The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki

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118 The Mitochondrial Free Radical Theory of Aging Table 10.1. Deviations from the standard code of various taxa’s mitochondrial genetic codes Taxon UGA = Trp? AUA = Met? AGR = Ser? AGR = stop? CUN = Leu? All vertebrates yes yes no yes no Most yes yes yes no no invertebrates Saccharomyces yes yes no no yes Most other sometimes no no no no fungi Plants, most no no no no no algae Most primitive yes no no no no eukaryotes See ref. 7 for more detail and primary references. R stands for “A or G”; N stands for “any base.” overlooks the fact that far fewer plants than animals have yet had their mitochondrial genomes sequenced, 14a so it is quite possible—in fact, many would say absolutely certain—that more such cases will be found. Another confounding factor is that, judging from the situation with Vigna, such transfers may be very easy to overlook. There are two stages to a transfer: the introduction of the DNA into the nuclear genome and its loss from the mitochondrial one. The functional transfer occurs when the nuclear copy is “turned on” and the mitochondrial one turned off; this must occur very soon after the DNA arrives in the nucleus, since otherwise it would undergo random mutations that would render it useless. But the inactive mitochondrial copy can, in theory, stay put indefinitely, since it is inactive. One might guess that it would usually be deleted rather quickly; but if we recall that there is a lot of “junk DNA” in plant mitochondria (as against essentially none in animals), perhaps this is not so obvious. And in fact, Nugent and Palmer found when they examined other legumes that the entire bean taxon uses a nuclear-coded cytochrome c oxidase subunit 2, even though only Vigna has lost the mitochondrial copy! This means that the inactive mitochondrial copy has been retained for up to 100 million years in most beans. The implication for discovery of other transfers is clear: simply probing the mtDNA by in situ hybridisation with genes from other organisms will not necessarily detect a transfer. The only reliable assay is more laborious: Northern blotting of fractionated samples, to detect whether the messenger RNA is localized in the mitochondria or the cytoplasm. In closing this topic, it should also be mentioned that a number of other proposals have been put forward to explain why we retain our mtDNA. These reasons are potentially relevant to the possibility of retarding aging by mitochondrial gene therapy, which is the subject of Chapter 15. Discussion of these will therefore be deferred to Section 15.8.
Frequently-Asked Questions Table 10.2. Consequences for gene transfer of different types of change in the mitochondrial genetic code Code change Human Newly silent Amino acid Function of example substitutions sequence of that transferee subsequent transferee coding to STOP AGA UGA to AGA C-terminal extension slightly impaired coding to coding AUA AUG to AUA conservative changes fair to middling STOP to coding UGA UGG to UGA early truncation nil A change from STOP to coding allows silent mtDNA mutations that cause subsequently transferred genes to encode truncated products with no activity, so inhibits successful gene transfer far more powerfully than other types of mtDNA code change. 10.3. How Does the Germ Line Avoid mtDNA Decay? This question also has two answers, but in this case that is because it is really two questions. The first is “How does mtDNA survive from one generation to the next?” and the second is “How does mtDNA survive in the ovum until fertilization?” So: 10.3.1. How Does mtDNA Survive from One Generation to the Next? Though the adult body is mainly composed of non-dividing cells, each generation goes through a period in which all cells are dividing rapidly: early embryogenesis. In Section 8.5.3 we saw that SOS will only matter in tissues composed of non-dividing—or at least rarely-dividing—cells, because if cells are dividing rapidly then they will replicate their mitochondria before any have had time to “go critical,” so the SOS mechanism is short-circuited. In fact such tissues are even better off than that. Consider a cell which carries some mutant mitochondria and some wild-type ones. When it divides, the mitochondria will be randomly partitioned between the daughters. Thus, the chances are that one daughter cell will receive slightly more mutant mitochondria than the other. The one with fewer normal mitochondria and more mutant ones will (at least initially) have less capacity to make ATP, so it will grow more slowly, so it will take longer to grow to a size ready to divide again. The same will apply to its remoter descendants, since they have more mutant mitochondria to partition in later divisions. Thus its descendants will be out-replicated by those of the daughter that received more normal mitochondria and fewer mutants. This therefore constitutes a strong selection against mtDNA mutants, resulting from intercellular competition. A word should be added about the manner in which this process can run to completion. The selective pressure described above will reduce the amount of mutant mtDNA in the early embryo, but when its level becomes very low, so that a typical cell has only a few mutant mitochondria and hundreds of working ones, the selective pressure against that cell will be negligible. At this point, however, another phenomenon will step in to finish the job: genetic drift. Genetic drift is not a biochemical pathway but a statistical phenomenon. If a dividing cell has only a few mutant mitochondria, and its mitochondria are randomly distributed between the daughters, there is a significant chance that all of them will be segregated into one daughter; this chance of course rises as the number of mutant 119
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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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10 The Mitochondrial Free Radical T
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18 Fig. 2.7. The respiratory chain.
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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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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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