Had to comment on this......
In general, and in most experiments that have been done with isolated
mito's (and a few in vivo ones), uncoupling mitochondria decreases their
superoxide generation because of removing the block on electron transport
and allowing the complexes to become oxidised again. However, there are a
few studies in which they found that uncouplers can promote superoxide
generation.
I agree with Aubrey in saying that uncoupling mito's would seem to be a
good strategy for wasting energy and burning fuels, but exactly how they
make the mito's choose to burn fat instead of sugar is beyond me - maybe
that's where the hydroxycitrate comes in (WTF does it do?). On a
historical note, the uncouplers most people use in the lab today were
discovered because they are intermediates in the manufacture of
explosives. Someone noticed that explosives workers were ingesting the
stuff and literally wasting away - unfortunately the desired weight loss
effect also resulted in loss of life, so maybe uncoupling isn't such a good
weight loss strategy after all. Wonder if any data is available on the
ageing symptoms of these folks? Has anyone fed FCCP to rats and seen
increased longevity?
The other thing to consider is that pyruvate is an excellent free radical
scavenger and part of its effects (if it ever gets taken up into the cells
above baseline levels) may be due to this. On an experimental note..... if
what they're saying is true (shuttling e-'s back through complex I to make
NADH), then they should have done a control with rotenone. In addition, I
fail to see how NADH can shuttle e-'s to the cytosol, and then the e's can
re-enter at CoQ. In the context of ketogenesis its OK, as you're storing
up something for later, but just making NADH doesn't burn energy, and will
eventualy be feedback inhibited. T he other thing worth remembering is
that this is in hepatocytes, which don't have a lot of fat just lying
around to be burned, but do have a lot of sugar. In the whole animal
you've still got to get round the obstacle of moving the fat from the
adipocytes to the place where it's being burned. It would make sense if
they went after an adipocyte way of doing this, rather than th liver. I
for one don't want my liver too uncoupled - think of all the work it has
to do, like burninfg alcohol..... talking of which....
Paul
_________________________________________
Dr. Paul S. Brookes. (brookes at uab.edu)
UAB Department of Pathology, G004 Volker Hall
1670 University Blvd., Birmingham AL 35294 USA
Tel (001) 205 934 1915 Fax (001) 205 934 1775
http://peir.path.uab.edu/brookes
The quality of e-mails can go down as well as up
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