The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki

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124 The Mitochondrial Free Radical Theory of Aging Fig.10.1. Three ways to maintain intramitochondrial ATP and proton gradient.
Frequently-Asked Questions SOS, since it would surely confer a selective disadvantage. But we must consider with care whether that disadvantage would be big enough to outweigh the advantage conferred by slow degradation. In non-dividing cells, when the mitochondrion has a whole month in which to import the proteins necessary to double its size, an impaired rate of import should not matter, since it could not be rate-limiting. In rapidly dividing cells, however, SOS is short-circuited and this disadvantage may have an important role in eliminating mutant mtDNA 14b (see Section 10.3.1). 10.7. Why Doesn’t the Polyploidy of Mitochondria Protect Them? Mitochondria do indeed possess more than one copy of the mtDNA. The average in human cells is about five. When a spontaneous mutation occurs, therefore, there is still plenty of backup for the creation of more protein from the other copies. This means that—if, as is reasonable, we presume that the remaining copies can be transcribed and/or translated 25% more often than normal—the affected mitochondrion will not, yet, experience any selective advantage over other, fully wild-type ones. (Note that this is the best-case scenario, because it does not cover the case where the mutation causes the protein to be constructed and incorporated into the enzyme complex as normal, but then to function abnormally. In that case, even one mutant copy may cause a 20% decline in function.) There is, therefore, still a 50-50 chance that it will be destroyed rather than replicated. If it is replicated, however, there is then a 50-50 chance that the two copies will be segregated into the same daughter mitochondrion. This daughter may then start to feel the effects of a diminished availability of the affected proteins, due to its wild-type mtDNA being depleted by 40% rather than only 20%. The effect may be small, but even a small effect is enough to make a big difference to the probability of going critical and being destroyed before being replicated. Moreover, the logic of the 50-50 chances mentioned above can be extended to subsequent mitochondrial divisions. A small proportion of spontaneous mutants will therefore inevitably achieve homozygosity in one mitochondrion, even if they have no selective advantage at all until that time, while the majority of spontaneous mutations will be destroyed by random chance before then. (This is called genetic drift, and was discussed in more detail in Section 10.3.1.) Indeed, we already have evidence that that is what happens 34 (see Section 6.6.2). 10.8. What About Mitochondrial Fusion? This is a phenomenon whose existence in normal mammalian cells has been in dispute for some years, though it is known to be a normal part of spermatogenesis in Drosophila 35 and may also occur in mammalian spermatogenesis. Its relevance to MiFRA is with regard to the ability of a mtDNA mutation to out-compete the wild-type mtDNA and take over a cell. The phenomenon of Darwinian selection relies absolutely on the link between genotype and phenotype: that is, on the existence of a population of individuals, of varying genetic content, whose “fitness” is at least partly determined by that genetic content. If mitochondria divide but never (or rarely) fuse, then this is what exists in the cell after a spontaneous mutation. If, on the other hand, mitochondrial fusion is frequent and allows the sharing, by all mitochondria in a cell, of all the proteins that any of them can encode, then the link between genotype and fitness is destroyed and no selective advantage can appear. Therefore, if mitochondrial fusion is indeed frequent in vivo, the apparent clonal amplification of mutations that has been so extensively reported (see Section 6.6) must, somehow, be an artifact. It is thus imperative to establish whether mitochondria fuse in vivo, and if so then how often. 125
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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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26 Fig. 2.10. Why the DNA bases pai
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CHAPTER 3 An Introduction to Free R
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An Introduction to Free Radicals Ta
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An Introduction to Free Radicals Fi
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An Introduction to Free Radicals Re
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CHAPTER 6 History of the Mitochondr
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History of the Mitochondrial Free R
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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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196 The Mitochondrial Free Radical
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198 The Mitochondrial Free Radical
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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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MOLECULAR BIOLOGY INTELLIGENCE UNIT
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