The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki

Frequently-Asked Questions
SOS, since it would surely confer a selective disadvantage. But we must consider with care
whether that disadvantage would be big enough to outweigh the advantage conferred by
slow degradation. In non-dividing cells, when the mitochondrion has a whole month in
which to import the proteins necessary to double its size, an impaired rate of import should
not matter, since it could not be rate-limiting. In rapidly dividing cells, however, SOS is
short-circuited and this disadvantage may have an important role in eliminating mutant
mtDNA 14b (see Section 10.3.1).
10.7. Why Doesn’t the Polyploidy of Mitochondria Protect Them?
Mitochondria do indeed possess more than one copy of the mtDNA. The average in
human cells is about five. When a spontaneous mutation occurs, therefore, there is still
plenty of backup for the creation of more protein from the other copies. This means
that—if, as is reasonable, we presume that the remaining copies can be transcribed and/or
translated 25% more often than normal—the affected mitochondrion will not, yet,
experience any selective advantage over other, fully wild-type ones. (Note that this is the
best-case scenario, because it does not cover the case where the mutation causes the protein
to be constructed and incorporated into the enzyme complex as normal, but then to function
abnormally. In that case, even one mutant copy may cause a 20% decline in function.)
There is, therefore, still a 50-50 chance that it will be destroyed rather than replicated. If
it is replicated, however, there is then a 50-50 chance that the two copies will be segregated
into the same daughter mitochondrion. This daughter may then start to feel the effects of a
diminished availability of the affected proteins, due to its wild-type mtDNA being depleted
by 40% rather than only 20%. The effect may be small, but even a small effect is enough to
make a big difference to the probability of going critical and being destroyed before being
replicated.
Moreover, the logic of the 50-50 chances mentioned above can be extended to subsequent
mitochondrial divisions. A small proportion of spontaneous mutants will therefore inevitably
achieve homozygosity in one mitochondrion, even if they have no selective advantage at all
until that time, while the majority of spontaneous mutations will be destroyed by random
chance before then. (This is called genetic drift, and was discussed in more detail in Section
10.3.1.) Indeed, we already have evidence that that is what happens 34 (see Section 6.6.2).
10.8. What About Mitochondrial Fusion?
This is a phenomenon whose existence in normal mammalian cells has been in dispute
for some years, though it is known to be a normal part of spermatogenesis in Drosophila 35
and may also occur in mammalian spermatogenesis. Its relevance to MiFRA is with regard
to the ability of a mtDNA mutation to out-compete the wild-type mtDNA and take over a
cell. The phenomenon of Darwinian selection relies absolutely on the link between genotype
and phenotype: that is, on the existence of a population of individuals, of varying genetic
content, whose “fitness” is at least partly determined by that genetic content. If mitochondria
divide but never (or rarely) fuse, then this is what exists in the cell after a spontaneous
mutation. If, on the other hand, mitochondrial fusion is frequent and allows the sharing, by
all mitochondria in a cell, of all the proteins that any of them can encode, then the link
between genotype and fitness is destroyed and no selective advantage can appear. Therefore,
if mitochondrial fusion is indeed frequent in vivo, the apparent clonal amplification of
mutations that has been so extensively reported (see Section 6.6) must, somehow, be an
artifact. It is thus imperative to establish whether mitochondria fuse in vivo, and if so then
how often.
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