The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki

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An Introduction to Mitochondria The journey of nuclear-coded proteins whose eventual destination is not the matrix but the inner membrane (or, in a few cases such as cytochrome c, the intermembrane space) is rather more heterogeneous. Some of them have no signal sequence and pass only through the outer membrane. 44 Others have two signal sequences of the sort described above: one which causes them to be imported completely into the matrix, and another (which is invisible to the relevant machinery until the first has been cleaved) that directs it part of the way out again. 45 Yet others also have two, but the second acts as a barrier to import, so that the mature protein stays in the intermembrane space even though the primary signal sequence penetrates into the matrix (where it is chopped off). 46 A few inner membrane proteins, particularly the carriers of anions such as ATP and phosphate, appear to find their way to mitochondria despite having no presequence, but they have been presumed to use the same pathway, because they were found to have internal sequences which are characteristic of standard presequences, so may fold into a hairpin-like shape that makes the internal sequence look like a presequence. 47 Quite recently, this has been elucidated in more detail: 48,49 these anion carrier proteins do indeed use broadly the same “Tom” machinery to get across the outer membrane, but they use a different “Tim” machinery, which embeds them in the inner membrane from the outside, rather than diverting them into the matrix. The varieties of mitochondrial protein import are depicted in Figure 2.9. 2.4.4. Curiosities of mtDNA The mtDNA of many species has been studied and sequenced. In animals it is always tiny: in humans, for example, it comprises only 16,569 base pairs, 40 of which virtually every one is necessary for its function. In most plants and fungi, however, it is much larger, containing large introns and other “junk DNA.” 50 This indicates that there has been considerable evolutionary pressure for conciseness of mtDNA in animals, but sometimes less elsewhere. We do not know the basis for this difference. In fact it may be somewhat less dramatic than it seems, because the compactness of animal mtDNA is permitted mainly by a single trick—the use of transfer RNA sequences as sites for chopping-up of a primary transcript of almost the whole genome into separate RNAs for each of the proteins—which relieves it of the need for any of the regulatory, untranslated sequence present in fungal and plant mtDNA. 51,52 One rather surprising thing about the mtDNA is that it exists at all, since ostensibly it is a major and unnecessary inconvenience. There is no formal need for it, because (as just noted) cells have a system for getting proteins into mitochondria even when they are encoded on nuclear genes: they are constructed in the usual way by ribosomes in the cytoplasm, and then they are transported to a mitochondrion and hauled through its membranes. Reasons why it has not been evolved away are explored in Section 10.2. But even more surprising was the discovery 53,54 that mitochondrial DNA—again, in animals but not plants—has a different genetic code than the nuclear DNA. The process of turning a sequence of nucleotides into a sequence of amino acids involves the recognition of triplets of nucleotides as coding for a particular amino acid, or else for “this is the end of the protein.” Since there are four different nucleotides, there are 4 3 = 64 possible triplets of nucleotides—“codons”—and, since there are 20 amino acids, 21 things to encode. The mapping between them is called the genetic code. The nuclear genome of virtually every free-living organism uses exactly the same code (though there are a few exceptions). 55 This is no great surprise, since any mutation causing a change to the code would necessarily change the amino acid sequences encoded by huge numbers of genes; a few might not matter, but there would inevitably be many for which the change was a lethal mutation. Conversely, it is less amazing that animals’ mitochondria can be more flexible about their code, since there are only 13 potential “victims.” Indeed, the mitochondrial genetic 23
24 Fig. 2.9. Types of protein import into mitochondria. The Mitochondrial Free Radical Theory of Aging code is not simply different from the nuclear code, but also differs from one species to another. Evolution seems to have allowed it to drift. All animals whose mitochondrial DNA has been sequenced encode exactly the same 13 genes on it, except that nematodes 56 and some mussels 57 encode only 12 of them. (The last, ATPase subunit 8, may be encoded on a nuclear gene, or it may have been completely lost; the latter option is plausible because the encoded protein is not a structural component of the complex but is merely involved in its assembly.) Nearly all plants so far examined* also have broadly the same set, plus usually a selection of extra ones. Some (though not all) 58 yeasts’ mitochondria only encode about half of the proteins encoded in animals’ mtDNA, but in this case there is not the uncertainty that attends nematodes’ ATPase 8: all the missing ones are subunits of Complex I, and these yeasts simply do not have a Complex I at all, so the genes for its subunits are absent from either genome. These yeasts do have an enzyme that takes electrons from matrix NADH and passes them to ubiquinone, but it is nothing like normal Complex I in structure; in particular it does not pump protons. 59 The evolutionary causes and effects of various organisms’ mitochondrial genetic complements will be discussed in Section 10.2. * We will come back to the exceptions in Chapter 15, since they may be extremely useful in the development of one particular life-extension therapy.
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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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CHAPTER 10 Frequently-Asked Questio
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Frequently-Asked Questions The effe
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Frequently-Asked Questions Table 10
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Frequently-Asked Questions through
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Frequently-Asked Questions SOS, sin
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Frequently-Asked Questions for almo
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Frequently-Asked Questions Fig. 10.
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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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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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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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The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki

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