The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki

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90 The Mitochondrial Free Radical Theory of Aging 19. Bodnar AG, Ouellette M, Frolkis M et al. Extension of life-span by introduction of telomerase into normal human cells. Science 1998; 279:349-352. 20. Vaziri H, Benchimol S. Reconstitution of telomerase activity in normal human cells leads to elongation of telomeres and extended replicative life span. Curr Biol 1998; 8:279-282. 21. Vaziri H. Extension of life span in normal human cells by telomerase activation: A revolution in cultural senescence. J Anti-Aging Med 1998; 1:125-130.
CHAPTER 8 The Search for How Mutant mtDNA Is Amplified This gap in the mitochondrial free radical theory was a particularly inviting challenge to a newcomer in the field. Superficially, it seemed that all the information was available to lead rapidly to a detailed mechanism for how mutant mitochondria out-competed wild-type ones; but in fact, only a few possibilities had been proposed, all of which had serious difficulties. 8.1. Does Deleted—Shorter—mtDNA Replicate Faster? An early suggestion 1 was that the mitochondria which were amplified were specifically those that had suffered a large deletion in their DNA. The idea was that, having less DNA to replicate, they could get it done more quickly and so out-replicate the normal mitochondria. Such mutations had been found, 2 and it was clear that they take over cells. Unfortunately, we now know that many point mutations are also amplified, 3 so this cannot be the whole story. Moreover, it has since been established 4 that some mtDNA duplications are amplified: thus, any selection there may be for small molecules must be easily overridden by some other factor. Also, the tiny size of the mtDNA molecule means that, on average, it need be replicated only at a rate of under ten base pairs per hour in order to keep up with the observed rate of mitochondrial turnover. This is so hugely slower than the typical DNA replication rate of about 2000 bases per minute 5 that it is hard to imagine mtDNA replication being rate-limiting. In fact, replication of the whole molecule takes 1-2 hours. 10 A variant on this model 6 avoids this problem, but has one of its own. It was proposed that certain parts of the mtDNA molecule act as inhibitors of mtDNA replication, only allowing replication to proceed when more mitochondria are needed. These sequences were hypothesised to be deleted or otherwise inactivated in mutant mtDNA, so that such molecules engaged in runaway replication. This proposal faces the major difficulty that no such cis-regulatory sequence has been identified, and that its existence becomes progressively less plausible with every new mutation that is found to accumulate in vivo. 8.2. Do Perinuclear Mitochondria Trigger Their Own Replication? A highly ingenious idea 7 was inspired by the discovery 8 that the cell does not replicate all its mitochondria at once. Nor is replication a constant process, however: the truth seems to be somewhere between. Mitochondria are replicated in pulses: a few percent of them are replicated simultaneously, then none for a while. This allows the possibility that the signal which tells the cell to replicate some mitochondria is somehow biased towards the replication of mutant ones. We do not know what this signal is, but a perfectly plausible candidate is a simple shortage of ATP in the nucleus. This may preferentially occur when there are (randomly) a lot of mutant mitochondria around the nucleus. Now, if the replication signal goes out from the nucleus and only gets to a few percent of the mitochondria in the cell, then the beneficiaries are most likely to be exactly the ones near the nucleus, namely the The Mitochondrial Free Radical Theory of Aging, by Aubrey D.N.J. de Grey. ©1999 R.G. Landes Company.
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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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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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MOLECULAR BIOLOGY INTELLIGENCE UNIT
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