unequal mDNA segregation

Aubrey de Grey ag24 at mole.bio.cam.ac.uk
Fri Mar 12 10:00:29 EST 1999

clejan wrote:

> Has there been any research showing unequal segregation of mitochondria
> in dividing (either mitotically or meiotically) mammalian cells?  Not
> unequal numerically, but in the sense of damaged mitochondria going to
> one cell and undamaged mitochondria going to the other cell?

Yes, but not like the yeast mechanism: rather, segregation is presumed
to be random (so usually a little unequal) but affects the fate of the
daughters.  For stem cells this may amount to the same thing, because as
far as I know it is not known when the decision is made, when a stem cell
divides, which daughter remains a stem cell and which one differentiates.
If it is made after the division is complete, the random distribution of
good and bad mitochondria could influence the result.

Experiments: yes, but they were a bit less illuminating than expected.  The
first such study was Yoneda et al., PNAS 89:11164, which showed that mutant
mtDNA often took over cell cultures.  The second study (Dunbar et al., PNAS
92:6562) showed that sometimes the opposite happened.  Followup work has
led to the conclusion that the nuclear background is a major determinant
of which way it goes.  These experiments were done on point mutations that
cause certain inherited diseases but are almost certainly not completely
lacking in OXPHOS activity.  I think the most informative evidence we have
at the moment is the tissue distribution of mtDNA mutations in vivo, namely
that those with a rapid cell turnover (blood, epidermis) have next to no
mutations whereas non-dividing cells (especially those that do a lot of
respiration) have more (eg Cortopassi et al., PNAS 89:7370).  This is not
in good accordance with your suggestion that cells age because their stem
cells become less able to renew them.  The simplest available model that
fits the facts is as follows:

1 cells which divide regularly compete with each other, and those which
    get lots of dodgy mtDNA lose out, so the tissue levels stay low
2 cells which divide rarely are sometimes taken over by dodgy mtDNA but
    are then slow to divide when asked to do so (or else actually die
    before that happens), so again the tissue levels stay low
3 cells which don't divide at all are sometimes taken over by dodgy mtDNA
    but don't necessarily die, finding other ways to make ATP, so tissue
    levels rise with age.

But as you say the evidence is still incomplete.  Ova should be in class
2 above, but presently we really don't know.  Probably there are several
mechanisms for minimising the chance of mutant mtDNA getting into the egg
cells that successfully form embryos.

Aubrey de Grey

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