MECHANISMS UNDERLYING INTRACELLULAR SELECTION OF MITOCHONDRIAL DNA

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Abstract

Different mtDNA variants can coexist within a single cell in a state of heteroplasmy, competing for the cellular resources necessary for their replication. In this review, we examine documented cases of selfish mitochondrial DNAs — variants that gain a replication advantage within cells but are detrimental at the cellular level — across a range of eukaryotic species, from humans to baker's yeast. This review discusses hypothetical mechanisms that may promote the proliferation of specific mtDNA variants over others in the heteroplasmic cells. Finally, we suggest that the risk posed by selfish mtDNAs has significantly shaped eukaryotic evolution, leading to the emergence of uniparental inheritance and constraints on mtDNA copy number.

About the authors

G. Muravyov

Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University

Moscow, Russia

D. A Knorre

Lomonosov Moscow State University, A.N. Belozersky Institute of Physico-Chemical Biology

Email: knorre@belozersky.msu.ru
Moscow, Russia

References

  1. Roger, A. J., Muñoz-Gómez, S. A., and Kamikawa, R. (2017) The origin and diversification of mitochondria, Curr. Biol., 27, R1177-R1192, https://doi.org/10.1016/j.cub.2017.09.015.
  2. Taanman, J. W. (1999) The mitochondrial genome: structure, transcription, translation and replication, Biochim. Biophys. Acta, 1410, 103-123, https://doi.org/10.1016/s0005-2728(98)00161-3.
  3. Medeiros, T. C., Thomas, R. L., Ghillebert, R., and Graef, M. (2018) Autophagy balances mtDNA synthesis and degradation by DNA polymerase POLG during starvation, J. Cell Biol., 217, 1601-1611, https://doi.org/10.1083/jcb.201801168.
  4. Zhang, Q., Wang, Z., Zhang, W., Wen, Q., Li, X., Zhou, J., et al. (2021) The memory of neuronal mitochondrial stress is inherited transgenerationally via elevated mitochondrial DNA levels, Nat. Cell Biol., 23, 870-880, https://doi.org/10.1038/s41556-021-00724-8.
  5. Galeota-Sprung, B., Fernandez, A., and Sniegowski, P. (2022) Changes to the mtDNA copy number during yeast culture growth, R. Soc. Open Sci., 9, 211842, https://doi.org/10.1098/rsos.211842.
  6. De Giorgi, C., and Saccone, C. (1989) Mitochondrial genome in animal cells. Structure, organization, and evolution, Cell Biophys., 14, 67-78, https://doi.org/10.1007/BF02797392.
  7. Rand, D. M. (2001) The units of selection on mitochondrial DNA, Annu. Rev. Ecol. Syst., 32, 415-448, https://doi.org/10.1146/annurev.ecolsys.32.081501.114109.
  8. Rossignol, R., Faustin, B., Rocher, C., Malgat, M., Mazat, J.-P., and Letellier, T. (2003) Mitochondrial threshold effects, Biochem. J., 370, 751-762, https://doi.org/10.1042/BJ20021594.
  9. Wallace, D. C. (1986) Mitotic segregation of mitochondrial DNAs in human cell hybrids and expression of chloramphenicol resistance, Somat. Cell Mol. Genet., 12, 41-49, https://doi.org/10.1007/BF01560726.
  10. Greaves, L. C., Preston, S. L., Tadrous, P. J., Taylor, R. W., Barron, M. J., Oukrif, D., Leedham, S. J., Deheragoda, M., Sasieni, P., Novelli, M. R., Jankowski, J. A. Z., Turnbull, D. M., Wright, N. A., and McDonald, S. A. C. (2006) Mitochondrial DNA mutations are established in human colonic stem cells, and mutated clones expand by crypt fission, Proc. Natl. Acad. Sci. USA, 103, 714-719, https://doi.org/10.1073/pnas.0505903103.
  11. Ågren, J. A., and Clark, A. G. (2018) Selfish genetic elements, PLoS Genet., 14, e1007700, https://doi.org/10.1371/journal.pgen.1007700.
  12. Khrapko, K., Bodyak, N., Thilly, W. G., van Orsouw, N. J., Zhang, X., Coller, H. A., Perls, T. T., Upton, M., Vijg, J., and Wei, J. Y. (1999) Cell-by-cell scanning of whole mitochondrial genomes in aged human heart reveals a significant fraction of myocytes with clonally expanded deletions, Nucleic Acids Res., 27, 2434-2441, https://doi.org/10.1093/nar/27.11.2434.
  13. Taylor, S. D., Ericson, N. G., Burton, J. N., Prolla, T. A., Silber, J. R., Shendure, J., and Bielas, J. H. (2014) Targeted enrichment and high-resolution digital profiling of mitochondrial DNA deletions in human brain, Aging Cell, 13, 29-38, https://doi.org/10.1111/acel.12146.
  14. Nekhaeva, E., Bodyak, N. D., Kraytsberg, Y., McGrath, S. B., Van Orsouw, N. J., Pluzhnikov, A., Wei, J. Y., Vijg, J., and Khrapko, K. (2002) Clonally expanded mtDNA point mutations are abundant in individual cells of human tissues, Proc. Natl. Acad. Sci. USA, 99, 5521-5526, https://doi.org/10.1073/pnas.072670199.
  15. Jenuth, J. P., Peterson, A. C., and Shoubridge, E. A. (1997) Tissue-specific selection for different mtDNA genotypes in heteroplasmic mice, Nat. Genet., 16, 93-95, https://doi.org/10.1038/ng0597-93.
  16. Korotkevich, E., Conrad, D. N., Gartner, Z. J., and O’Farrell, P. H. (2025) Selfish mutations promote age-associated erosion of mtDNA integrity in mammals, Nat. Commun., 16, 5435, https://doi.org/10.1038/s41467-025-60477-y.
  17. Stewart, J. B., Freyer, C., Elson, J. L., Wredenberg, A., Cansu, Z., Trifunovic, A., and Larsson, N.-G. (2008) Strong purifying selection in transmission of mammalian mitochondrial DNA, PLoS Biol., 6, e10, https://doi.org/10.1371/journal.pbio.0060010.
  18. Wei, W., Tuna, S., Keogh, M. J., Smith, K. R., Aitman, T. J., Beales, P. L., Bennett, D. L., Gale, D. P., Bitner-Glindzicz, M. A. K., Black, G. C., Brennan, P., Elliott, P., Flinter, F. A., Floto, R. A., Houlden, H., Irving, M., Koziell, A., Maher, E. R., Markus, H. S., et al. (2019) Germline selection shapes human mitochondrial DNA diversity, Science, 364, eaau6520, https://doi.org/10.1126/science.aau6520.
  19. Franco, M., Pickett, S. J., Fleischmann, Z., Khrapko, M., Cote-L’Heureux, A., Aidlen, D., Stein, D., Markuzon, N., Popadin, K., Braverman, M., Woods, D. C., Tilly, J. L., Turnbull, D. M., and Khrapko, K. (2022) Dynamics of the most common pathogenic mtDNA variant m.3243A > G demonstrate frequency-dependency in blood and positive selection in the germline, Hum. Mol. Genet., 31, 4075-4086, https://doi.org/10.1093/hmg/ddac149.
  20. Zhang, H., Esposito, M., Pezet, M. G., Aryaman, J., Wei, W., Klimm, F., Calabrese, C., Burr, S. P., Macabelli, C. H., Viscomi, C., Saitou, M., Chiaratti, M. R., Stewart, J. B., Jones, N., and Chinnery, P. F. (2021) Mitochondrial DNA heteroplasmy is modulated during oocyte development propagating mutation transmission, Sci. Adv., 7, eabi5657, https://doi.org/10.1126/sciadv.abi5657.
  21. Franco, M., Cote-L’Heureux, A., Fleischmann, Z., Chen, Z., Khrapko, M., Vyshedskiy, B., Braverman, M., Popadin, K., Pickett, S., Woods, D. C., Tilly, J. L., Turnbull, D., and Khrapko, K. (2023) A novel, wave-shaped profile of germline selection of pathogenic mtDNA mutations is discovered by bypassing a classical statistical bias, bioRxiv, https://doi.org/10.1101/2023.11.21.568140.
  22. Fleischmann, Z., Cote-L’Heureux, A., Franco, M., Oreshkov, S., Annis, S., Khrapko, M., Aidlen, D., Popadin, K., Woods, D. C., Tilly, J. L., and Khrapko, K. (2024) Reanalysis of mtDNA mutations of human primordial germ cells (PGCs) reveals NUMT contamination and suggests that selection in PGCs may be positive, Mitochondrion, 74, 101817, https://doi.org/10.1016/j.mito.2023.10.005.
  23. Mishra, P., and Chan, D. C. (2014) Mitochondrial dynamics and inheritance during cell division, development and disease, Nat. Rev. Mol. Cell Biol., 15, 634-646, https://doi.org/10.1038/nrm3877.
  24. Taylor, R. W., and Turnbull, D. M. (2005) Mitochondrial DNA mutations in human disease, Nat. Rev. Genet., 6, 389-402, https://doi.org/10.1038/nrg1606.
  25. Zhang, J., Liu, H., Luo, S., Chavez-Badiola, A., Liu, Z., Yang, M., Munne, S., Konstantinidis, M., Wells, D., and Huang, T. (2016) First live birth using human oocytes reconstituted by spindle nuclear transfer for mitochondrial DNA mutation causing Leigh syndrome, Fertil. Steril., 106, e375-e376, https://doi.org/10.1016/j.fertnstert.2016.08.004.
  26. Kang, E., Wu, J., Gutierrez, N. M., Koski, A., Tippner-Hedges, R., Agaronyan, K., Platero-Luengo, A., Martinez-­Redondo, P., Ma, H., Lee, Y., Hayama, T., van Dyken, C., Wang, X., Luo, S., Ahmed, R., Li, Y., Ji, D., Kayali, R., Cinnioglu, C., et al. (2016) Mitochondrial replacement in human oocytes carrying pathogenic mitochondrial DNA mutations, Nature, 540, 270-275, https://doi.org/10.1038/nature20592.
  27. Clark, K. A., Howe, D. K., Gafner, K., Kusuma, D., Ping, S., Estes, S., and Denver, D. R. (2012) Selfish little circles: transmission bias and evolution of large deletion-bearing mitochondrial DNA in Caenorhabditis briggsae nematodes, PLoS One, 7, e41433, https://doi.org/10.1371/journal.pone.0041433.
  28. Gitschlag, B. L., Pereira, C. V., Held, J. P., McCandlish, D. M., and Patel, M. R. (2024) Multiple distinct evolutionary mechanisms govern the dynamics of selfish mitochondrial genomes in Caenorhabditis elegans, Nat. Commun., 15, 8237, https://doi.org/10.1038/s41467-024-52596-9.
  29. Ma, H., and O’Farrell, P. H. (2016) Selfish drive can trump function when animal mitochondrial genomes compete, Nat. Genet., 48, 798-802, https://doi.org/10.1038/ng.3587.
  30. Linnane, A. W., Saunders, G. W., Gingold, E. B., and Lukins, H. B. (1968) The biogenesis of mitochondria. V. Cytoplasmic inheritance of erythromycin resistance in Saccharomyces cerevisiae, Proc. Natl. Acad. Sci. USA, 59, 903-910, https://doi.org/10.1073/pnas.59.3.903.
  31. Ephrussi, B., de Margerie-Hottinguer, H., and Roman, H. (1955) Suppressiveness: a new factor in the genetic determinism of the synthesis of respiratory enzymes in yeast, Proc. Natl. Acad. Sci. USA, 41, 1065-1071, https://doi.org/10.1073/pnas.41.12.1065.
  32. De Zamaroczy, M., Marotta, R., Faugeron-Fonty, G., Goursot, R., Mangin, M., Baldacci, G., and Bernardi, G. (1981) The origins of replication of the yeast mitochondrial genome and the phenomenon of suppressivity, Nature, 292, 75-78, https://doi.org/10.1038/292075a0.
  33. Karavaeva, I. E., Golyshev, S. A., Smirnova, E. A., Sokolov, S. S., Severin, F. F., and Knorre, D. A. (2017) Mitochondrial depolarization in yeast zygotes inhibits clonal expansion of selfish mtDNA, J. Cell Sci., 130, 1274-1284, https://doi.org/10.1242/jcs.197269.
  34. Kashko, N. D., Muravyov, G., Karavaeva, I., Glagoleva, E. S., Logacheva, M. D., Garushyants, S. K., and Knorre, D. A. (2025) Inheritance bias of deletion-harbouring mtDNA in yeast: The role of copy number and intracellular selection, PLoS Genet., 21, e1011737, https://doi.org/10.1371/journal.pgen.1011737.
  35. Taylor, D. R., Zeyl, C., and Cooke, E. (2002) Conflicting levels of selection in the accumulation of mitochondrial defects in Saccharomyces cerevisiae, Proc. Natl. Acad. Sci. USA, 99, 3690-3694, https://doi.org/10.1073/pnas.072660299.
  36. Røyrvik, E. C., and Johnston, I. G. (2020) MtDNA sequence features associated with “selfish genomes” predict tissue-specific segregation and reversion, Nucleic Acids Res., 48, 8290-8301, https://doi.org/10.1093/nar/gkaa622.
  37. Clayton, D. A. (1982) Replication of animal mitochondrial DNA, Cell, 28, 693-705, https://doi.org/10.1016/0092-8674(82)90049-6.
  38. Korhonen, J. A., Pham, X. H., Pellegrini, M., and Falkenberg, M. (2004) Reconstitution of a minimal mtDNA replisome in vitro, EMBO J., 23, 2423-2429, https://doi.org/10.1038/sj.emboj.7600257.
  39. Yasukawa, T., and Kang, D. (2018) An overview of mammalian mitochondrial DNA replication mechanisms, J. Biochem., 164, 183-193, https://doi.org/10.1093/jb/mvy058.
  40. Falkenberg, M., and Gustafsson, C. M. (2020) Mammalian mitochondrial DNA replication and mechanisms of deletion formation, Crit. Rev. Biochem. Mol. Biol., 55, 509-524, https://doi.org/10.1080/10409238.2020.1818684.
  41. Kowald, A., Dawson, M., and Kirkwood, T. B. L. (2014) Mitochondrial mutations and ageing: can mitochondrial deletion mutants accumulate via a size based replication advantage? J. Theor. Biol., 340, 111-118, https://doi.org/10.1016/j.jtbi.2013.09.009.
  42. Diaz, F., Bayona-Bafaluy, M. P., Rana, M., Mora, M., Hao, H., and Moraes, C. T. (2002) Human mitochondrial DNA with large deletions repopulates organelles faster than full-length genomes under relaxed copy number control, Nucleic Acids Res., 30, 4626-4633, https://doi.org/10.1093/nar/gkf602.
  43. Seshadri, A., and Badrinarayanan, A. (2025) Exonuclease action of replicative polymerase gamma drives damage-induced mitochondrial DNA clearance, EMBO Rep., 26, 1385-1405, https://doi.org/10.1038/s44319-025-00380-1.
  44. Freel, K. C., Friedrich, A., and Schacherer, J. (2015) Mitochondrial genome evolution in yeasts: an all-encompassing view, FEMS Yeast Res., 15, fov023, https://doi.org/10.1093/femsyr/fov023.
  45. Sato, M., and Sato, K. (2013) Maternal inheritance of mitochondrial DNA by diverse mechanisms to eliminate paternal mitochondrial DNA, Biochim. Biophys. Acta, 1833, 1979-1984, https://doi.org/10.1016/j.bbamcr.2013.03.010.
  46. Chen, Z., Zhang, F., Lee, A., Yamine, M., Wang, Z.-H., Zhang, G., Combs, C., and Xu, H. (2025) Mitochondrial DNA removal is essential for sperm development and activity, EMBO J., 44, 1749-1773, https://doi.org/10.1038/s44318-025-00377-5.
  47. Lim, Y., Rubio-Peña, K., Sobraske, P. J., Molina, P. A., Brookes, P. S., Galy, V., and Nehrke, K. (2019) Fndc-1 contributes to paternal mitochondria elimination in C. elegans, Dev. Biol., 454, 15-20, https://doi.org/10.1016/j.ydbio.2019.06.016.
  48. Busch, K. B., Kowald, A., and Spelbrink, J. N. (2014) Quality matters: how does mitochondrial network dynamics and quality control impact on mtDNA integrity? Philos. Trans. R. Soc. Lond. B Biol. Sci., 369, 20130442, https://doi.org/10.1098/rstb.2013.0442.
  49. Knorre, D. A. (2020) Intracellular quality control of mitochondrial DNA: evidence and limitations, Philos. Trans. R. Soc. Lond. B Biol. Sci., 375, 20190176, https://doi.org/10.1098/rstb.2019.0176.
  50. Wilkens, V., Kohl, W., and Busch, K. (2013) Restricted diffusion of OXPHOS complexes in dynamic mitochondria delays their exchange between cristae and engenders a transitory mosaic distribution, J. Cell Sci., 126, 103-116, https://doi.org/10.1242/jcs.108852.
  51. Lieber, T., Jeedigunta, S. P., Palozzi, J. M., Lehmann, R., and Hurd, T. R. (2019) Mitochondrial fragmentation drives selective removal of deleterious mtDNA in the germline, Nature, 570, 380-384, https://doi.org/10.1038/s41586-019-1213-4.
  52. Milani, L., Ghiselli, F., Maurizii, M. G., Nuzhdin, S. V., and Passamonti, M. (2014) Paternally transmitted mitochondria express a new gene of potential viral origin, Genome Biol. Evol., 6, 391-405, https://doi.org/10.1093/gbe/evu021.
  53. Selifanova, M., Demianchenko, O., Noskova, E., Pitikov, E., Skvortsov, D., Drozd, J., Vatolkina, N., Apel, P., Kolodyazhnaya, E., Ezhova, M. A., Tzetlin, A. B., Neretina, T. V., and Knorre, D. A. (2023) ORFans in mitochondrial genomes of marine polychaete Polydora, Genome Biol. Evol., 15, evad219, https://doi.org/10.1093/gbe/evad219.
  54. Peeva, V., Blei, D., Trombly, G., Corsi, S., Szukszto, M. J., Rebelo-Guiomar, P., Gammage, P. A., Kudin, A. P., Becker, C., Altmüller, J., Minczuk, M., Zsurka, G., and Kunz, W. S. (2018) Linear mitochondrial DNA is rapidly degraded by components of the replication machinery, Nat. Commun., 9, 1727, https://doi.org/10.1038/s41467-018-04131-w.
  55. Nissanka, N., Bacman, S. R., Plastini, M. J., and Moraes, C. T. (2018) The mitochondrial DNA polymerase gamma degrades linear DNA fragments precluding the formation of deletions, Nat. Commun., 9, 2491, https://doi.org/10.1038/s41467-018-04895-1.
  56. DeLuca, S. Z., and O’Farrell, P. H. (2012) Barriers to male transmission of mitochondrial DNA in sperm development, Dev. Cell, 22, 660-668, https://doi.org/10.1016/j.devcel.2011.12.021.
  57. Wolters, J. F., LaBella, A. L., Opulente, D. A., Rokas, A., and Hittinger, C. T. (2023) Mitochondrial genome diversity across the subphylum Saccharomycotina, Front. Microbiol., 14, 1268944, https://doi.org/10.3389/fmicb.2023.1268944.
  58. Megarioti, A. H., and Kouvelis, V. N. (2020) The coevolution of fungal mitochondrial introns and their homing endonucleases (GIY-YIG and LAGLIDADG), Genome Biol. Evol., 12, 1337-1354, https://doi.org/10.1093/gbe/evaa126.
  59. De Grey, A. D. (1997) A proposed refinement of the mitochondrial free radical theory of aging, Bioessays, 19, 161-166, https://doi.org/10.1002/bies.950190211.
  60. Chernyak, B. V., Izyumov, D. S., Lyamzaev, K. G., Pashkovskaya, A. A., Pletjushkina, O. Y., Antonenko, Y. N., Sakharov, D. V., Wirtz, K. W. A., and Skulachev, V. P. (2006) Production of reactive oxygen species in mitochondria of HeLa cells under oxidative stress, Biochim. Biophys. Acta, 1757, 525-534, https://doi.org/10.1016/j.bbabio.2006.02.019.
  61. Skulachev, V. P. (2002) Programmed death phenomena: from organelle to organism, Ann. NY Acad. Sci., 959, 214-237, https://doi.org/10.1111/j.1749-6632.2002.tb02095.x.
  62. Degtyareva, N. P., Saini, N., Sterling, J. F., Placentra, V. C., Klimczak, L. J., Gordenin, D. A., and Doetsch, P. W. (2019) Mutational signatures of redox stress in yeast single-strand DNA and of aging in human mitochondrial DNA share a common feature, PLoS Biol., 17, e3000263, https://doi.org/10.1371/journal.pbio.3000263.
  63. Iliushchenko, D., Efimenko, B., Mikhailova, A. G., Shamanskiy, V., Saparbaev, M. K., Matkarimov, B. T., Mazunin, I., Voronka, A., Knorre, D., Kunz, W. S., Kapranov, P., Denisov, S., Fellay, J., Khrapko, K., Gunbin, K., and Popadin, K. (2025) Deciphering the foundations of mitochondrial mutational spectra: replication-driven and damage-induced signatures across chordate classes, Mol. Biol. Evol., 42, msae261, https://doi.org/10.1093/molbev/msae261.
  64. Shokolenko, I., Venediktova, N., Bochkareva, A., Wilson, G. L., and Alexeyev, M. F. (2009) Oxidative stress induces degradation of mitochondrial DNA, Nucleic Acids Res., 37, 2539-2548, https://doi.org/10.1093/nar/gkp100.
  65. Wiedemann, N., and Pfanner, N. (2017) Mitochondrial machineries for protein import and assembly, Annu. Rev. Biochem., 86, 685-714, https://doi.org/10.1146/annurev-biochem-060815-014352.
  66. Quintana-Cabrera, R., and Scorrano, L. (2023) Determinants and outcomes of mitochondrial dynamics, Mol. Cell, 83, 857-876, https://doi.org/10.1016/j.molcel.2023.02.012.
  67. Yang, L., Long, Q., Liu, J., Tang, H., Li, Y., Bao, F., Qin, D., Pei, D., and Liu, X. (2015) Mitochondrial fusion provides an “initial metabolic complementation” controlled by mtDNA, Cell. Mol. Life Sci., 72, 2585-2598, https://doi.org/10.1007/s00018-015-1863-9.
  68. Edwards, D. M., Røyrvik, E. C., Chustecki, J. M., Giannakis, K., Glastad, R. C., Radzvilavicius, A. L., and Johnston, I. G. (2021) Avoiding organelle mutational meltdown across eukaryotes with or without a germline bottleneck, PLoS Biol., 19, e3001153, https://doi.org/10.1371/journal.pbio.3001153.
  69. Palozzi, J. M., Jeedigunta, S. P., Minenkova, A. V., Monteiro, V. L., Thompson, Z. S., Lieber, T., and Hurd, T. R. (2022) Mitochondrial DNA quality control in the female germline requires a unique programmed mitophagy, Cell Metab., 34, 1809-1823.e6, https://doi.org/10.1016/j.cmet.2022.10.005.
  70. Birky, C. W., Jr. (2008) Uniparental inheritance of organelle genes, Curr. Biol., 18, R692-R695, https://doi.org/10.1016/j.cub.2008.06.049.

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