The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki

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The Mitochondrial Free Radical Theory of Aging
was measured in rapidly dividing cells, which need more energy for biogenesis than a
non-dividing cell needs just to survive—and which, incidentally, do not accumulate high
levels of these mutations in vivo! Presumably null mutations, if present in the oocyte, are
sufficiently debilitating to cause early termination of embryogenesis or even failure of
ovulation; this is discussed further in Section 10.3.2.
Nevertheless, these inherited diseases may still be useful: after all, there is no a priori
reason why a mild mutation should behave qualitatively differently (in terms of selective
advantage) to a null mutation, which most spontaneous ones are likely to be. Irritatingly,
however—or perhaps, in the end, instructively—it seems clear that they do behave differently.
The “all-or-none” distribution of cytochrome c oxidase activity in normal aging is shown,
by in situ hybridisation, 57 to be caused directly by a similar, though not quite “all-or-none”,
distribution of a mtDNA mutation. But in the inherited diseases, in situ hybridisation reveals
many muscle fiber segments with intermediate levels of the mutation. This goes a long way
towards explaining how the overall levels in tissue can be so high—cells have a substantial
surplus of mitochondrial capacity, 81 so a cell (or fiber segment) with 50% or less mutant
mtDNA would show very little loss of performance—but it raises two big questions. The
first is: why is the cytochrome c oxidase activity all-or-none when the DNA is not? This has
become known as the threshold effect—when the level of wild-type DNA falls below a
threshold level, something happens to the expression of the nuclear-coded OXPHOS
machinery which abruptly eliminates all cytochrome c oxidase activity—but we have no
idea of the mechanism. But the second question is: why don’t these mutations get rapidly
amplified all the way to nearly 100%? Again we have no idea, though the existence of the
threshold effect may be a hint—if the selective advantage in normal aging is due to loss of
OXPHOS function of individual mitochondria (which seems reasonable, and see Chapter 8
for a detailed hypothesis), and if nuclear factors disable OXPHOS in the residual wild-type
mitochondria, then the selective advantage disappears. But whatever the reasons, the fact
that they don’t rise to the same levels—which, again, may have a lot to do with why they can
be inherited at all (see Section 10.3.2)—means again that they are a very dubious model for
mtDNA decline in normal aging.
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