The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki

The Search for How Mutant mtDNA is Amplified
directly visualised under the electron microscope. 27,28 Thus, it seemed clear that the lifetime
of a mitochondrion must necessarily be finite.
This was all purely conceptual though (apart from the existence of autophagocytosis):
there was no direct evidence that self-inflicted damage was the trigger for turnover. On the
other hand, it was plausible: lysosomal detection of a damaged mitochondrion could
realistically be mediated by way of a proteinaceous signal that is triggered by either the
oxygen depletion or the rise in temperature around the affected mitochondrion.
But this logic forces us to consider how the cell retains any mitochondria at all in the
long term. Somehow it must avert the above process by maintaining the degree of
contamination of its mitochondrial membranes at a stable level. Superficially, this might
look like a cast-iron refutation of the role of self-inflicted damage, but there is a way out:
stability of damage can be achieved by mitochondrial replication. This works because the
new membrane lipid and protein that is added to the parent mitochondrion, in order to
bring it to a size ready to divide, has not been exposed to LECs so is pristine. Replication of
a mitochondrion thus acts to dilute its existing membrane damage, by roughly a factor of
two.
Accordingly, my first proposal was that mitochondrial turnover in non-dividing cells is
driven by this membrane damage (see Fig. 8.1). Mitochondria accumulate damage until
they become poisonous, and are then digested. This randomly happens to some mitochondria
sooner than others, so the number of mitochondria in the cell steadily falls. Mitochondrial
replication occurs when the cell detects a shortage of ATP, caused directly by the diminished
numbers of mitochondria. Of necessity, the mitochondria that are replicated are those that
have not already been digested. The cell would probably not tolerate a loss of half its
mitochondria before initiating replication, so the pulse of replication* would be
“sub-saturating”—as proposed in the model described in Section 8.2, it would target only
the mitochondria near the nucleus.
8.5.2. Survival of the Slowest, or SOS; Amplification of Mutant mtDNA
This situation is stable while all mitochondria are genetically functional. At some point,
however, a mtDNA mutation may occur that lowers the respiratory capability of its host
mitochondrion. That mitochondrion’s lower level of respiration results (eventually—see
Section 6.6.2) in a smaller proton gradient across its inner membrane. That, in turn, will
translate into a lower concentration of harmful LECs in its immediate environment.** This
will result in a slower accumulation of damage to its inner membrane than is occurring in
properly respiring ones. Such a mitochondrion will, therefore, preferentially still be intact
when many of the cell’s non-mutant mitochondria have succumbed to the degradation
process hypothesised above. Thus it will be preferentially replicated (see Fig. 8.2). Repetition
of this cycle will rapidly divest the cell of all its properly respiring mitochondria. I have
termed this process “survival of the slowest,” or SOS.
8.5.3. Why SOS Doesn’t Happen in Dividing Cells
Dividing cells must replicate their mitochondria at least once per cell division, so as to
maintain the number of mitochondria per cell. This replication is proposed to be driven by
exactly the same mechanism as in non-dividing cells, namely shortage of ATP. But that
* In principle it actually need not be a pulse: if the regulation of replication rate is precise enough, it could
tick over at a broadly constant rate.
** The whole of Chapter 11 is devoted to a defence of this sentence, which rests on a challenge to some central
principles of textbook bioenergetics. 29
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