some questions from Aubrey's book

Aubrey de Grey ag24 at mole.bio.cam.ac.uk
Wed Jan 26 09:21:33 EST 2000

Michael Rae wrote:

> > mitochondria in CR animals spent more
> > time in clean-burning state 3 and less time in dirty state 4, and
> > that this was triggered by the change in thyroid hormone balance and
> > output.
> You can help with interpretation, but I take these abstracts to suggest
> my conclusion above, as they seem uniform in saying that thyroid
> hormones stimulate state 3 relative to state 4

OK, I think you're interpreting "decrease in state 3 respiration" to
mean "switch from state 3 to state 4", which it doesn't.  I think you
know that state 4 is when there is no turnover of the ATP synthase, due
to unavailability of its substrate, so that all proton influx into the
mitochondrion is proton leak through the membrane, whereas in state 3
proton influx is mostly through the ATP synthase because its substrates
are present in excess.  State 4 respiration tends to have higher free
radical production than state 3 because the proton gradient is raised
by the respiratory chain struggling to make ATP.  But then I think you
infer from that that "decrease in state 3 respiration" means a decrease
in the proportion of proton influx that is through the ATP synthase, in
the live animal, without a change in the total amount of proton influx
via both paths.  What it actually means is a decrease in the rate of
oxygen utilisation in the presence of excess substrate for ATP
synthase, i.e. they isolate mitochondria from the animals and give them
plenty of ADP and phosphate and ask how fast they respire.  That tells
us nothing direct about what state those mitochondria were in in the
animal, e.g. how much ADP they had.

So in particular, if we do something to an animal which makes its
mitochondrial membranes leakier, such as giving it a lot of thyroid
hormone, and then we isolate its mitochondria and ask how fast they can
respire in the presence of no ADP (i.e. state 4), we will get a bigger
number than before the thyroid supplementation because more protons
will be able to get back into the mitochondria by leak, so more can be
pumped out by respiration.  If we take those same leaky mitochondria
and give them excess ADP (state 3) we will ALSO get more respiration,
for the same reason.  That's why in the Liu et al abstract "The
state-4 AND state-3 respirations ... were elevated in hyperthyroid
animals but attenuated in hypothyroid ones".  If we ask the converse
question about similarly treated animals, namely how big a proton
gradient the mitochondria can make with a given rate of respiration,
we get a lower proton gradient for leakier mitochondria and a higher
one for less leaky ones: "At any given respiration rate mitochondria
isolated from hypothyroid rats had a protonmotive force greater than
mitochondria isolated from euthyroid controls, and mitochondria
isolated from hyperthyroid rats had a protonmotive force less than
mitochondria isolated from euthyroid controls" from the Hafner paper.
(Oligomycin inhibition means inhibition of ATP synthase, i.e. it's a
way of enforcing state 4 even if ADP is present.)

However, there's more.  What I've said so far suggests that states 3
and 4 respiration are always varied in the same direction by anything.
But of course I've only considered one variable, the leakiness of the
membrane, as being affected by the treatments.  The Chance abstract
reports that thyroid hormone raises state 4 respiration, same as the
other papers do, but they say that it lowers state 3 respiration.  I
wil have to look at the paper to see the details, but it's possible
that in their experimental conditions the ATPase was inhibited.  The
hypotheses of Hoch is completely new to me and again I'll have to read
the paper.  Unfortunately I am going to California for two weeks in a
couple of days and I don't have the time to to this now.  Paul knows
as much about this topic as me - perhaps he will comment.

Aubrey de Grey

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