questions about mitochondria

Aubrey de Grey ag24 at mole.bio.cam.ac.uk
Tue Aug 15 11:57:36 EST 2000


Iuval Clejan wrote:

> > 2. Actually I don't understand oogenesis. My understanding is that
> > mitosis occurs a few times in the embryo and that the cells are then
> > called oogonia. After the first meiotic division the cells are called
> > primary oocytes (diploid?). And after the second meiotic division (which
> > occurs during sexual maturity) the cells are called secondary oocytes.
> > Is this correct? Some people have told me that meiosis is not complete
> > until ovulation (how so?)
>
> The primary oocytes enter a dictyate resting stage during fetal life (I'm
> talking mammals here).  Meiosis only resumes around ovulation and in fact
> activation of the oocyte (normally by sperm penetration) is the trigger
> for the second meiotic division.

> Huh? So when does the first meiotic division occur? And what are the
> secondary oocytes? I thought that when the sperm penetrates the egg you
> start dividing by mitosis again. Isn't the egg before fertilization
> haploid (as is the sperm)? In which case it has already undergone the
> second meiotic division.  Please explain. What about the drosophila
> question?

Well, that's a lot to explain.  Actually this may be a good topic on
which to plug NCBI's really splendid new idea of linking abstracts to
graduate-level (or so) textbook descriptions of the topics addressed.
At present there's only one textbook so linked, but it's one of the best
ever -- Molecular Biology of the Cell by Alberts et al.  Just search
Medline for something general like "oogenesis" and then hit the "Books"
link, and the abstract reappears with various terms hyperlinked to the
corresponding section[s] of Alberts.  This seems to me to be a really
brilliant teaching (and especially self-teaching) aid, and I'd be very
interested in feedback on how well it works as such.  (I have nothing
at all to do with it, by the way -- I'm just interested to know whether
it's as useful as it seems.)

But to answer a couple of your points: the cells arising from the first
meiotic division are haploid.  Drosophila arrest at a different point,
late in the second division.  Primary oocytes are the cells before the
first meiotic division, so they're diploid.  In mammals there are two
arrests, in fact - one early in the first division, which is released
at ovulation, and another at the time that Drosophila arrest, which is
released at fertilisation.  The 16-cell cyst formed in Drosophila is
formed by four mitoses, all prior to meiosis.  15 of them then become
nurse cells.  Meiosis is always a two-division process.

> > The thing that
> > happens much earlier is a mtDNA population bottleneck; that process is
> > not selection in and of itself, but it amplifies the power of the later
> > selection process by reducing the possibility that there will be some
> > but not many mutant mtDNA genomes in the oocyte at the time of ovulation.
> 
> I need to read those references because I don't understand this. Why is
> some but not many bad? Many is worse than some. What is the net result
> of the selection process? Very few mutants?

The idea is actually not complicated.  If an oocyte has a lot of mutant
mtDNA, it won't become the "winning" oocyte at ovulation so it won't be
fertilised.  If it has only a small amount, it will have enough energy
that it can potentially be fertilised, but the resulting embryo then
has a heaed start in mitochondrial mutation accumulation.  In other
words, the selection at ovulation is a blunt instrument that only works
well because of the removal of this intermediate possibility.  The net
result is, as you say, very few mutant mtDNA molecules in any egg that
gets fertilised.

I stress that the above is consistent with known data but not proven.

> > > Why is tellomerase anti-apopototic? Is it
> > > possible that senescent cells stop expressing some of the genes
> > > necessary for mitochondrial welfare?
> >
> > The only theory I know of (see Zhang et al, Genes Dev. 13:2388) is that
> > telomerase specifically inhibits apoptosis caused by aneuploidy.
>
> But Fu et al, J. Bio. Chem. 274 11:7264 show that it inhibits apoptosis
> caused by a few apoptotic inducers that have nothing to do with
> aneuploidy. Conversely tellomerase

You won't get far searching Medline for "tellomerase".

> inhibitors enhance apoptosis in the presence of the apoptotic inducers.
> Also a correlation was observed between decrease in tellomerase
> activity and sensistivity to apoptosis after differentiation of cells
> into nerve cells, but I didn't see a causal link there. I also didn't
> understand if they were using immortalized cells or not, and if the
> latter how short their tellomeres were (I recall papers saying that
> senescence is entered much before the chromosomes are short enough for
> aneuploidy and that P53 somehow sensed the shortness of the tellomeres
> and stopped the cell cycle)

Thanks for this - I didn't know that article.  They were indeed using
immortalised cells -- you can be pretty sure of this whenever the cell
type ends in "oma".  See also a recent paper from the same lab: Zhu et
al, J Neurochem 75:117.

It should be pointed out in this context that if telomerase indeed has
rather wide-raging anti-apoptotic effects, its reintroduction into cells
that are near or at replicative senescence would have an additional risk
(over and above the oft-cited one of removing one barrier to cancer):
namely, that cells might be unable to execute the apoptotic program when
they got into trouble, and could thus become deleterious to the body as
a whole.  It's important to remember that apoptosis is a physiologically
beneficial process which happens when it's better for the body to lose
the cell than to keep it, and therefore inhibiting apoptosis in vivo is
likely to be bad for us.

> I think you hypothesized  (I saw one of your abstracts on medline) that
> some mutations are actually selected FOR, although by a different
> mechanism having to do with less likely lysosomal degradation of the
> mito which doesn't produce as much ROS.

Yes.  But that mechanism isn't yet proven.  I just wanted to stress that
mutations aren't necessarily selected against -- which is of course a
prerequisite for mutants being selected for -- whereas typical mutations
in free-living bacteria *are* selected against.

> > > One thing that might keep
> > > them from reproducing is a nuclear clock (e.g. tellomere shortening
> > > followed by activation of P53 followed by apoptotic signals) This
> > > scenario would favor mitos in post mitotic cells, if other
> > > mechanisms didn't come into play.
> >
> > You've lost me here.  Favour mutant mitos in post mitotic cells?
> 
> Mutant or not, as long as they're in cells that don't have shortening
> tellomeres (post mitotic cells) they'll be able to either replicate,
> repair or transcribe their own DNA better than the ones in post mitotic
> cells, which get a signal from the nucleus that stops the
> aforementioned functions. Please try to poke holes in this hypothesis.
> If no conceptual holes, I think there are a few experiments that can be
> done to test it.

I'm still not sure I understand what your hypothesis is.  It seems quite
plausible that the genes whose expression is changed during replicative
senescence would include some whose products have mitochondrial roles,
and thus that mitochondrial function might be impaired in such cells.
But what has that got to do with p53 and apoptosis?

Aubrey de Grey







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