OK, sorry for confusing your theory with one of Skulachev's - he says that
apoptosis is the cells' way of getting rid of ROS producing mitochondria.
The reason I say ANT doesn't have much control over ox-phos is Rod'
Hafner's paper when he was in Martin brand's lab. In state 3 the
phosphorylating system as a whole (ANT, ATPase, Pi transporter) might have
about 1/3 of the control, but anywhere more than state 3 this falls off.
Even if cells operate at state 3.5, the ANT will never have more than about
0.15 of the control. I seem to remember a Ph.D student of Kevin
Brindle's overexpressed the ANT 4-6 fold in yeast and showed no effect on
ox-phos. Don't know if he knocked it out though.
I hadn't heard your other proposal, about cells overtaken by mutant mito's
producing extracellular O2.- Is this really the case, as I thought all
O2.- made by mito's was dismuted to H2O2 - you can only detect O2.-
production by mito's if you knock out MnSOD or use sub-mitochondrial
particles.
I'm not that convinced by any of the arguments that show inhibition of
ATPase or ANT increases O2.- production. It appears to me that the
delta-psi will be raised, and this will kick in H+ leak to dissipate the H+
gradient, thereby alleviating the problem. From what I can tell, the
further back along the eTC you inhibit, the greater the effect on
superoxide production. Even KCN inhibition of Cx IV doesn't increase O2.-
production by much (<5%). I think it is very important to draw a
distinction between inhibition of electron transport at the complexes,
which is a genuine inhibition with no "escape route" for the electrons
except O2.- production, and inhibition by feedback from further down the
system, in which case proton leak is an effective alleviator.
Ignoring the above and assuming your idea about the increased intermembrane
pH is correct, it is rather interesting that HO2. is membrane permeant -
Liu et al propose that this is one mechanism by which superoxide casues
proton leak. It is, of course, incorrect, as the amounts of O2.- produced
are wildly insufficient to account for the levels of H+ leak observed. I
propose (in the ONOO- J. Neurochem. paper) that it might be due to lipid
peroxidation but we're currently no closer to elucidating a mechanism tha
we were a year ago.
Regards
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
