The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki

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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.