The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki

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80 The Mitochondrial Free Radical Theory of Aging was measured in rapidly dividing cells, which need more energy for biogenesis than a non-dividing cell needs just to survive—and which, incidentally, do not accumulate high levels of these mutations in vivo! Presumably null mutations, if present in the oocyte, are sufficiently debilitating to cause early termination of embryogenesis or even failure of ovulation; this is discussed further in Section 10.3.2. Nevertheless, these inherited diseases may still be useful: after all, there is no a priori reason why a mild mutation should behave qualitatively differently (in terms of selective advantage) to a null mutation, which most spontaneous ones are likely to be. Irritatingly, however—or perhaps, in the end, instructively—it seems clear that they do behave differently. The “all-or-none” distribution of cytochrome c oxidase activity in normal aging is shown, by in situ hybridisation, 57 to be caused directly by a similar, though not quite “all-or-none”, distribution of a mtDNA mutation. But in the inherited diseases, in situ hybridisation reveals many muscle fiber segments with intermediate levels of the mutation. This goes a long way towards explaining how the overall levels in tissue can be so high—cells have a substantial surplus of mitochondrial capacity, 81 so a cell (or fiber segment) with 50% or less mutant mtDNA would show very little loss of performance—but it raises two big questions. The first is: why is the cytochrome c oxidase activity all-or-none when the DNA is not? This has become known as the threshold effect—when the level of wild-type DNA falls below a threshold level, something happens to the expression of the nuclear-coded OXPHOS machinery which abruptly eliminates all cytochrome c oxidase activity—but we have no idea of the mechanism. But the second question is: why don’t these mutations get rapidly amplified all the way to nearly 100%? Again we have no idea, though the existence of the threshold effect may be a hint—if the selective advantage in normal aging is due to loss of OXPHOS function of individual mitochondria (which seems reasonable, and see Chapter 8 for a detailed hypothesis), and if nuclear factors disable OXPHOS in the residual wild-type mitochondria, then the selective advantage disappears. But whatever the reasons, the fact that they don’t rise to the same levels—which, again, may have a lot to do with why they can be inherited at all (see Section 10.3.2)—means again that they are a very dubious model for mtDNA decline in normal aging. References 1. Pearl R. The rate of living. New York: Knopf, 1928. 2. Commoner B, Townsend J, Pake GE. Free radicals in biological materials. Nature 1954; 174:689-691. 3. a)Gerschman, R, Gilbert DL, Nye SW et al. Oxygen poisoning and X-irradiation: A mechanism in common. Science 1954; 119:623-626. 3. b)Harman D. Aging: A theory based on free radical and radiation chemistry. J Gerontol 1956; 11:298-300. 4. Ephrussi B, de Margarie-Hottinguer H, Roman H. Suppressiveness: A new factor in the genetic determinism of the synthesis of respiratory enzymes in yeast. Proc Natl Acad Sci USA 1956; 41:1065-1071. 5. Mewes HW, Albermann K, Bahr M et al. Overview of the yeast genome. Nature 1997; 387:7-65. 6. Ephrussi B, Hottinguer H, Chimènes AM. Action de l’acriflavine sur les levures. I. La mutation “petite colonie.” Ann Inst Pasteur 1949; 76:351-367. 7. Slonimski PP, Ephrussi B. Action de l’acriflavine sur les levures. V. Le système des cytochromes des mutants “petite colonie.” Ann Inst Pasteur 1949; 77:47-63. 8. McCord JM, Fridovich I. Superoxide dismutase. An enzymic function for erythrocuprein (hemocuprein). J Biol Chem 1969; 244:6049-6055. 9. Harman D. The biologic clock: The mitochondria? J Am Geriatr Soc 1972; 20:145-147. 10. Harman D. Free radical theory of aging: Effect of free radical reaction inhibitors on the mortality rate of male LAF1 mice. J Gerontol 1968; 23:476-482.
History of the Mitochondrial Free Radical Theory of Aging, 1954-1995 11. Harman D. Free radical theory of aging: effect of free radical reaction inhibitors on the mortality rate of male LAF1 mice—second experiment. Gerontologist 1968; 8:13. 12. Harman D. Free radical theory of aging: Effects of antioxidants on mitochondrial function. Age 1987; 10:58-61. 13. Anderson S, Bankier AT, Barrell BG et al. Sequence and organization of the human mitochondrial genome. Nature 1981; 290:457-465. 14. Corral-Debrinski M, Shoffner JM, Lott MT et al. Association of mitochondrial DNA damage with aging and coronary atherosclerotic heart disease. Mutat Res 1992; 275:169-180. 15. Cortopassi GA, Shibata D, Soong NW et al. A pattern of accumulation of a somatic deletion of mitochondrial DNA in aging human tissues. Proc Natl Acad Sci USA 1992; 89:7370-7374. 16. Soong NW, Hinton DR, Cortopassi G et al. Mosaicism for a specific somatic mitochondrial DNA mutation in adult human brain. Nature Genet 1992; 2:318-323. 17. Müller-Höcker J, Schneiderbanger K, Stefani FH et al. Progressive loss of cytochrome c oxidase in the human extraocular muscles in ageing—a cytochemical-immunohistochemical study. Mutat Res 1992; 275:115-124. 18. Miquel J, Economos AC, Fleming J et al. Mitochondrial role in cell aging. Exp Gerontol 1980; 15:575-591. 19. Fleming JE, Miquel J, Cottrell SF et al. Is cell aging caused by respiration-dependent injury to the mitochondrial genome? Gerontology 1982; 28:44-53. 20. Gadaleta MN, Rainaldi G, Lezza AMS et al. Mitochondrial DNA copy number and mitochondrial DNA deletion in adult and senescent rats. Mutat Res 1992; 275:181-193. 21. Black JT, Judge D, Demers L et al. Ragged-red fibers. A biochemical and morphological study. J Neurol Sci 1975; 26:479-488. 22. Shoffner JM, Lott MT, Lezza AMS et al. Myoclonic epilepsy and ragged-red fiber disease (MERRF) is associated with a mitochondrial DNA tRNA(Lys) mutation. Cell 1990; 61:931-937. 23. Pinz KG, Shibutani S, Bogenhagen DF. Action of mitochondrial DNA polymerase gamma at sites of base loss or oxidative damage. J Biol Chem 1995; 270:9202-9206. 24. Schmidt-Nielsen K. Scaling: Why is animal size so important? Cambridge: Cambridge University Press, 1984. 25. Perez-Campo R, Lopez-Torres M, Cadenas S et al. The rate of free radical production as a determinant of the rate of aging: Evidence from the comparative approach. J Comp Physiol B 1998; 168:149-158. 26. Loeb J, Northrop JH. Is there a temperature coefficient for the duration of life? Proc Natl Acad Sci USA 1916; 2:456-457. 27. Edney EB, Gill RW. Evolution of senescence and specific longevity. Nature 1967; 220:281-282. 28. Austad SN. Retarded senescence in an insular population of Virginia opossums (Didelphis virginiana). J Zool 1993; 229:695-708. 29. Kirkwood TBL, Holliday R. The evolution of ageing and longevity. Proc R Soc Lond B Biol Sci 1979; 205:531-546. 30. Helbock HJ, Beckman KB, Shigenaga MK et al. DNA oxidation matters: the HPLC-electrochemical detection assay of 8-oxo-deoxyguanosine and 8-oxo-guanine. Proc Natl Acad Sci USA 1998; 95:288-293. 31. Pamplona R, Prat J, Cadenas S et al. Low fatty acid unsaturation protects against lipid peroxidation in liver mitochondria from long-lived species: The pigeon and human case. Mech Ageing Dev 1996; 86:53-66. 32. Barja G, Cadenas S, Rojas C et al. Low mitochondrial free radical production per unit O2 consumption can explain the simultaneous presence of high longevity and high aerobic metabolic rate in birds. Free Radic Res 1994; 21:317-327. 33. Cosgrove JP, Church DF, Pryor WA. The kinetics of the autoxidation of polyunsaturated fatty acids. Lipids 1987; 22:299-304. 34. Herrero A, Barja G. Sites and mechanisms responsible for the low rate of free radical production of heart mitochondria in the long-lived pigeon. Mech Ageing Dev 1997; 98:95-111. 81
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COMPANY de Grey The Mitochondrial F
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ISBN: 1-57059-564-X MOLECULAR BIOLO
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7. The Status of Gerontological The
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17. Conclusion: The Role of the Ger
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I cannot overstate my profound grat
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CHAPTER 1 Introduction 1.1. What Is
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Introduction Some may feel that all
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6 The Mitochondrial Free Radical Th
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8 The Mitochondrial Free Radical Th
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10 The Mitochondrial Free Radical T
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18 Fig. 2.7. The respiratory chain.
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24 Fig. 2.9. Types of protein impor
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Frequently-Asked Questions Fig. 10.
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Frequently-Asked Questions of elect
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Frequently-Asked Questions Referenc
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Frequently-Asked Questions 45. Clay
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CHAPTER 11 A Challenge from Textboo
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A Challenge from Textbook Bioenerge
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160 The Mitochondrial Free Radical
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CHAPTER 14 Ablation of Anaerobic Ce
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Ablation of Anaerobic Cells: Techni
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CHAPTER 15 Transgenic Copies of mtD
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Transgenic Copies of mtDNA: Techniq
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CHAPTER 16 Prospective Impact on th
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Prospective Impact on the Healthy H
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Prospective Impact on the Healthy H
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Index Symbols “~”, 19 A Acetald
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Index Copper 35, 107 see also trans
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Index Heart comparison to man-made
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Index genetic code 23, 115-118, 177
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Index Perhydroxyl radical 41, 122,
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Index protonation see protonation (
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