Modeling Mitochondrial DNA Mutations

  • T. B. L. Kirkwood
  • A. Kowald


Ever since the first mitochondria entered into symbiotic relationship with ances-tral eukaryotic cells, an event which probably occurred around 1–2 billion years ago,1–3 the interaction between the mitochondrial genome and the host, or nuclear, genome has presented interesting dynamic possibilities. Blackstone4 has discussed this process from a units of evolution’ perspective and argued that to achieve a stable association, any conflicts inherent in this interaction must have given way to intracellular harmony (see also ref. 5). This perspective contributes significantly to the understanding of present-day interactions between mitochondrial and host genomes. Early in the evolution of the symbiotic relationship, a variant mitochondrion could have destabilized the host-symbiont relationship, for example, if the variant failed to export ATP to the cell and adopted a `selfish’ strategy that favored its own replication. Such a variant would lose out in the long term, when its faster replication rate might lead to elimination of the normal mitochondrion and the host cell, now possessing a metabolism that required higher ATP levels, would die. However, the short term advantage enjoyed by variant mitochondria would pose a continual threat to the host-symbiont relationship. Probably for this reason, natural selection at the host cell level necessitated the transfer to the nucleus of key mitochondrial genes that control the replication, transcription, and energy metabolism of the mitochondrial population. Nonetheless, present-day mitochondria retain some autonomy of replication that keeps the threat of destabilization alive.


Mitochondrial Genome Mitochondrial Mutation Damage Mitochondrion Mitochondrial Population Plant Mitochondrial Genome 
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  1. 1.
    Cavalier-Smith T. The simultaneous symbiotic origin of mitochondria, chloroplasts, and microbes. Ann NY Acad Sci 1987; 503: 55–71.PubMedCrossRefGoogle Scholar
  2. 2.
    Jenkins RJF. The early environment. In: Bryant C, ed. Metazoan Life Without Oxygen. London: Chapman and Hall, 1991: 38–64.Google Scholar
  3. 3.
    Knoll AH. The early evolution of eukaryotes: A geological perspective. Science 1992; 256: 622–627.PubMedCrossRefGoogle Scholar
  4. 4.
    Blackstone NW. A units-of-evolution perspective on the endosymbiont theory of the origin of the mitochondrion. Evolution 1995; 49 (5): 785–796.CrossRefGoogle Scholar
  5. 5.
    Maynard Smith J, Szathmâry E, eds. The Major Transitions in Evolution. Oxford: W.H. Freeman, 1995.Google Scholar
  6. 6.
    Satoh M, Kuroiwa T. Organization of multiple nucleoids and DNA molecules in mitochondria of a human cell. Exp Cell Res 1991; 196: 137–140.PubMedCrossRefGoogle Scholar
  7. 7.
    Halliwell B, Gutteridge JMC. Free Radicals in Biology and Medicine. (2nd ed.) New York: Oxford University Press, 1989.Google Scholar
  8. 8.
    Joenje H. Genetic toxicology of oxygen. Mutation Res 1989; 219: 193–208.PubMedCrossRefGoogle Scholar
  9. 9.
    Münscher C, Müller-Höcker J, Kadenbach B. Human aging is associated with various point mutations in tRNA genes of mitochondrial DNA. Biol Chem 1993; 374: 1099–1104.Google Scholar
  10. 10.
    Hayakawa M, Katsumata K, Yoneda M, Tanaka M, Sugiyama S, Ozawa T. Age related extensive fragmentation of mitochondrial DNA into minicircles. Biochem Biophys Res Comm 1996; 226: 369–377.PubMedCrossRefGoogle Scholar
  11. 11.
    Richter C. Do mitochondrial DNA fragments promote cancer and aging? FEBS Letters 1988; 241: 1–5.PubMedCrossRefGoogle Scholar
  12. 12.
    Linnane AW, Marzuki S, Ozawa T, Tanaka M. Mitochondrial DNA mutations as an important contributor to aging and degenerative diseases. The Lancet 1989; March 25: 642–645.Google Scholar
  13. 13.
    Kirkwood TBL, Holliday R. The stability of the translation apparatus. J Mol Biol 1975; 97257–265.Google Scholar
  14. 14.
    Goel NS, Islam S. Error catastrophe in and the evolution of the protein synthesizing machinery. J Theor Biol 1977; 68: 167–182.PubMedCrossRefGoogle Scholar
  15. 15.
    Kowald A, Kirkwood TBL. Accuracy of tRNA charging and codon:anticodon recognition: Relative Importance for cellular stability. J Theor Bio11993; 160: 493–508.Google Scholar
  16. 16.
    Kowald A, Kirkwood TBL. Mitochondrial mutations, cellular instability and aging: Modelling the population dynamics of mitochondria. Mutation Res 1993; 295: 93–103.PubMedCrossRefGoogle Scholar
  17. 17.
    Kowald A, Kirkwood TBL. A network theory of aging: the interactions of defective mitochondria, aberrant proteins, free radicals and scavengers in the aging process. Mutation Res 1996; 316: 209–236.PubMedCrossRefGoogle Scholar
  18. 18.
    Beregovskaya N, Maiboroda R. Mitochondrial DNA damage and efficiency of ATP biosynthesis: Mathematical model. J Theor Biol 1995; 172: 161–168.PubMedCrossRefGoogle Scholar
  19. 19.
    Atlan A, Couvet D. A model simulating the dynamics of plant mitochondrial genomes. Genetics 1993; 135: 213–222.PubMedGoogle Scholar
  20. 20.
    Albert B, Godelle B, Atlan A, De Paepe R, Gouyon PH. Dynamics of plant mitochondrial genome: Model of a three level selection process. Genetics 1996; 144: 369–382.PubMedGoogle Scholar
  21. 21.
    Phillips PD, Cristofalo VJ. Recent advances in cellular aging research: Understanding the limited life span of normal human fibroblasts. Rev Biol Res in Aging 1990; 4: 265–279.Google Scholar
  22. 22.
    Smith JR, Pereira-Smith OM. Replicative senescence: Implications for in vivo aging and tumor suppression. Science 1996; 273: 63–67.PubMedCrossRefGoogle Scholar
  23. 23.
    Schleyer M, Schmidt B, Neupert W. Requirement of a membrane potential for the posttranslational transfer of proteins into mitochondria. Eur J Biochem 1982; 125: 109–116.PubMedCrossRefGoogle Scholar
  24. 24.
    Harmey MA, Hallermayer G, Korb H, Neupert W. Transport of cytoplasmically synthesized proteins into the mitochondria in a cell free system from Neurospora crassa. Eur J Biochem 1977; 81: 533–544.PubMedCrossRefGoogle Scholar
  25. 25.
    Menzies RA, Gold PH. The turnover of mitochondria in a variety of tissues of young adult and aged rats. J Biol Chem 1971; 246 (8): 2425–2429.PubMedGoogle Scholar
  26. 26.
    Huemer RP, Lee KD, Reeves AE, Bickert C. Mitochondrial studies in senescent mice-II. Specific activity, bouyant density, and turnover of mitochondrial DNA. Exp Gerontol 1971; 6: 327–334.PubMedCrossRefGoogle Scholar
  27. 27.
    Ferguson LR, Vonborstel RC. Induction of the cytoplasmic petite mutation by chemical and physical agents in Saccharomyces cerevisiae. Mutation Res 1992; 265: 103–148.PubMedCrossRefGoogle Scholar
  28. 28.
    Miguel J, Fleming J. Theoretical and experimental support for an “Oxygen Radical-Mitochondrial Injury” hypothesis of cell aging. J Modern Aging Res 1986; 8: 51–74.Google Scholar
  29. 29.
    Cortopassi GA, Shibata D, Soong NW, Arnheim N. A pattern of accumulation of a somatic deletion of mitochondrial DNA in aging human tissues. Proc Natl Acad Sci USA 1992; 89: 7370–7374.PubMedCrossRefGoogle Scholar
  30. 30.
    Tauchi H, Sato T. Age changes in size and number of mitochondria of human hepatic cells. J Gerontol1968; 23:454–461•Google Scholar
  31. 31.
    Massie HR, Baird MB, McMahon MM. Loss of Mitochondrial DNA with aging in Drosophila melanogaster. Gerontologia 1975; 21: 231–238.PubMedCrossRefGoogle Scholar
  32. 32.
    Farmer KJ, Sohal RS. Relationship between superoxide anion radical generation and aging in the housefly, Musca domestica. Free Radical Biology and Medicine 1989; 7: 23–29.PubMedCrossRefGoogle Scholar
  33. 33.
    Sohal RS, Sohal BH. Hydrogen peroxide release by mitochondria increases during aging. Mechanisms of Aging and Development 1991; 57: 187–202.CrossRefGoogle Scholar
  34. 34.
    Sawada M, Carlson JC. Changes in superoxide radical and lipid peroxide formation in the brain, heart and liver during the lifetime of the rat. Mechanisms of Aging and Development1987; 41: 125–137.Google Scholar
  35. 35.
    Cardellach F, Galofre J, Cusso R, Urbano-Marquez A. Decline in skeletal muscle mitochondrial respiratory chain function with aging. Lancet 1989; iî:44–45.Google Scholar
  36. 36.
    Byrne E, Dennett X, Trounce I. Oxidative energy failure in post-mitotic cells: A major factor in senescence. Rev Neurol (Paris) 1991; 147: 6–7.Google Scholar
  37. 37.
    Yen TC, Chen YS, King KL, Yeh SH, Weih YH. Liver mitochondrial respiratory functions decline with age. Biochem Biophys Res Comm 1990; 165: 994–1003.CrossRefGoogle Scholar
  38. 38.
    Manzelmann MS, Harmon HJ. Lack of age-dependent changes in rat heart mitochondria. Mechanisms of Aging and Development 1987; 39: 281–288.CrossRefGoogle Scholar
  39. 39.
    Bodenteich A, Mitchell LG, Merril CR. A lifetime of retinal light exposure does not appear to increase mitochondrial mutations. Gene 1991; 108: 305–310.PubMedCrossRefGoogle Scholar
  40. 40.
    Kirkwood TBL. Evolution of aging. Nature 1977; 270: 301–304.PubMedCrossRefGoogle Scholar
  41. 41.
    Kirkwood TBL, Holliday R. The evolution of aging and longevity. Proc Royal Soc, London 1979; 205. 531–546.Google Scholar
  42. 42.
    Kirkwood TBL. Repair and its evolution: Survival versus reproduction. In: Townsend CR, Calow P, eds. Physiological Ecology: An Evolutionary Approach to Resource Use. Oxford: Blackwell Scientific, 1981: 165–189.Google Scholar
  43. 43.
    Kirkwood TBL, Rose MR. Evolution of senescence: Late survival sacrificed for reproduction. Philosophical Transactions of the Royal Society, London B 1991; 332: 15–24.Google Scholar
  44. 44.
    Kirkwood TBL, Franceschi C. Is aging as complex as it would appear? Ann NY Acad Sci 1992; 663: 412–417.PubMedCrossRefGoogle Scholar
  45. 45.
    Sharma H, Prasanna H, Lane R, Rothstein M. The effect of age on enolase turnover in the free-living nematode, Turbatrix aceti. Arch Biochem Biophys1979; 194: 275–282.Google Scholar
  46. 46.
    Lavie L, Reznick A, Gershon D. Decreased protein and puronycinyl-peptide degradation in liver of senescent mice. Biochem J 1982; 202: 47–51.PubMedGoogle Scholar
  47. 47.
    Young V, Munro H. N y-methylhistidine and muscle protein turnover. Federation Proceedings 1978; 372291–3000.Google Scholar
  48. 48.
    Dice JF. Altered degradation of proteins microinjected into senescent human fibroblasts. J Biol Chem 1982; 257: 14624–14627.PubMedGoogle Scholar
  49. 49.
    Sawada M, Carlson JC. Biochemical changes associated with the mechanism controlling superoxide radical formation in the aging rotifer. J Cell Biochem 199o; 44: 153–165.Google Scholar
  50. 5o.
    Reiss U, Gershon D. Rat-liver superoxide dismutase. Purification and age-related modifications. Eur J Biochem 1976; 63: 617–623.PubMedCrossRefGoogle Scholar
  51. 51.
    Vanella A, Geremia E, D’Urso G et al. Superoxide-dismutase activity in aging rat-brain. Gerontology 1982; 28: 108–113.PubMedCrossRefGoogle Scholar
  52. 52.
    Sohal RS, Farmer KJ, Allen RG, Cohen NR. Effects of physical activity on superoxide dismutase, catalase, inorganic peroxides and glutathione in the adult male house fly, Musca domestica. Mechanisms of Aging and Development 1983; 26: 75–81.CrossRefGoogle Scholar
  53. 53.
    Thompson KVA, Holliday R. The longevity of diploid and polyploid human fibroblasts: Evidence against the somatic mutation theory of cellular aging. Experimental Cell Research 1978; 112: 281–287.PubMedCrossRefGoogle Scholar
  54. 54.
    Metzler DE. Biochemistry. The Chemical Reactions of Living Cells. New York: Academic Press, 1977.Google Scholar
  55. 55.
    Ward BL, Anderson RS, Bendich AJ. The mitochondrial genome is large and variable in a family of plants (cucurbitacea). Cell 1981; 25: 793–803.PubMedCrossRefGoogle Scholar
  56. 56.
    Wolfe KH, Li WH, Sharp PM. Rates of nucleotide substitution vary greatly among plant mitochondrial, chloroplast and nuclear DNAs. Proc Natl Acad Sci USA 1987; 84: 9054–9058.PubMedCrossRefGoogle Scholar
  57. 57.
    Szathmâry E. The eukaryotic cell as an information integrator. Endocytobiol Cell Res 1986; 3: 113–132.Google Scholar

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© Springer-Verlag Berlin Heidelberg 1998

Authors and Affiliations

  • T. B. L. Kirkwood
  • A. Kowald

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