questions about mitochondria
clejan at mindspring.com
Fri Aug 18 01:07:10 EST 2000
Aubrey de Grey wrote:
> 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.)
I'll give it a try. Thanks.
> But to answer a couple of your points: the cells arising from the first
> meiotic division are haploid.
But they do have a full complement of DNA because they replicate before
dividing. So maybe haploid in some sense.
> 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".
Maybe the search engine was written by an american, in which case the double "l"
may be OK (since americans are so
smart and write good software, not because they can't spell)
> > 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.
> > > > 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?
I thought that P53 was somehow involved in triggering replicative senescence by
sensing short tellomeres as DNA damage, I don't recall where I read this, or if I
somewhere. The connection between apoptosis and replicative senescence is also
vague, I recall seeing references to this, maybe on this newsgroup. The mind of a
physicist seeks unity, where perhaps there is none. And the other connection
between replicative senescence and mitochondria is that tellomere shortening
triggers replicative senescence which according to my hypothesis affects the well
being of mitochondria (or their efficiency in oxphos). On the other hand, mitos
are involved heavily in apoptosis. One thing I'd like to try is to see if
replicative senescence affects mitochondrial replication. This should be easy to
do by standard techniques (?).
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