Mitochondrial Genome (mtDNA) and Human Diseases
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Published
Sep 17, 2021
Abstract
Mitochondria not only provide necessary energy for cells, but more importantly, they participate in the regulation of various biological functions and activities of cells. As one of the critical components of the body’s genome, mitochondrial genome (mtDNA) is the key to cell bioenergetics and genetics. However, since no protection of histones and a complete self-repair system, mtDNA is extremely prone to mutate. Human diseases caused by mtDNA mutations are only transmitted through the maternal line. The same phenotype can come from multiple mtDNA mutations, and the same mtDNA mutation can lead to multiple phenotypes. This is the major reason that makes the diagnosis and identification of mtDNA genetic diseases difficult. Meanwhile, mtDNA mutations may be the culprit involved in mediating the aging and tumorigenesis. Currently, no effective therapeutics for diseases caused by mtDNA mutations, but with the deepening of research and technological advancement, it is promising that breakthroughs in the diagnosis and treatment of mitochondrial-related diseases in the near future.
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Keywords
Mitochondrial DNA, Diseases, Genetics, Mutation, Therapeutics
References
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3. Abate M, Festa A, Falco M, Lombardi A, Luce A, Grimaldi A, Zappavigna S, Sperlongano P, Irace C, Caraglia M, Misso G. Mitochondria as playmakers of apoptosis, autophagy and senescence. Semin Cell Dev Biol 2020; 98:139-153. DOI: https://doi.org/10.1016/j.semcdb.2019.05.022
4. Saki M, Prakash A. DNA damage related crosstalk between the nucleus and mitochondria. Free Radic Biol Med 2017; 107:216-227. DOI: https://doi.org/10.1016/j.freeradbiomed.2016.11.050
5. Basu U, Bostwick AM, Das K, Dittenhafer-Reed KE, Patel SS. Structure, mechanism, and regulation of mitochondrial DNA transcription initiation. J Biol Chem 2020; 295(52):18406-18425. DOI: https://doi.org/10.1074/jbc.REV120.011202
6. Luft R, Ikkos D, Palmieri G, Ernster L, Afzelius B. A case of severe hypermetabolism of nonthyroid origin with a defect in the maintenance of mitochondrial respiratory control: a correlated clinical, biochemical, and morphological study. J Clin Invest 1962; 41(9):1776-1804. DOI: https://doi.org/10.1172/JCI104637
7. Holt IJ, Harding AE, Morgan-Hughes JA. Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies. Nature 1988; 331(6158):717-719. DOI: https://doi.org/10.1038/331717a0
8. Wallace DC, Singh G, Lott MT, Hodge JA, Schurr TG, Lezza AM, Elsas LJ II, Nikoskelainen EK. Mitochondrial DNA mutation associated with Leber’s hereditary optic neuropathy. Science 1988; 242(4884):1427-1430. DOI: https://doi.org/10.1126/science.3201231
9. Singh G, Lott MT, Wallace DC. A mitochondrial DNA mutation as a cause of Leber’s hereditary optic neuropathy. N Engl J Med 1989; 320(20):1300-1305. DOI: https://doi.org/10.1056/NEJM198905183202002
10. Yan C, Duanmu X, Zeng L, Liu B, Song Z. Mitochondrial DNA: Distribution, mutations, and elimination. Cells 2019; 8(4):379. DOI: https://doi.org/10.3390/cells8040379
11. Ott M, Amunts A, Brown A. Organization and regulation of mitochondrial protein synthesis. Annu Rev Biochem 2016; 85:77-101. DOI: https://doi.org/10.1146/annurev-biochem-060815-014334
12. Farge G, Falkenberg M. Organization of DNA in mammalian mitochondria. Int J Mol Sci 2019; 20(11):2770. DOI: https://doi.org/10.3390/ijms20112770
13. Giles RE, Blanc H, Cann HM, Wallace DC. Maternal inheritance of human mitochondrial DNA. Proc Natl Acad Sci USA 1980; 77(11):6715-6719. DOI: https://doi.org/10.1073/pnas.77.11.6715
14. Schwartz M, Vissing J. Paternal inheritance of mitochondrial DNA. N Engl J Med 2002; 347(8):576-580. DOI: https://doi.org/10.1056/NEJMoa020350
15. Taylor RW, McDonnell MT, Blakely EL, Chinnery PF, Taylor GA, Howell N, Zeviani M, Briem E, Carrara F, Turnbull DM. Genotypes from patients indicate no paternal mitochondrial DNA contribution. Ann Neurol 2003; 54(4):521-524. DOI: https://doi.org/10.1002/ana.10673
16. Schwartz M, Vissing J. No evidence for paternal inheritance of mtDNA in patients with sporadic mtDNA mutations. J Neurol Sci 2004; 218(1-2):99-101. DOI: https://doi.org/10.1016/j.jns.2003.11.008
17. Sutovsky P, Moreno RD, Ramalho-Santos J, Dominko T, Simerly C, Schatten G. Ubiquitin tag for sperm mitochondria. Nature 1999; 402(6760):371-372. DOI: https://doi.org/10.1038/46466
18. Sutovsky P, Moreno RD, Ramalho-Santos J, Dominko T, Simerly C, Schatten G. Ubiquitinated sperm mitochondria, selective proteolysis, and the regulation of mitochondrial inheritance in mammalian embryos. Biol Reprod 2000; 63(2):582-590. DOI: https://doi.org/10.1095/biolreprod63.2.582
19. St John J, Sakkas D, Dimitriadi K, Barnes A, Maclin V, Ramey J, Barratt C, De Jonge C. Failure of elimination of paternal mitochondrial DNA in abnormal embryos. Lancet 2000; 355(9199):200. DOI: https://doi.org/10.1016/s0140-6736(99)03842-8
20. Jeppesen TD, Schwartz M, Frederiksen AL, Wibrand F, Olsen DB, Vissing J. Muscle phenotype and mutation load in 51 persons with the 3243A>G mitochondrial DNA mutation. Arch Neurol 2006; 63(12):1701-1706. DOI: https://doi.org/10.1001/archneur.63.12.1701
21. Frederiksen AL, Andersen PH, Kyvik KO, Jeppesen TD, Vissing J, Schwartz M. Tissue specific distribution of the 3243A->G mtDNA mutation. J Med Genet 2006; 43(8):671-677. DOI: https://doi.org/10.1136/jmg.2005.039339
22. Rossignol R, Faustin B, Rocher C, Malgat M, Mazat JP, Letellier T. Mitochondrial threshold effects. Biochem J 2003; 370(Pt 3):751-762. DOI: https://doi.org/10.1042/BJ20021594
23. Rebolledo-Jaramillo B, Su MS, Stoler N, McElhoe JA, Dickins B, Blankenberg D, Korneliussen TS, Chiaromonte F, Nielsen R, Holland MM, Paul IM, Nekrutenko A, Makova KD. Maternal age effect and severe germ-line bottleneck in the inheritance of human mitochondrial DNA. Proc Natl Acad Sci USA 2014; 111(43):15474-15479. DOI: https://doi.org/10.1073/pnas.1409328111
24. Shoubridge EA, Wai T. Mitochondrial DNA and the mammalian oocyte. Curr Top Dev Biol 2007; 77:87-111. DOI: https://doi.org/10.1016/S0070-2153(06)77004-1
25. Cao L, Shitara H, Horii T, Nagao Y, Imai H, Abe K, Hara T, Hayashi J, Yonekawa H. The mitochondrial bottleneck occurs without reduction of mtDNA content in female mouse germ cells. Nat Genet 2007; 39(3):386-390. DOI: https://doi.org/10.1038/ng1970
26. Chappel S. The role of mitochondria from mature oocyte to viable blastocyst. Obstet Gynecol Int 2013; 2013:183024. DOI: https://doi.org/10.1155/2013/183024
27. Taylor RW, Turnbull DM. Mitochondrial DNA mutations in human disease. Nat Rev Genet 2005; N6(5):389-402. DOI: https://doi.org/10.1038/nrg1606
28. Schon EA, DiMauro S, Hirano M. Human mitochondrial DNA: Roles of inherited and somatic mutations. Nat Rev Genet 2012; 13(12):878-890. DOI: https://doi.org/10.1038/nrg3275
29. McInnes, J. Mitochondrial-associated metabolic disorders: Foundations, pathologies and recent progress. Nutr Metab (Lond) 2013; 10:63. DOI: https://doi.org/10.1186/1743-7075-10-63
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How to Cite
Davidson, R. L. (2021). Mitochondrial Genome (mtDNA) and Human Diseases. Science Insights, 38(4), 317–325. https://doi.org/10.15354/si.21.re201
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