The Mitochondrial Free Radical Theory of Aging - Supernova: Pliki

98
The Mitochondrial Free Radical Theory of Aging
Fig. 8.3. Cell division short-circuits the mechanism by pre-empting degradation.
concentration falls; this again triggers mitochondrial replication. Finally, we can consider
the case of the mutant mitochondrion: it can make some ATP and import more as needed,
but will not have the same ATP concentration as a wild-type mitochondrion so engages in
runaway (or at least accelerated) replication.
This extremely neat model suffers, as noted above, only from rather inconclusive
inconsistency with the evidence. The results of Chambers and Gingold 13 (see Section 8.3)
are a direct refutation of preferential replication, but they have not been repeated in
mammalian cells. Point mutations in ATPase subunits should be amplified by this mechanism
just like other lesions, since the consequently greater proton gradient will cause faster
membrane damage so trigger more frequent replication; but the evidence that such mutations
do not accumulate is still restricted to only one report. 26 A third possible challenge derives
from the segmental distribution of mutant mitochondria in muscle—the removal by
lysosomes of supernumerary mitochondria in muscle fibers must be very assiduous, in order
to prevent rapid propagation of a mutation along a fiber—but since we have no knowledge
of this mechanism we cannot say that it is not so assiduous. A fourth is the report 8 that
mitochondria undergo replication independent of the time since their previous division:
this is incompatible with damage-driven replication because damage would be continuous,
so mitochondrial generation time should be fairly uniform. This too is only weak evidence,
though, because the experiment in question used dividing cells in culture, whereas a role for
damage in mitochondrial replication is proposed only for non-dividing cells. Perhaps the
best test would be to establish whether the replication of mitochondria in non-dividing