The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki

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An Introduction to Mitochondria 2.4.5. The Vulnerability of mtDNA and Mitochondrial Function The 13 proteins encoded in the mtDNA are absolutely essential for OXPHOS to occur. It is therefore just as important for an organism to maintain its mtDNA intact (in all cells, not simply the germ line) as to maintain its nuclear, chromosomal DNA. However, for reasons connected with mitochondria’s evolutionary origin (which was described in Section 2.1), cells fail to maintain their mtDNA to the nuclear standard. The mtDNA is much more prone to suffer spontaneous changes to its sequence, which result in the production of incorrect or truncated proteins—or, in some cases, failure to produce any protein at all. This vulnerability takes several forms. Firstly, the mtDNA is much more exposed than the nuclear DNA to free radicals that can induce mutations. This is because mitochondria are the main cellular site of production of free radicals; this will be explained in Section 3.3. There are no mitochondria in the nucleus, so the nuclear DNA is exposed to a much lower concentration of free radicals. A second source of mtDNA vulnerability is that it is “naked.” Nuclear DNA is always wrapped around special proteins called histones, which keep it somewhat protected from mutagenic attack. mtDNA does not have these. 60 Another reason is that, once damage is done to it, mtDNA is less well repaired than nuclear DNA. Certain classes of damage to DNA are rapidly reversed when they occur in the nucleus, but do not get mended in mitochondria. For some years it was believed that mtDNA was not repaired at all, but this was a piece of bad luck: the first researchers to address this question 61 had happened to analyse a class of damage called a pyrimidine dimer,* which indeed is not repaired at all in mtDNA, and most investigators incorrectly presumed that this was true of other types of damage too. Yet another problem for mtDNA is that it contains a high level of short sequences which appear twice, some way apart. This is dangerous, because it is possible for the circular mtDNA molecule to wrap around into a figure of eight, with the two identical sequences lying next to each other. When that happens, there is occasionally a “crossover”—the strands come apart and join up the other way, just as chromosomes do in meiosis. For a mtDNA molecule, however, this is fatal, because the single circle of DNA becomes two circles, each with only a subset of the necessary genetic material (see Fig. 2.11). Worse yet, one of those two circles will be without the D loop, a small stretch of DNA which contains no genes but which is essential for initiating replication of the molecule. Thus, the circle without the D loop will never be replicated and will eventually be lost, so that the final result is a deletion of a large chunk of the mtDNA. Indeed, these are easily detected in humans in vivo. In theory, the longer the stretch of duplicated sequence the greater will be the tendency for this to occur. In practice, one particular deletion is much more prevalent than any other 62a —so * The four nucleotides that endow DNA with its informational content are classified into two sets of two, on account of their atomic structure. Cytosine and thymine are pyrimidines, with a single-ring structure; adenine and guanine are purines, which have a double-ring structure. Thus, the complementary bases on opposite strands of the double helix are always one pyrimidine and one purine. The other discriminant, which causes (e.g.) adenine always to be paired with thymine rather than with cytosine, is that adenine and thymine are prone to form two hydrogen bonds whereas guanine and cytosine form three (see Fig. 2.10). A pyrimidine dimer is the result of a covalent bond being formed between adjacent pyrimidines on the same strand. 25
26 Fig. 2.10. Why the DNA bases pair only with their complements. The Mitochondrial Free Radical Theory of Aging much so that it is usually called the “common deletion”—and, indeed, it is precisely flanked by the longest relevant* direct repeat in the human mtDNA, 13 base pairs. 40 * Actually there are three other 13-bp direct repeats and even one 15-bp one. These are not observed to give rise to deletions. But this is no surprise, because two of these four have one of the repeats actually within the D loop region (so neither of the resultant circles would have a complete D loop), and the other two would put the D loop on one circle and the light strand origin (which is also needed for replication) on the other. Thus, each of these only create molecules that cannot be replicated. 62b
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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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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 Fig. 10.
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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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MOLECULAR BIOLOGY INTELLIGENCE UNIT
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