The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki

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An Introduction to Mitochondria Fig. 2.11. Formation of a mtDNA deletion by illegitimate recombination. the other purine or a pyrimidine to the other pyrimidine. Replication error is known to be strongly biased towards transitions, 67 basically because purines are a very different shape from pyrimidines so the replication enzymes are less likely to mistake one for the other;* many mutagens, by contrast, are known to be biased towards transversions, because damage *For a more specific reason see Section 5.2. 29
30 The Mitochondrial Free Radical Theory of Aging to certain nucleotides makes (for example) guanine “look like” thymine. 68 The predominance of replication error as a source of mutations may also explain why the mitochondrial tRNA genes are particularly prone to pick up spontaneous mutations: relative to nuclear DNA, an unusually long stretch of the mtDNA is single-stranded during replication, and while a tRNA gene is in that state it may have a tendency to fold up into the configuration it adopts as RNA, which would impede DNA synthesis of the other strand and increase the chance of errors. 69 2.4.6. Mitochondrial Turnover Around the same time that mtDNA was identified, a related discovery was made. Each time a cell divides, its mitochondria must also divide—not necessarily at once, but eventually—or else the daughter cells will have progressively fewer mitochondria, which will eventually deprive them of energy. But in 1961 it was shown that mitochondria divide more often than that. As noted in the previous section, many cells in the human body are permanently non-dividing, or postmitotic: they can do their job in the body, but they can never divide again. Nerves and muscle fibres are prominent examples. Numerous other cell types, such as glia and fibroblasts, are in almost the same class: they can divide, but in practice they virtually never do so except in response to tissue damage (such as a wound). Paradoxically, even in non-dividing cells (postmitotic or not), there is a turnover of the mtDNA: the average mtDNA molecule lives less than a month. 70 Now, all the proteins in a mitochondrion could—in theory—be recycled individually, rather like parts of a car, without actually having the mitochondrion divide. But if the mtDNA is being recycled, the mitochondria themselves must be dividing. This means that mitochondria must also be getting destroyed in postmitotic cells, since otherwise the cells would fill up with mitochondria. This logic was soon confirmed by direct electron-microscope observation: 71,72 they are engulfed by lysosomes, which are the cell’s generic garbage collector. Incidentally, this explains why cells need not bother to repair pyrimidine dimers in mtDNA. The enzyme responsible for mitochondrial DNA replication is not able to copy a pyrimidine dimer—in fact, it cannot even jump across and resume replication on the other side of one. 61 So mtDNA molecules that have suffered that particular type of damage are never replicated, and are eventually destroyed, by random chance, along with their host mitochondrion. This acts as a perfectly good mechanism to stop them accumulating, so no active repair process is necessary. There is another feature of mitochondria in non-dividing cells which will be central to the theory outlined later on, and which is therefore worth mentioning here. Tissues composed of non-dividing cells, especially ones which use a lot of energy (such as the heart), are found to accumulate much higher levels of mutant mitochondrial DNA during aging than dividing cells. 73 We will come back to this feature of mtDNA decline in Section 6.6. References 1. Wallin IE. Symbionticism and the origin of species. Baltimore: Williams and Wilkins, 1927. 2. Altmann R. Die Elementarorganismen und ihre Beziehungen zu den Zellen. Leipzig: Verlag von Veit & Co., 1890. 3. Poitier P. Les symbiotes. Paris: Masson & cie., 1910. 4. Lange RT. Bacterial symbiosis with plants. In: Henry SM, ed. Symbiosis, Vol. 1. New York: Academic Press, 1966:99-170. 5. Sagan L. On the origin of mitosing cells. J Theor Biol 1967; 14:225-274. 6. Margulis L. Origin of eukaryotic cells. New Haven: Yale University Press, 1970. 7. Searcy DG. Origins of mitochondria and chloroplasts from sulfur-based symbioses. In: Hartman H, Matsuno K, eds. The origin and evolution of the cell. Singapore: World Scientific, 1992:47-78.
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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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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 has been
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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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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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