The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki

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The Mitochondrial Free Radical Theory of Aging
mitochondria falls. This acts as a selective pressure against the mutants, because it is
unidirectional: once a cell has no mutants, its descendants stay that way unless and until
there is a new mutation event, whereas a cell that retains a few mutants can give rise at any
future time to mutant-free descendants. See Section 10.7 for more about genetic drift.
A difficulty with the above explanation is that genetic drift will only exert a significant
pressure to eliminate mutant mtDNA once its copy number is very low, and the typical cell
has a surplus of bioenergetic capacity, so the pressure due to intercellular competition may
not get the number of mutant molecules low enough for drift to take over. A better
explanation was provided recently: 14b that the necessarily slower protein import of mutant
mitochondria, though probably irrelevant in non-dividing cells due to the time available
(see Section 10.6), will select against the mutant mtDNA in dividing cells where SOS is
absent.
10.3.2. How Does mtDNA Survive in the Ovum Until Fertilization?
This is harder—in fact, it is still a flourishing research topic. Since the ovum is a
non-dividing cell until fertilization, it is potentially susceptible to SOS, and it has to avoid it
for dozens of years. An age-related increase in oocyte mtDNA deletions has indeed been
found. 14c
Three explanations have been explored, and—unusually—they are probably all correct.
The first is that ova are extremely quiescent until ovulation. 15 They have almost no energy
requirements. Thus they probably generate hardly any LECs, so their mitochondria probably
have very little chance to mutate; also, if a mutation arose through replication error, it would
be only very slowly amplified. This is probably sufficient to deal with the case of mutations
that arise in the ovum, rather than being already present when it was formed, since those
few mutant mitochondria would be so diluted out during early embryogenesis that they
would be easy prey to replication disadvantage and genetic drift (see above).
The second explanation deals with the opposite end of the spectrum: the case where a
substantial proportion of the mtDNA in the ovum was mutant when it was formed. In such
cases, SOS will ensure that there is no normal mtDNA left by the time of ovulation. A
substantial burst of energy output on the part of the ovum is demanded during its ovulation
and rapid early divisions, which is impossible without working mitochondria. If this
energy is not forthcoming, subsequent cell division of that embryo fails, so no gestation will
occur. The mother may have to wait another month, or have a litter one offspring smaller,
but that is cheap in evolutionary terms.
What is really expensive in evolutionary terms is the third, intermediate situation:
when there is some mutant mtDNA in the ovum at formation, but not quite so much that
SOS can cause failure of early embryogenesis. That circumstance allows the possibility
that the ovum would be fertilised, but that during embryogenesis a proportion of cells
would retain enough mutant mitochondria that genetic drift would not eliminate them.
This would mean that the embryo could develop normally, but its aging process would
have a head start. Thus, the affected ovum would get all the biological investment needed
to get it as far as birth and perhaps some way beyond, but it would not get far enough to
have its own offspring, so in evolutionary terms all that investment (of parental care, etc.)
would have been wasted. This is a plausible explanation for the very rare occurrence of
sporadic (non-inherited) mtDNA-linked diseases such as Kearns-Sayre syndrome. 16
It seems that evolution has found an extremely ingenious way to minimise the chance
of this last scenario. 17 In the average cell there are at least 1000 mtDNA genomes, but in the
ovum there are about 100,000. The simple way to get from 1000 to 100,000 is to engage in
about seven rounds of mitochondrial replication; but that is not what happens. Instead, the
mitochondrial population that is destined to inhabit the ovum is first depleted! It is forced