From: Rafal Smigrodzki (rafal@smigrodzki.org)
Date: Fri Apr 25 2003 - 17:50:57 MDT
Aubrey de Grey wrote:
>
>> only two mt proteins have *not* been found in the nucleus in one
>> organism or the other.
>
> Wrong (though often stated). Only two (cytochrome oxidase I and
> cytochrome b) have always been found in the mt, but that's not the
> same, because Complex I is completely absent in some yeasts and in
> Plasmodium -- they get by with an enzyme that does the electron
> transport but no proton pumping (for which they manage with the
> contributions of Complexes III and IV). There are four subunits of
> Complex I for which these are the only species that lack the genes in
> the mtDNA, and of course they also lack them in the nDNA.
### Good points.
-------------------------
>
>> Possibly the reason for stability of the mtDNA in
>> evolution is not the protein import problem, but the difference in
>> the nuclear and mito genetic code.
>
> That works for animals, but not plants (see my mail of yesterday).
### But in plants we have huge mitos with introns, 57 genes. Either there is
another insurmountable barrier but a different one from hydrophobicity, or,
more likely IMO, plants do not have a strong selective pressure against
large mitochondrial genomes.
Also, there are many highly hydrophobic proteins made in the nucleus and
imported into membranes, or through membranes.
The genetic code difference makes sense to me because it implies the need
for at least three independent mutational events for mtDNA-nDNA gene
transfer in vertebrates. You have to make a nuclear pseudogene from a mtDNA
gene, then mutate it into a form which will produce a viable protein if read
by the nuclear tRNA's, and then you have to couple it to a mitochondrial
leader peptide. Each event happens all the time, but all three together
would be quite uncommon.
-----------------------------------
>
>> ### Human mt-mRNA is polycistronic.
>
> Sort of..... it's transcribed as one message for each strand, but they
> are then chopped up and each bit polyadenylated before translation.
> Two of the protein-coding products of the chopping-up are dicistronic,
> the rest mono.
### Yes, three polycistronic transcripts getting chopped up.
--------------------------------
>
>> Is there some alpha-synuclein in lysosomes simply because stuff ends
>> up in lysosomes, or is it's presence in the lysosomes the mechanism
>> of its detrimental action? This has not been answered so far, AFAIK.
>
> I agree, but who cares? -- the only thing that matters is whether NON-
> lysosomal alpha-synuclein is bad for cells, and no one has postulated
> any way that it could be.
### You lost me here. For the outcome of a xenohydrolase treatment it
definitely matters whether the lysosomal aggregates are detrimental or not.
-----------------------
>> ### Atheromatous material may be difficult to digest, but is not
>> non-digestible. With some treatments you can have regression of
>> atherosclerotic changes implying digestion of macroscopic amounts of
>> plaque. There is a dynamic balance between plaque accumulation and
>> digestion.
>
> That doesn't follow. At any given instant, there will certainly be a
> proportion of the atheroma core that's digestible (and is indeed being
> digested). That proportion will diminish as a result of treatments
> that slow down the arrival of new material, etc., so the total size
> of the plaque will also diminish. But that doesn't tell us whether
> there is *also* stuff there that *can't* be degraded. In fact we can
> say with confidence that there is, because the plaque appears out of
> nothing. The originating macrophages that enter our artery wall in
> youth, for example, can only become foam cells by hanging out ther
> and taking in a steady stream of LDL etc and failing to break it all
> down -- else they would remain as healthy macrophages forever.
### You are talking about the so called "fatty streaks", right? Fatty
streaks can fully disappear. The only way you can tell there is totally
indigestible stuff in the plaque is if you cannot digest it in vitro in cell
culture, and if injected in vivo in a young animal, it doesn't get
phagocytosed. Otherwise the existence of humanly indigestible plaque is a
hypothesis, and interesting one, but not a theory or fact.
---------------------------
Same
> goes for the core of the mature plaque -- there's a constant stream
> on new macrophages arriving all the time to do battle with it, and
> if they were able to break down everything there they would do so.
### A different explanation is that there is a dynamic balance between the
influx of digestible fatty material, and the ability of endothelium and
macrophages to deal with it. As time goes by, the balance tilts towards
buildup, with first only occasional macrophages dying, then as the quality
of macrophages goes down with age (and it does), there isn't enough to deal
with plaque even if it's still digestible, also because of scarring, and
calcification.
To my knowledge, there is still no final answer on atherosclerosis.
---------------------------------
>
>> it is indeed possible to replace full length mtDNA now, so it's
>> just a matter of time before somebody manages to do something useful
>> with it.
>
> Probably not in respect of aging. Unfortunately it seems that the
> mutant mtDNA molecule has a selective advantage in post-mitotic cells
> and clonally expands at the expense of the wild-type, eventually
> taking over the whole cell. This process would overcome any attempt
> to replace mutant mtDNA by wild-type copies. No one has come up with
> any feasible way to reverse this selective pressure (and not for want
> of trying!). Putting in mtDNA that reduces superoxide production
> may be a different matter though -- but (broken record time) that's
> just retardation, not repair/reversal/obviation.
### It is not clear that the mutant sequences, aside perhaps from some
deletion mutants, have a selective advantage. Chinnery and Turnbull did some
calculations showing that mtDNA can widely fluctuate and fix mutations into
homozygosity if only random processes are taken into account. A mutational
ratchet mechanism tends to favor mutated DNA's in a 3 to 1 ratio, but this
is not a selective advantage.
Actually, once you have mitofection, there are at least two feasible methods
to select the mutated mtDNA's out of the cell. Previous attempts failed
because of lack of the ability to introduce DNA into mitos, but this has now
changed.
Rafal
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