The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki

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Prospects for Intervention to do better than that would be to identify refinements that no species has yet found; that would require an astronomical improvement in our understanding of the relationship between a protein’s sequence and its function. Option i is the next against the wall. OXPHOS appears to have evolved only once in history; it is an astoundingly subtle process. Our chances of coming up with something equivalent (which lacks OXPHOS’s side-effects) are vanishingly small. This is not least because the laws of thermodynamics dictate that energy conversion can be done efficiently only by extracting it in a series of small steps. It is no use getting energy out of chemical bonds (in glucose, etc.) if it mostly goes into heat—it has to be channelled into phosphorylation— and any such system must, in order to achieve the same energetic efficiency, be about as complex as OXPHOS itself is. Biology we might hope to tinker with; physics is another matter. Now let us consider option g. I believe that it can be discarded even without extending it to a specific proposal for implementing it (which, in the first place, is not by any means easy to think of). If mitochondria with reduced ability to generate a proton gradient were somehow selected against, it follows that mitochondria with an unusually large proton gradient would be selected for. And, as noted in Section 8.5.4, this is exactly the predicted property of mitochondria that have suffered a point mutation in an ATP synthase subunit. Such mitochondria are clearly no more useful to the cell than those which SOS amplifies. In fact, the reversal of SOS may be even worse than that: it may be rapidly lethal to all cells, irrespective of their mitochondrial genotype(s). If it were implemented in the most direct way, by reversing the preference of lysosomes to digest mitochondria that have become dysfunctionally leaky to protons, then in one mitochondrial generation all cells would become populated mainly with mitochondria that are burning oxygen for all they are worth and making no ATP. That leaves four lines of exploration: c, f, h and j. All have been touted as realistic ways forward. However, I believe that c and f are likely to fail. The problem they both face is that the restoration of normal mtDNA in the cell cannot be instantaneous: it can only act to increase the number of functioning mitochondria, steadily, until the cell is restored to health. But, as we have seen, a cell some of whose mitochondria are working and some not exerts a huge selective pressure to amplify the mutant ones and to destroy the wild-type ones. I therefore predict that either option c, reintroduction of wildtype mtDNA 2-4 or option f, destruction of mutant mtDNA (either explicitly or by suppressing its ability to be replicated) so as to promote amplification, by default, of the residual wildtype mtDNA 5-7 will be overpowered by selective pressure the other way. Destruction of mutant mtDNA has an additional risk: it may in fact accelerate the loss of OXPHOS. The fact that we can make mtDNA-less (ρ 0 ) cells in vitro by inhibiting mtDNA replication tells us that mitochondria can, if forced, divide even when they have failed to replicate their DNA. Genetic drift ensures that nearly all mitochondria in a heteroplasmic cell are homozygous; thus, many cells may harbour some mitochondria homozygous for a mild, hypomorphic mutation which reduces OXPHOS but not so much as to give a selective advantage. (This is particularly the case in the inherited diseases discussed in Section 6.6.5.) If this hypomorphic mtDNA were destroyed, mitochondria would be formed which had no mtDNA and were thus completely OXPHOS-less; these, unlike the hypomorphs, would be clonally amplified and take over their host cell (see Fig. 13.1). This leaves us with options h and j, which are the subject of the rest of this chapter and the following two. Some may feel that the process of elimination I have conducted above is unjustifiably cavalier. I certainly see nothing wrong with trying to influence the aging process by any of the means I have rejected above. For example, option a might be attempted by targeting a SOD to the intermembrane space, as has recently been done in yeast; 8 option k 167
168 The Mitochondrial Free Radical Theory of Aging Fig. 13.1. An undesirable potential result of selectively inhibiting replication of mutant mtDNA. could be tried by inhibiting the PMOR without killing overexpressing cells. My only purpose is to draw attention to their potential difficulties, so that such efforts do not proceed in a vacuum, oblivious to the obstacles ahead.
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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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CHAPTER 6 History of the Mitochondr
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History of the Mitochondrial Free R
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CHAPTER 7 The Status of Gerontologi
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The Status of Gerontological Theory
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The Status of Gerontological Theory
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CHAPTER 8 The Search for How Mutant
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The Search for How Mutant mtDNA is
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CHAPTER 9 The Search for How So Few
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The Search for How So Few Anaerobic
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Page 195 and 196: Prospective Impact on the Healthy H
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Page 203 and 204: Index Symbols “~”, 19 A Acetald
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Page 207 and 208: Index Heart comparison to man-made
Page 209 and 210: Index genetic code 23, 115-118, 177
Page 211 and 212: Index Perhydroxyl radical 41, 122,
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