Magnus Lynch wrote:
> Instead of relying on cellular mechanisms of destroying non oxphos
> mitochondria why don't we destroy them directly by attacking them with
> "mitochondrial antibiotics".
...
> To make the compound selective for damaged mitochondria it should
> probably have a region which is cleaved or otherwise inactivated by one
> of the oxphos enzymes. I don't know how practical this would be. It
> would be best for the compound to destroy the mitochondia from within
> e.g. inhibit protein synthesis as we don't want to wipe out all of the
> mitochondria in the body.
This last point is probably the main obstacle to such an approach. The
example of inhibiting protein synthesis highlights the problem -- the
typical mutant mitochondrion already has no protein synthesis, due to
loss of tRNA genes, so this would only make matters worse. What seems
to be needed is a system that causes the mitochondrion to be targeted
for degradation, and (as I mentioned the other day in reply to Michael
Sherman) that may be very tricky if it turns out that that targeting is
normally reliant on active OXPHOS.
Jim Cummins wrote:
> A related approach has also been demonstrated in vitro. By targeting
> peptide nucleic acids complementary to mutant sequences, it's possible to
> selectively inhibit mutant mtDNA replication. Taylor, R.W., Chinnery,
> P.F., Turnbull, D.M. et al. (1997) Selective inhibition of mutant human
> mitochondrial DNA replication in vitro by peptide nucleic acids. Nature
> Genetics, 15212-215. This, of course, would not be feasible with ageing
> as you'd have to construct (and deliver) PNAs to all possible
> mutations/deletions.
Right. My other worry about this approach, which may make it unsuitable
even for the rare mitochondriopathies, is that mitochondria are probably
mostly homozygous even in heteroplasmic cells (that is, within the cell
there are both mutant and wild-type mtDNA molecules but nearly every
mitochondrion will have either all mutant or all wild-type). This is a
consequence of genetic drift, so it can only be avoided if mitochondria
fuse a lot or if segregation of mtDNA molecules at mitochondrial division
is not random; both have been suggested but my view is that neither is
very likely in vivo. And if so, inhibition of mutant mtDNA replication
will tend to create mitochondria with no mtDNA at all, rather as we can
do in vitro with ethidium bromide; such mtDNA-less mitochondria may be
a lot more harmful than the original mutant ones (whose mutations are
generally rather mild hypomorphs, in my view).
> An alternative but rather drastic approach was recently demonstrated by
> Shoubridge et al in a patient with mitochondrial encephalomyopathy -
> exhaustion of the mutant mitochondria by strenuous overexercise allowed
> repopulation with wild-type mtDNA from undifferentiat ed myoblasts.
> Shoubridge, E.A., Johns, T. and Karpati, G. (1997) Complete restoration
> of a wild-type mtDNA genotype in regenerating muscle fibres in a patient
> with a tRNA point mutation and mitochondrial encephalomyopathy. Human
> Molecular Genetics, 6,13, 2239-2242.
Yes, an inspired approach -- but it wasn't exhaustion of the mutant
mitochondria, it was physical damage to the muscle fibres (a previous
biopsy, in fact) causing them to undergo necrosis and be replaced. A
more recent Shoubridge paper looked at regeneration caused by exercise
(Human Mol Genet 8:1047). Turnbull's group tried a similar thing: they
induced necrosis of fibres with bupivacaine and similarly the satellite
cells regenerated wild-type fibres. Clark et al, Nature Genet 16:222.
Aubrey de Grey
