The Origin of Mitochondria and their Role in the Evolution of Life and Human Health

In studies of many medical and biological problems, there is a clear underestimation of the fundamental role of mitochondria in the evolution of eukaryotic organisms on the planet, including fungi, plants and fauna. It is  important to take into consideration numerous fundamental functions of mitochondria when studying the  human physiology and pathology, aging mechanisms. In this lecture, we briefly discuss the origin of mitochondria and their importance in the emergence of plants, which appeared on the planet 1–1.5 billion years later than eukaryotes with mitochondria, and served as the food basis for the rapid evolution of all species of the animal world. In the course of transformation of protobacteria into mitochondria, approximately 1000–1500 genes were transferred to the nucleus of eukaryotes, and the remaining 37 mitochondrial genes (mtDNA) exist in all types of animals. The presence of mitochondria in eukaryotes led to increased production  of reactive oxygen species and accelerated mutations in mtDNA. The spread of sexual reproduction may have been the way of protection against the accumulation of harmful mutations in mtDNA. At the same time, in all animal species mtDNA is inherited only maternally. In humans, the maternal inheritance of mtDNA led to uneven distribution, in small or inbred populations in particular, of a number of diseases with large prevalence in men, as well as male infertility, and in general accelerated aging and shorter lifespan in men, as compared with women. These negative consequences of the maternal inheritance of mtDNA were termed as “mother’s curse”. Recent studies have shown that mtDNA mutations are not the cause of human aging. The crisis of the mitochondrial free radical theory of aging is largely associated with the neglect of the protonated form of the superoxide radical, the perhydroxyl radical, which activates the peroxidation of polyunsaturated fatty acids in mitochondrial phospholipids. This results in production of various biologically active molecules and toxins. Therefore, initially aging may lack the manifestation of specific symptoms because of gradual accumulation of a wide variety of disorders and damages to the structure and functions of mitochondria and cells that finally lead to the development of diseases. The pathologies appear primarily in those organs that have a wide range of functional activity and a high dependence on oxygen consumption, namely the heart, brain, skeletal muscles and vascular epithelium.

mitochondria, aging, evolution, mitochondrial DNA, mother’s curse, gender differences, metabolism

1. Wallace DC. Structure and evolution of organelle genomes. Microbiol Rev. 1982; 46(2): 208-240.

2. Wallace DC. Diseases of the mitochondrial DNA. Annu Rev Biochem. 1992; 61: 1175-1212. doi: 10.1146/annurev.bi.61.070192.005523

3. Wallace DC. A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine. Annu Rev Genet. 2005; 39: 359-407. doi: 10.1146/annurev.genet.39.110304.095751

4. Wallace DC. Why do we still have a maternally inherited mitochondrial DNA? Insights from evolutionary medicine. Annu Rev Biochem. 2007; 76: 781-821. doi: 10.1146/annurev.biochem.76.081205.150955

5. Wallace DC. Mitochondria as chi. Genetics. 2008; 179(2): 727-735. doi: 10.1534/genetics.104.91769

6. Wallace DC, Fan W. Energetics, epigenetics, mitochondrial genetics. Mitochondrion. 2010; 10(1): 12-31. doi: 10.1016/j.mito.2009.09.006

7. Hörandl E, Speijer D. How oxygen gave rise to eukaryotic sex. Proc Biol Sci. 2018; 285(1872): 20172706. doi: 10.1098/rspb.2017.2706

8. Gaziev AI, Shaikhaev GO. Nuclear mitochondrial pseudogenes. Molecular Biology. 2010; 44(3): 405-417. doi: 10.1134/S0026893310030027

9. Behe MJ. Darwin’s Black Box. New York: Free Press; 1996.

10. Thompson В, Harrub B. Molecular evidence of human origins – [Part II]. Reason and Revelation. 2005; 25(5): 33-39.

11. Sagan L. On the origin of mitosing cells. J Theor Biol. 1967; 14(3): 255-274. doi: 10.1016/0022-5193(67)90079-3

12. Lang BF, Gray MW, Burger G. Mitochondrial genome revolution and the origin of eukaryotes. Annu Rev Genet. 1999; 33: 351-397. doi: 10.1146/annurev.genet.33.1.351

13. Lang BF, Burger B, O’Kelly CJ, Cedergren R, Golding GB, Lemieux C, et al. An ancestral mitochondrial DNA resembling a eubacterial genome in miniature. Nature. 1997; 387(6632): 493-497. doi: 10.1038/387493a0

14. Gray MW, Burger G, Lang BF. Mitochondrial evolution. Science. 1999; 283(5407): 1476-1481. doi: 10.1126/science.283.5407.1476

15. Gregersen N, Hansen J, Palmfeldt J. Mitochondrial proteomics – a tool for the study of metabolic disorders. J Inherit Metab Dis. 2012; 35(4): 715-726. doi: 10.1007/s10545-012-9480-3

16. Price DC, Chan CX, Su Yoon H, Yang EC, Qiu H, Weber AP, et al. Cyanophora paradoxa genome elucidates origin of photosynthesis in algae and plants. Science. 2012; 335(6070): 843-847. doi: 10.1126/science.1213561

17. Archibald JM. The puzzle of plastid evolution. Curr Biol. 2009; 19(2): R81-R88. doi: 10.1016/j.cub.2008.11.067

18. McFadden GI, Van Dooren GG. Evolution: red algal genome affirms a common origin of all plastids. Curr Biol. 2004; 14(13): R514-R516. doi: 10.1016/j.cub.2004.06.041

19. Greiner S, Sobanski J, Bock R. Why are most organelle genomes transmitted maternally? Bioessays. 2015; 37(1): 80-94. doi: 10.1002/bies.201400110

20. Christie JR, Beekman M. Uniparental inheritance promotes adaptive evolution in cytoplasmic genomes. Mol Biol Evol. 2017; 34(3): 677-691. doi: 10.1093/molbev/msw266

21. Mootha VK, Bunkenborg J, Olsen JV, Hjerrild M, Wisniewski JR, Stahl E, et al. Integrated analysis of protein composition, tissue diversity, and gene regulation in mouse mitochondria. Cell. 2003; 115(5): 629-640. doi: 10.1016/S0092-8674(03)00926-7

22. Woodson JD, Chory J. Coordination of gene expression between organellar and nuclear genomes. Nat Rev Genet. 2008; 9(5): 383-395. doi: 10.1038/nrg2348

23. Chacinska A, Koehler CM, Milenkovic D, Lithgow T, Pfanner N. Importing mitochondrial proteins: machineries and mechanisms. Cell. 2009; 138(4): 628-644. doi: 10.1016/j.cell.2009.08.005

24. Bensasson D, Feldman MW, Petrov DA. Rates of DNA duplication and mitochondrial DNA insertion in the human genome. J Mol Evol. 2003; 57(3): 343-354. doi: 10.1007/s00239-003-2485-7

25. Picard M, Wallace DC, Burelle Y. The rise of mitochondria in medicine. Mitochondrion. 2016; 30: 105-116. doi: 10.1016/j.mito.2016.07.003

26. Kazak L, Reyes A, Holt IJ. Minimizing the damage: repair pathways keep mitochondrial DNA intact. Nat Rev Mol Cell Biol. 2012; 13(10): 659-671. doi: 10.1038/nrm3439

27. Gilkerson R, Bravo L, Garcia I, Gaytan N, Herrera A, Maldonado A, et al. The mitochondrial nucleoid: integrating mitochondrial DNA into cellular homeostasis. Cold Spring Harb Perspect Biol. 2013; 5(5): a011080. doi: 10.1101/cshperspect.a011080

28. Tarnopolsky MA. Gender differences in substrate metabolism during endurance exercise. Can J Appl Physiol. 2000; 25(4): 312-327. doi: 10.1139/h00-024

29. Dionne I, Despres JP, Bouchard C, Tremblay A. Gender difference in the effect of body composition on energy metabolism. Int J Obes Relat Metab Disord. 1999; 23(3): 312-319. doi: 10.1038/sj.ijo.0800820

30. Leskanicova A, Chovancova O, Babincak M, Verboova L, Benetinova Z, Macekova D, et al. Sexual dimorphism in energy metabolism of Wistar rats using data analysis. Molecules. 2020; 25(10): 2353. doi: 10.3390/molecules25102353

31. 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: 10.1073/pnas.77.11.6715

32. Morrow JD, Awad JA, Wu A, Zackert WE, Daniel VC, Roberts LJ. Nonenzymatic free radical-catalyzed generation of thromboxane-like compounds (isothromboxanes) in vivo. J Biol Chem. 1996; 271(38): 23185-23190. doi: 10.1074/jbc.271.38.23185

33. Roberts LJ, Montine TJ, Markesbery WR, Tapper AP, Hardy H, Chemtob S, et al. Formation of isoprostane-like compounds (neuroprostanes) in vivo from docosahexaenoic acid. J Biol Chem. 1998; 273(22): 13605-13612. doi: 10.1074/jbc.273.22.13605

34. Panov A. Perhydroxyl radical (HO2•) as inducer of the isoprostane lipid peroxidation in mitochondria. Molecular Biology. 2018; 52(3): 347-359. doi: 10.1134/S0026893318020097

35. Panov AV, Dikalov SI. Mitochondrial metabolism and the age-associated cardiovascular diseases. EC Cardiology. 2018; 5.11: 750-769.

36. Panov AV, Golubenko MV. Human metabolic syndrome as one of the last stages of postembryonic ontogenesis. Understanding human heart diseases at old age. EC Cardiology. 2020; 7.8: 41-47.

37. Panov AV, Dikalov SI. Cardiolipin, perhydroxyl radicals and lipid peroxidation in mitochondrial dysfunctions and aging. Oxidative Medicine and Cellular Longevity. 2020; 1323028. doi: 10.1155/2020/1323028

38. Panov A, Orynbayeva Z. Determination of mitochondrial metabolic phenotype through investigation of the intrinsic inhibition of succinate dehydrogenase. Analytical Biochemistry. 2018; 552: 30-37. doi: 10.1016/j.ab.2017.10.010

39. Harman D. Aging: a theory based on free radical and radiation chemistry. J Gerontol. 1956; 11(3): 298-300. doi: 10.1196/annals.1354.003

40. Harman D. Free radical theory of aging: Consequences of mitochondrial aging. Age.1983; 6: 86-94. doi: 10.1007/BF02432509

41. Beckman KB, Ames BN. The free radical theory of aging matures. Physiol Rev. 1998; 78(2): 547-581. doi: 10.1152/physrev.1998.78.2.547

42. Kukat C, Wurm CA, Spahr H, Falkenberg M, Larsson NG, Jakobs S. Super-resolution microscopy reveals that mammalian mitochondrial nucleoids have a uniform size and frequently contain a single copy of mtDNA. Proc Natl Acad Sci USA. 2011; 108(33): 13534-13539. doi: 10.1073/pnas.1109263108

43. Anderson AP, Xuemei L, William R, Yin YW. Oxidative damage diminishes mitochondrial DNA polymerase replication fidelity. Nucleic Acids Research. 2020; 48(2): 817-829. doi: 10.1093/nar/gkz1018

44. Trifunovic A, Hansson A, Wredenberg A, Rovio AT, Dufour E, Khvorostov I, et al. Somatic mtDNA mutations cause aging phenotypes without affecting reactive oxygen species production. Proc Natl Acad Sci USA. 2005; 102(50): 17993-17998. doi: 10.1073/pnas.0508886102

45. Panov AV. A new look at the causes of heart failure at old age. EC Cardiology. 2020; 7.2: 01-07.

46. Neckelmann N, Li K, Wade RP, Shuster R, Wallace DC. cDNA sequence of a human skeletal muscle ADP/ATP translocator: lack of a leader peptide, divergence from a fibroblast translocator cDNA, and coevolution with mitochondrial DNA genes. Proc Natl Acad Sci USA. 1987; 84(21): 7580-7584. doi: 10.1073/pnas.84.21.7580

47. Szczepanowska K, Trifunovic A. Origins of mtDNA mutations in ageing. Essays in Biochemistry. 2017; 61.3: 325-337. doi: 10.1042/EBC20160090

48. Back JW, Sanz MA, De Jong L, De Koning LJ, Nijtmans GL, De Koster CG, et al. A structure for the yeast prohibitin complex: Structure prediction and evidence from chemical crosslinking and mass spectrometry. Protein Sci. 2002; 11(10): 2471-2478. doi: 10.1110/ps.0212602

49. Gemmell NJ, Metcalf VJ, Allendorf FW. Mother’s curse: the effect of mtDNA on individual fitness and population viability. Trends Ecol Evol. 2004; 19: 238-244. doi: 10.1016/j.tree.2004.02.002

50. Muller M, Martin W. The genome of Rickettsia prowazekii and some thoughts on the origin of mitochondria and hydrogenosomes. Bioessays. 1999; 21(5): 377-381. doi: 10.1002/(SICI)1521-1878(199905)21:5<377::AID-BIES4>3.0.CO;2-W

51. Hoekstra RF. Evolutionary biology: why sex is good. Nature. 2005; 434(7033): 571-573. doi: 10.1038/434571a

52. Hoekstra RF. Evolutionary origin and consequences of uniparental mitochondrial inheritance. Hum Reprod. 2000; 15(Suppl 2): 102-111. doi: 10.1093/humrep/15.suppl_2.102

53. Muller HJ. The relation of recombination to mutational advance. Mutat Res. 1964; 1(1): 2-9. doi: 10.1016/0027-5107(64)90047-8

54. Jenuth JP, Peterson AC, Fu K, Shoubridge EA. Random genetic drift in the female germline explains the rapid segregation of mammalian mitochondrial DNA. Nat Genet. 1996; 14(2): 146-151. doi: 10.1038/ng1096-146

55. Bergstrom CT, Pritchard J. Germline bottlenecks and the evolutionary maintenance of mitochondrial genomes. Genetics. 1998; 149(4): 2135-2146.

56. Michaels GS, Hauswirth WW, Laipis PJ. Mitochondrial DNA copy number in bovine oocytes and somatic cells. Dev Biol. 1982; 94(1): 246-251. doi: 10.1016/0012-1606(82)90088-4

57. Reynier P, May-Panloup P, Chretien MF, Morgan CJ, Jean M, Savagner F, et al. Mitochondrial DNA content affects the fertilizability of human oocytes. Mol Hum Reprod. 2001; 7(5): 425-429. doi: 10.1093/molehr/7.5.425

58. 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: 10.1038/46466

59. Thompson WE, Ramalho-Santos J, Sutovsky P. Ubiquitination of prohibitin in mammalian sperm mitochondria: possible roles in the regulation of mitochondrial inheritance and sperm quality control. Biol Reprod. 2003; 69(1): 254-260. doi: 10.1095/biolreprod.102.010975

60. Artal-Sanz M, Tavernarakis N. Prohibitin and mitochondrial biology. Trends Endocrinol Metab. 2009; 20(8): 394-401. doi: 10.1016/j.tem.2009.04.004

61. Frank SA, Hurst LD. Mitochondria and male disease. Nature. 1996; 383: 224. doi: 10.1038/383224a0

62. Ruiz-Pesini E, Lapena AC, Diez-Sanchez C, Perez-Martos A, Montoya J, Alvarez E, et al. Human mtDNA haplogroups associated with high or reduced spermatozoa motility. Am J Hum Genet. 2000; 67(3): 682-696. doi: 10.1086/303040

63. Gemmell NJ, Allendorf FW. Mitochondrial mutations may decrease population viability. Trends Ecol Evol. 2001; 16: 115-117. doi: 10.1016/S0169-5347(00)02087-5

64. Rand DM. The units of selection on mitochondrial DNA. Annu Rev Ecol Syst. 2001; 32: 415-449. doi: 10.1146/annurev.ecolsys.32.081501.114109

65. Lynch M, Blanchard JL. Deleterious mutation accumulation in organelle genomes. Genetica. 1998; 102-103(1-6): 29-39. doi: 10.1023/A:1017022522486

66. Lewontin RC. The units of selection. Annu Rev Ecol Syst. 1970; 1: 1-18. doi: 10.1146/annurev.es.01.110170.000245

67. Reid RA. Selfish DNA in “petite” mutants. Nature. 1980; 285: 620. doi: 10.1038/285620b0

68. Wallace DC. Mitochondrial diseases in man and mouse. Science. 1999; 283: 1482-1488. doi: 10.1126/science.283.5407.1482

69. Craig DM. Group selection versus individual selection: an experimental analysis. Evolution. 1982; 36(2): 271-282. doi: 10.2307/2408045

70. Goodnight CJ, Stevens L. Experimental studies of group selection: what do they tell us about group selection in nature? Am Nat. 1997; 150(1): S59-S79. doi: 10.1086/286050

71. Swenson W, Wilson DS, Elias R. Artificial ecosystem selection. Proc Natl Acad Sci USA. 2000; 97(17): 9110-9114. doi: 10.1073/pnas.150237597

72. Goodnight CJ. Heritability at the ecosystem level. Proc Natl Acad Sci USA. 2000; 97(17): 9365-9466. doi: 10.1073/pnas.97.17.9365

73. Sanders JM, Monogue ML, Jodlowski TZ, Cutrell JB. Pharmacologic treatments for coronavirus disease 2019 (COVID-19). JAMA. 2020; 323(18): 1824-1836. doi: 10.1001/jama.2020.6019

74. Blinov VM, Zverev VV, Krasnov GS, Filatov FP, Shargunov AV. Viral component of the human genome. Molecular Biology. 2017; 51, 205-215. doi: 10.1134/S0026893317020066

75. Brown JA, Sammy MJ, Ballinger SW. An evolutionary, or “mitocentric” perspective on cellular function and disease. Redox Biol. 2020; 36: 101568. doi: 10.1016/j.redox.2020.101568

76. Mereschkowsky C. Über Natur und Ursprung der Chromatophoren imPflanzenreiche. Biol Centralbl. 1905; 25: 593-604.

77. Portier P. Les Symbiotes. Paris: Masson; 1918.

78. Walli IE. Symbionticism and the origin of species. Baltimore: Williams & Wilkins Company; 1927.

79. Sagan L. On the origin of mitosing cells. J Theor Biol. 1967; 14(3): 255-274. doi: 10.1016/0022-5193(67)90079-3

80. Lake JA. Lynn Margulis (1938-2011). Nature. 2011; 480(7378): 458. doi: 10.1038/480458a

81. Schwartz RM, Dayhoff MO. Origins of prokaryotes, eukaryotes, mitochondria, and chloroplasts. Science. 1978; 199(4327): 395-403. doi: 10.1126/science.202030