Mitochondrial intervention

Aubrey de Grey ag24 at mole.bio.cam.ac.uk
Mon Feb 28 08:47:18 EST 2000

Paul Brookes wrote:

> >It is proposed that certain of these mutations reduce the rate of free
> >radical production giving that mitochondrium a survival advantage
> >within the cell. Selection subsequently causes the mutant mitochondrial
> >genome to become the predominant species within that cell.
> Has anyone ever shown "gain of function" in which a mtDNA mutation leads to 
> less ROS production?  It was my understanding that just about all of them 
> increased ROS production.   Of course by screening a library of yeast mtDNA 
> mutants one might actually be able to find low ROS producers - has anyone 
> tried this?

This is one of the more popular myths of mitochondrial biology.  It arose,
as far as I can tell, by analogy with the increase of ROS production that
results from chemical inhibition of respiration (antimycin etc).  The flaw
in the analogy is that mutations may cause the respiratory chain complexes
to fail to assemble at all, and such failure may cause coenzyme Q not to
redox-cycle and form the radical ubisemiquinone which seems to be the main
source of superoxide.  Interestingly, the paper most often cited as saying
that mutations would increase ROS production (Bandy and Davison 1990, Free
Radic Biol Med 8:523-539) was actually very cautious on this point, citing
a 1986 finding that the Rieske protein doesn't assemble into complex III
if cytochrome b (the only mitochondrially encoded subunit of that complex)
is absent.  (Of course we now have the crystal structure and it's totally
obvious that there would be no assembly, since cytb is smack in the middle
of the enzyme.)  The reason why all this is relevant to the question of
whether a typical mtDNA mutation would lower or raise ROS production is
that as far as we can tell, large deletions are the commonest category of
spontaneous mutation, and they always delete at least one tRNA gene, thus
abolishing synthesis of all 13 mt-coded proteins.  There was also a nice
study from McCord's lab (J Biol Chem 1993; 268:26699-26703) showing that
yeast with no mtDNA were more tolerant to hyperoxia, so this is not just

> Quite why a low ROS producing mito' has a selective advantage over a
> medium-high ROS one is still puzzling to me.

My model from BioEssays 1997; 19:161-6 is still unchallenged by any
data.   You do have a copy, don't you? :-)

> Is there any evidence
> that if one artificially raises (antimycin A) or lowers (FCCP)
> mitochondrial ROS in a cell, that the mitochondrial turnover is
> changed, or the cell degrades / promotes replication of said mito's
> differently?

There is still pitifully little data on mitochondrial turnover rates in
different situations, and none answering your specific question.  I've
been grumbling out loud about this for some time.  Quite a few other
people are now also grumbling out loud about it, which I suppose can be
considered progress...

Aubrey de Grey

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