some questions from Aubrey's book

Aubrey de Grey ag24 at mole.bio.cam.ac.uk
Fri Jan 14 15:20:56 EST 2000

Michael Sherman wrote:

> Do you know if there is any ongoing research to elucidate the mechanisms
> of lysosome selectivity?

There is some relevant work going on, but there's a long way to go.  A
couple of very promising papers came out back-to-back in Sept. 1998:
van Leyen et al, Nature 395:392 and Mizushima et al, Nature 395:395.
I'm kicking myself for not sneaking those references into the book at
gally proof time ... well, one more reason to hope for a reprinting :-)

> Suppose the SOS effect could be reversed on just an occasional basis,
> say by a once-a-month treatment.  Because of the very small numbers of
> mutant mtDNA in the early stages, that could very well serve to reduce
> their number to zero in many cells.  The cost would be a small increase
> in the number of ATP synthase-damaged mitochondria.

But also, and more seriously, in the number of non-mutant but severely
membrane-damaged mitochondria, unless the intervention which reverses
SOS applied to mutants but not non-mutants.  The fact that degradation
by lysosomes is proposed to have this dual role (to drive mitochondrial
maintenance in the absence of mutations, but to drive SOS once mutant
mitochondria are present) is really the main sticking point, in my view.

> But that might only be temporary, because such noisy-but-useless
> mitochondria would not, as I understand it, have the SOS advantage once
> normal operation were resumed.  I also presume their number to be even
> smaller than the other mutants, because they require a mutation to a
> particular gene. 

True, and the first point is also true for the non-mutant but severely
membrane-damaged ones.  Something that could really reliably be turned
on briefly, and trigger extremely prompt engulfment of a lot of mutant
mitochondria, and then be really reliably turned off again in all cells,
would (I agree) have the benefit you're suggesting.  But sufficiently
reliable switching in vivo is a very tall order.

> Do you still feel this would be a dead end as a MiFRA intervention?

I wouldn't go so far as "dead end" -- as I wrote at the end of that
section, my survey was deliberately quite cavalier and really I only
wanted to rank possible approaches with regard to feasibility.  But I
do have trouble thinking of even the germ of a specific implementation
of this approach.  Once we know more about how autophagocytosis is
triggered, I may change my mind.

Aubrey de Grey

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