Telomeric Theory - Related Reseach - Mitochondria

Aubrey de Grey ag24 at mole.bio.cam.ac.uk
Fri Oct 2 10:14:15 EST 1998


Tom Matthews wrote:

> 1. Is this "fumbling" pure chance?

Yes, since the potential for fumbling of a particular electron depends
on the exact timing of proximity of an oxygen molecule to accept the
electron and the time that the electron stays in the fumblable places
in the respiratory chain.

> 2. Is the percentage reasonably constant for all mitochondria in all
> cell of a given individual?

Reasonably, but it varies somewhat from tissue to tissue and depending
on rate of energy consumption, because these translate into variations
of the timings noted above.

> 3. Does the percentage vary between individuals?

After factoring out the above, probably not very much -- except with
age.  Mitochondria become less functional in many ways with age, of
which this is one.  (This is not specific to mitochondria that have
suffered mtDNA mutations: see below.)

> 4. If it varies not by pure chance, has any research been done to
> determine what are the causes of variation?

Yes, but there's plenty still to do.  We know that mitochondria of
elderly people fumble more electrons, and that's probably because of
changes to the mitochondrial membranes, notably loss of cardiolipin.
Bruce Ames's lab has done really useful stuff on this topic recently,
which you in fact posted here a month or so ago.  This happens to all
mitochondria, not just mutant ones.  The research that I consider to
be the most useful in this area is the interspecies work that I've
mentioned a few times in the past.

> Would it be accurate to say that a prooxidant is something which creates
> one or more free radicals or converts weak ones into stronger (nastier)
> ones or into more of the same strength (ie increases the total weighed
> free radical strength), whereas an antioxidant is something which
> eliminates one or more free radicals or converts stronger ones into
> weaker ones (ie decreases the total weighed free radical strength)?

Well, not really.  The whole terminology ("prooxidant", "antioxidant",
"oxidative stress") is part of the problem.  "Oxidation" really denotes
a reaction in which the more reactive participant removes an electron
from the less reactive one; when the more reactive participant donates
an electron it's called "reduction".  So the "oxidant"-based terminology
assumes that the reactive molecules which really matter in the body are
ones which remove electrons.  This is true for most of them, but not all.
Superoxide is the major exception.  It's a reductant, since it passes an
electron on (typically to a metal atom), and the metal atom then becomes
a reductant.  Hydrogen peroxide is really not an oxidant or a reductant,
because it's essentially harmless until it receives an electron from a
metal atom, which splits it into a (harmless) hydroxide anion and a
(vicious, oxidant) hydroxyl radical.

The other problem with your formulation is that "strength" really only
means speed with which a reaction occurs.  Hydroxyl radical is the most
reactive free radical known, but when it reacts with something (such as
a lipid) it only makes one lipid radical, and in doing so it becomes a
completely unreactive water molecule.  So the "weighed free radical
strength" has gone down.  But the lipid radical (after a few intermediate
rearrangements) can then react with a metal atom -- that's the branching
stage -- to form two lipid radicals.  So even though lipid radicals are
less reactive than hydroxyl by any measure, they're more harmful.

So in short answer to your question: best is to learn the chemistry and
take no notice of the terminology!

> Has anyone given thought to the possibility of a chemical or virus
> directed attempt to kill off these damaged mitochondria (before they
> dominate a cell) so that they would be naturally replaced by the
> remaining fully functional ones? If this were possible, then everyone
> could be truly "rejuvenated" periodically.

This is indeed one of the major proposed approaches (see ref. 13 in my
article).  The major perceived problem with it is the identification of
which ones to kill off: if the mechanism I proposed (see ref. 9) for the
ongoing maintenance of mitochondria by turnover) is correct, then the
mutant mitochondria will "look" for all the world like the ones that
must NOT be destroyed because they're the ones that are working the best.

Aubrey de Grey




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