cuaj.932 |pmc=2950771 |pmid=20944788}}</ref><ref name="pmid20084081">{{Cite journal |display-authors=6 |vauthors=Robinson K, Creed J, Reguly B, Powell C, Wittock R, Klein D, Maggrah A, Klotz L, Parr RL, Dakubo GD |date=June 2010 |title=Accurate prediction of repeat prostate biopsy outcomes by a mitochondrial DNA deletion assay |journal=Prostate Cancer and Prostatic Diseases |volume=13 |issue=2 |pages=126–131 |doi=10.1038/pcan.2009.64 |pmid=20084081 |s2cid=25050759}}</ref>
mtDNA alterations can be detected in the bio-fluids of patients with cancer.<ref name="Mair">{{Cite journal |display-authors=6 |vauthors=Mair R, Mouliere F, Smith CG, Chandrananda D, Gale D, Marass F, Tsui DW, Massie CE, Wright AJ, Watts C, Rosenfeld N, Brindle KM |date=January 2019 |title=Measurement of Plasma Cell-Free Mitochondrial Tumor DNA Improves Detection of Glioblastoma in Patient-Derived Orthotopic Xenograft Models |url=https://www.repository.cam.ac.uk/handle/1810/286401 |url-status=live |journal=Cancer Research |volume=79 |issue=1 |pages=220–230 |doi=10.1158/0008-5472.CAN-18-0074 |pmc=6753020 |pmid=30389699 |archive-url=https://web.archive.org/web/20190924104515/https://www.repository.cam.ac.uk/handle/1810/286401 |archive-date=24 September 2019 |access-date=24 September 2019}}</ref> 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]], heart failure, and cancer.{{cn|date=November 2024}}

===Relationship with ageing===
Though the idea is controversial, some evidence suggests a link between aging and mitochondrial genome dysfunction.<ref>{{Cite book |url=http://www.sens.org/files/pdf/MiFRA-06.pdf |title=The Mitochondrial Free Radical Theory of Aging |vauthors=de Grey A |publisher=Landes Bioscience |year=1999 |isbn=978-1-57059-564-6 |access-date=1 May 2016 |archive-url=https://web.archive.org/web/20160603015443/http://www.sens.org/files/pdf/MiFRA-06.pdf |archive-date=3 June 2016 |url-status=live}}{{page needed|date=April 2015}}</ref> 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.<ref name=pmid19796285/> Also, [[Naked mole-rat|naked mole rats]], [[rodent]]s about the size of [[Mouse|mice]], live about eight times longer than mice despite having reduced, compared to mice, antioxidant defenses and increased oxidative damage to biomolecules.<ref>{{Cite journal |vauthors=Lewis KN, Andziak B, Yang T, Buffenstein R |date=October 2013 |title=The naked mole-rat response to oxidative stress: just deal with it |journal=Antioxidants & Redox Signaling |volume=19 |issue=12 |pages=1388–1399 |doi=10.1089/ars.2012.4911 |pmc=3791056 |pmid=23025341}}</ref> 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.<ref>{{Cite journal |vauthors=Shigenaga MK, Hagen TM, Ames BN |date=November 1994 |title=Oxidative damage and mitochondrial decay in aging |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=91 |issue=23 |pages=10771–10778 |bibcode=1994PNAS...9110771S |doi=10.1073/pnas.91.23.10771 |jstor=2365473 |pmc=45108 |pmid=7971961 |doi-access=free}}</ref> 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.<ref>{{Cite journal |display-authors=6 |vauthors=Trifunovic A, Hansson A, Wredenberg A, Rovio AT, Dufour E, Khvorostov I, Spelbrink JN, Wibom R, Jacobs HT, Larsson NG |date=December 2005 |title=Somatic mtDNA mutations cause aging phenotypes without affecting reactive oxygen species production |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=102 |issue=50 |pages=17993–17998 |bibcode=2005PNAS..10217993T |doi=10.1073/pnas.0508886102 |jstor=4152716 |pmc=1312403 |pmid=16332961 |doi-access=free}}</ref> 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.<ref>{{Cite journal |vauthors=Aledo JC, Li Y, de Magalhães JP, Ruíz-Camacho M, Pérez-Claros JA |date=April 2011 |title=Mitochondrially encoded methionine is inversely related to longevity in mammals |journal=Aging Cell |volume=10 |issue=2 |pages=198–207 |doi=10.1111/j.1474-9726.2010.00657.x |pmid=21108730 |doi-access=free}}</ref> The application of a mitochondrial-specific ROS scavenger, which lead to a significant longevity of the mice studied,<ref>{{Cite journal |display-authors=6 |vauthors=Shabalina IG, Vyssokikh MY, Gibanova N, Csikasz RI, Edgar D, Hallden-Waldemarson A, Rozhdestvenskaya Z, Bakeeva LE, Vays VB, Pustovidko AV, Skulachev MV, Cannon B, Skulachev VP, Nedergaard J |date=February 2017 |title=Improved health-span and lifespan in mtDNA mutator mice treated with the mitochondrially targeted antioxidant SkQ1 |journal=Aging |volume=9 |issue=2 |pages=315–339 |doi=10.18632/aging.101174 |pmc=5361666 |pmid=28209927}}</ref> 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.<ref>{{Cite journal |vauthors=Ferrari CK |year=2004 |title=Functional foods, herbs and nutraceuticals: towards biochemical mechanisms of healthy aging |journal=Biogerontology |volume=5 |issue=5 |pages=275–289 |doi=10.1007/s10522-004-2566-z |pmid=15547316 |s2cid=11568208}}</ref><ref>{{Cite journal |vauthors=Taylor RW |date=February 2005 |title=Gene therapy for the treatment of mitochondrial DNA disorders |journal=Expert Opinion on Biological Therapy |volume=5 |issue=2 |pages=183–194 |doi=10.1517/14712598.5.2.183 |pmid=15757380 |s2cid=35276183}}</ref> 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.<ref>{{Cite journal |vauthors=Bjelakovic G, Nikolova D, Gluud C |date=September 2013 |title=Antioxidant supplements to prevent mortality |journal=JAMA |volume=310 |issue=11 |pages=1178–1179 |doi=10.1001/jama.2013.277028 |pmid=24045742}}</ref>
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.<ref>{{Cite journal |display-authors=6 |vauthors=Gureev AP, Andrianova NV, Pevzner IB, Zorova LD, Chernyshova EV, Sadovnikova IS, Chistyakov DV, Popkov VA, Semenovich DS, Babenko VA, Silachev DN, Zorov DB, Plotnikov EY, Popov VN |date=September 2022 |title=Dietary restriction modulates mitochondrial DNA damage and oxylipin profile in aged rats |url=https://febs.onlinelibrary.wiley.com/doi/10.1111/febs.16451 |journal=The FEBS Journal |volume=289 |issue=18 |pages=5697–5713 |doi=10.1111/febs.16451 |pmid=35373508 |s2cid=247938550 |url-access=subscription |archive-url=https://web.archive.org/web/20220504105319/https://febs.onlinelibrary.wiley.com/doi/10.1111/febs.16451 |archive-date=4 May 2022 |access-date=11 May 2022}}</ref>

=== Neurodegenerative diseases ===

Increased mt[[DNA damage (naturally occurring)|DNA damage]] is a feature of several [[neurodegeneration|neurodegenerative diseases]].

The brains of individuals with [[Alzheimer's disease]] have elevated levels of [[DNA oxidation|oxidative DNA damage]] in both [[nuclear DNA]] and mtDNA, but the mtDNA has approximately 10-fold higher levels than nuclear DNA.<ref name="pmid15857398">{{Cite journal |vauthors=Wang J, Xiong S, Xie C, Markesbery WR, Lovell MA |date=May 2005 |title=Increased oxidative damage in nuclear and mitochondrial DNA in Alzheimer's disease |journal=Journal of Neurochemistry |volume=93 |issue=4 |pages=953–962 |doi=10.1111/j.1471-4159.2005.03053.x |pmid=15857398 |doi-access=free}}</ref> It has been proposed that aged [[mitochondrion|mitochondria]] is the critical factor in the origin of neurodegeneration in Alzheimer's disease.<ref name="pmid24733654">{{Cite journal |vauthors=Bonda DJ, Wang X, Lee HG, Smith MA, Perry G, Zhu X |date=April 2014 |title=Neuronal failure in Alzheimer's disease: a view through the oxidative stress looking-glass |journal=Neuroscience Bulletin |volume=30 |issue=2 |pages=243–252 |doi=10.1007/s12264-013-1424-x |pmc=4097013 |pmid=24733654}}</ref> 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.<ref>{{Cite journal |vauthors=Canugovi C, Shamanna RA, Croteau DL, Bohr VA |date=June 2014 |title=Base excision DNA repair levels in mitochondrial lysates of Alzheimer's disease |journal=Neurobiology of Aging |volume=35 |issue=6 |pages=1293–1300 |doi=10.1016/j.neurobiolaging.2014.01.004 |pmc=5576885 |pmid=24485507}}</ref>

In [[Huntington's disease]], mutant [[huntingtin protein]] causes [[mitochondrial dysfunction]] involving inhibition of [[mitochondrial]] [[electron transport chain|electron transport]], higher levels of [[reactive oxygen species]] and increased [[oxidative stress]].<ref name="pmid28785371">{{Cite journal |vauthors=Liu Z, Zhou T, Ziegler AC, Dimitrion P, Zuo L |date=2017 |title=Oxidative Stress in Neurodegenerative Diseases: From Molecular Mechanisms to Clinical Applications |journal=Oxidative Medicine and Cellular Longevity |volume=2017 |page=2525967 |doi=10.1155/2017/2525967 |pmc=5529664 |pmid=28785371 |doi-access=free}}</ref> Mutant huntingtin protein promotes oxidative damage to mtDNA, as well as nuclear DNA, that may contribute to Huntington's disease [[pathology]].<ref name="pmid23602907">{{Cite journal |vauthors=Ayala-Peña S |date=September 2013 |title=Role of oxidative DNA damage in mitochondrial dysfunction and Huntington's disease pathogenesis |journal=Free Radical Biology & Medicine |volume=62 |pages=102–110 |doi=10.1016/j.freeradbiomed.2013.04.017 |pmc=3722255 |pmid=23602907}}</ref>

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 neuron]]s are impaired.<ref name="pmid11904761">{{Cite journal |vauthors=Kikuchi H, Furuta A, Nishioka K, Suzuki SO, Nakabeppu Y, Iwaki T |date=April 2002 |title=Impairment of mitochondrial DNA repair enzymes against the accumulation of 8-oxo-guanine in the spinal motor neurons of amyotrophic lateral sclerosis |journal=Acta Neuropathologica |volume=103 |issue=4 |pages=408–414 |doi=10.1007/s00401-001-0480-x |pmid=11904761 |s2cid=2102463}}</ref> Thus oxidative damage to mtDNA of motor neurons may be a significant factor in the [[etiology]] of ALS.{{cn|date=November 2024}}

=== Correlation of the mtDNA base composition with animal life spans ===
[[File:Correlation between the mtDNA GC% and maximum life span across 387 different mammalian species.png|thumb|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 [[Correlation and dependence|correlations]] exist between the mtDNA base composition and animal species-specific maximum life spans.<ref name="Lehmann et al., 2006">{{Cite journal |vauthors=Lehmann G, Budovsky A, Muradian KK, Fraifeld VE |year=2006 |title=Mitochondrial genome anatomy and species-specific lifespan |journal=Rejuvenation Research |volume=9 |issue=2 |pages=223–226 |doi=10.1089/rej.2006.9.223 |pmid=16706648}}</ref><ref name="Lehmann et al., 2008">{{Cite journal |vauthors=Lehmann G, Segal E, Muradian KK, Fraifeld VE |date=April 2008 |title=Do mitochondrial DNA and metabolic rate complement each other in determination of the mammalian maximum longevity? |journal=Rejuvenation Research |volume=11 |issue=2 |pages=409–417 |doi=10.1089/rej.2008.0676 |pmid=18442324}}</ref><ref name="Lehmann et al., 2013">{{Cite journal |vauthors=Lehmann G, Muradian KK, Fraifeld VE |year=2013 |title=Telomere length and body temperature-independent determinants of mammalian longevity? |journal=Frontiers in Genetics |volume=4 |issue=111 |page=111 |doi=10.3389/fgene.2013.00111 |pmc=3680702 |pmid=23781235 |doi-access=free}}</ref> As demonstrated in their work, higher mtDNA [[guanine]] + [[cytosine]] content ([[GC-content|GC%]]) strongly associates with longer [[maximum life span]]s across animal species. An additional observation is that the mtDNA GC% correlation with the maximum life spans is independent of the well-known correlation between animal species' metabolic rate and maximum life spans. The mtDNA GC% and resting metabolic rate explain the differences in animal species' maximum life spans in a multiplicative manner (i.e., species maximum life span = their mtDNA GC% * metabolic rate).<ref name="Lehmann et al., 2008" /> To support the scientific community in carrying out comparative analyses between mtDNA features and longevity across animals, a dedicated database was built named [http://www.mitoage.info/ MitoAge].<ref>{{Cite journal |vauthors=Toren D, Barzilay T, Tacutu R, Lehmann G, Muradian KK, Fraifeld VE |date=January 2016 |title=MitoAge: a database for comparative analysis of mitochondrial DNA, with a special focus on animal longevity |journal=Nucleic Acids Research |volume=44 |issue=D1 |pages=D1262–D1265 |doi=10.1093/nar/gkv1187 |pmc=4702847 |pmid=26590258}}</ref>

=== 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.<ref>{{Cite journal |display-authors=6 |vauthors=Mikhailova AG, Mikhailova AA, Ushakova K, Tretiakov EO, Iliushchenko D, Shamansky V, Lobanova V, Kozenkov I, Efimenko B, Yurchenko AA, Kozenkova E, Zdobnov EM, Makeev V, Yurov V, Tanaka M, Gostimskaya I, Fleischmann Z, Annis S, Franco M, Wasko K, Denisov S, Kunz WS, Knorre D, Mazunin I, Nikolaev S, Fellay J, Reymond A, Khrapko K, Gunbin K, Popadin K |date=October 2022 |title=A mitochondria-specific mutational signature of aging: increased rate of A &gt; G substitutions on the heavy strand |journal=Nucleic Acids Research |volume=50 |issue=18 |pages=10264–10277 |doi=10.1093/nar/gkac779 |pmc=9561281 |pmid=36130228}}</ref> 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.{{cn|date=November 2024}}

=== 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.<ref>{{Cite journal |vauthors=Damas J, Carneiro J, Gonçalves J, Stewart JB, Samuels DC, Amorim A, Pereira F |date=September 2012 |title=Mitochondrial DNA deletions are associated with non-B DNA conformations |journal=Nucleic Acids Research |volume=40 |issue=16 |pages=7606–7621 |doi=10.1093/nar/gks500 |pmc=3439893 |pmid=22661583}}</ref> 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.<ref>{{Cite journal |vauthors=Oliveira PH, da Silva CL, Cabral JM |year=2013 |title=An appraisal of human mitochondrial DNA instability: new insights into the role of non-canonical DNA structures and sequence motifs |journal=PLOS ONE |volume=8 |issue=3 |pages=e59907 |bibcode=2013PLoSO...859907O |doi=10.1371/journal.pone.0059907 |pmc=3612095 |pmid=23555828 |doi-access=free}}</ref>