The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki

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The Mitochondrial Free Radical Theory of Aging
structure at submolecular resolution. 24 The membrane becomes substantially thinner as its
internal organisation breaks down and the fatty acids from the two layers become
interdigitated. It is no surprise that this increases proton leak.
8.5. Less Degradation, Not More Replication
The story outlined in this chapter and the two preceding it summarizes the state of the
mitochondrial free radical hypothesis of aging in late February,1996, when I made my initial
contribution to it. My idea was published a year later. 25 It claims to provide the detailed
mechanism for amplification of mutant mtDNA that had eluded the field hitherto.
In seeking a mechanism whereby mutant mtDNA is amplified, I tried also to address
two enigmatic features of mitochondrial turnover that were noted in previous chapters.
Firstly: Why is the amplification so much more severe in postmitotic cells than in dividing
cells? And secondly: why does mitochondrial turnover in postmitotic cells happen at
all—what drives it?
The breakthrough came when I saw that the field had been unwittingly making an
unfounded assumption about the amplification process. Just as Mitchell’s colleagues had
been held back by their commitment to a chemical nature of the intermediate between the
respiratory chain and the ATPase (see Section 2.3.4), so in this case people were presuming
that preferential amplification of mutant mtDNA must occur by preferential replication. In
fact, in postmitotic cells at least, there was another option—“anti-preferential” degradation.
That is, the replication machinery may be completely unbiased with regard to whether it
acts on mutant or normal mitochondria, but the lysosomal degradation machinery, when
given the choice, may select normal ones in preference to mutant ones. This would have
exactly the same ultimate effect. Moreover, it matched the observations of Chambers and
Gingold in yeast (see Section 8.3).
Of course this initial idea is merely a paradigm: it doesn’t constitute a mechanism. In
principle, it might have been just as hard to come up with a detailed mechanism based on
biased degradation as it had been to find one based on biased replication. As it turned out,
however, this was not the case: a detailed mechanism was rapidly apparent. It provides an
explanation of all three of the observations under consideration: the existence of turnover,
the amplification of mutant mtDNA in non-dividing cells, and its non-amplification in
dividing cells. And as a bonus, it made a prediction which was in line with Schon’s report
from the same year 26a (see Section 6.6.4): that a particular class of lesion, mutations affecting
only the ATPase subunits, would not be amplified, even in non-dividing cells. Detailed
discussions of this hypothesis have since appeared. 26b-26e
8.5.1. The Mechanism Driving Turnover
The concept begins from the realization that mitochondrial turnover in non-dividing
cells is unavoidable, because mitochondria do themselves harm by LEC production. Most
importantly, the peroxidation and polymerisation of the lipid molecules of the inner
mitochondrial membrane by LECs is substantially not repaired. A respiring mitochondrion
will therefore accumulate such damage to its inner membrane. In due course, if nothing is
done, the membrane will become unable to perform its main function, which is the
maintenance of the proton gradient created by the respiratory chain. If and when this becomes
severe enough, the mitochondrion will engage in runaway (and futile) consumption of oxygen
and nutrients, since the proton gradient is the brake on the respiratory chain. This wastage
of oxygen and nutrients is unarguably bad for the cell and the organism, so the offending
mitochondrion must be destroyed without delay. The cell has a system for this: lysosomal
autophagocytosis and degradation of the mitochondrion, a phenomenon which has been