Paul Brookes wrote:
> mice deficient in the heart/muscle isoform of the adenine nucleotide
> translocase (ANT) exhibit higher levels of oxidative stress. They show
> that this is due to increased mitochondrial production of H2O2
> these cells will have an impaired apoptotic ability. This means the
> tissue will not be able to dispose of cells that contain "high ROS
> producing" mitochondria, a la Aubrey's theory on mito's and cell
> death.
First things first - you've forgotten my theory. It has nothing to do
with apoptosis of high ROS-producing cells, nor in fact with apoptosis
at all. I proposed (BioEssays 19:161-6) that cells get rid of their
high HEAT-producing mitochondria, one by one, by lysosomal phagocytosis.
My hypothesis is that this is the method by which mitochondrial
homeostasis is maintained in all non-dividing cells: mitochondria
sustain accumulated damage from the ROS that they produce, and
eventually the damage to the inner membrane reaches levels that
prohibit the maintenance of an OXPHOS-competent proton gradient, at
which point the mitochondrion has to be got rid of fast because it is
gobbling pyruvate and oxygen and only making heat. This steadily
depletes the number of mitochondria in the cell, which eventually has
to be dealt with by replication of some of those which remain; this
replication dilutes away the membrane damage to those mitochondria,
giving them a new lease of life even if they were on the point of going
critical. I suggested that this explains three things: (a) why/how
mitochondria turn over (as a unit) at all, (b) why mtDNA mutations
that affect the respiratory chain are selectively amplified by this
turnover: they do themselves slower damage (those who don't believe
this should read Guidot et al 1993, J Biol Chem 268:26699) so they get
destroyed less often, but they get replicated just as often as the
rest; and (c) why this selective amplification doesn't happen in
rapidly dividing cell types: cell division drives mitochondrial
division before membrane damage gets significant, so phagocytosis
never gets a look in.
Later I proposed (perhaps this is what you're thinking of) that cells
(and especially muscle fibre segments) which have been taken over by
mutant mitochondria by the above process generate extracellular O2.-
in the process of staying alive (ie maintaining redox homeostasis),
and thus that selective ablation of such cells/segments might be of
therapeutic value; for some cell types this ablation might best be
achieved by triggering apoptosis. But the *mitochondria* of such
cells don't produce much ROS at all. (J. Anti-Aging Med. 1:53-66.)
Whew - back to Esposito et al. I'm not with you. As they say in the
abstract, losing the ANT powerfully inhibits OXPHOS - by effectively
inducing state 4 (no matrix ADP). This seems to me to be a fine way
to increase ROS production, because the respiratory chain is intact,
so the proton gradient will rise, so complexes I and III will be more
reduced, so they will fumble electrons more often. (And also, though
I know this is heretical, the intermembrane pH will be lowered so more
of the O2.- will be protonated to HO2. and will thereby cause trouble
even without invoking Fenton chemistry.) This was my explanation in
the BioEssays paper for Pallotti et al. (Am. J. Human Genet. 1996)
finding no accumulation of a point mutation in ATP6.
Why do you say that the ANT has little control over OXPHOS?
Aubrey de Grey
