Regulation of Ca2+ transport in brain mitochondria. II. The mechanism of the adenine nucleotides enhancement of Ca2+ uptake and retention.
ADP greatly enhances the rate of Ca2+ uptake and retention in Ca2+ loaded mitochondria. Atractyloside, a specific inhibitor of the ADP/ATP translocator, completely inhibits the ADP effect, while bongkrekate, another specific inhibitor of the translocator enhances the effect of ADP. These results indicate that locking the ADP/ATP translocator in the M-state is sufficient to produce the ADP effect. Cyclosporin A, a specific inhibitor of the Ca2(+)-induced membrane permeabilization does not substitute for ADP, indicating that ADP directly affect the rate of electrogenic Ca2+ uptake. The effect of the translocator conformation on the rate of electrogenic Ca2+ uptake is independent of the concentration of Pi and is not caused by changes in membrane potential. However, locking the carrier in the M-state appears to increase the negative surface charge on the matrix face of the inner membrane. This may lead to an enhanced rate of Ca2+ dissociation from the electrogenic carrier at the matrix surface. The rate of Na(+)-independent Ca2+ efflux is only slightly inhibited by locking the carrier in the M-state, presumably due to the same mechanism. In the presence of ADP, Pi inhibits the Na(+)-independent efflux. In the presence of physiological concentrations of spermine, Pi and Mg2+, the rate of Ca2+ uptake, Ca2+ retention and Ca2+ set points depend sharply on ADP concentration at the physiological range of ADP. Thus, changes of cytosolic ADP concentration may lead to change in the rate of Ca2+ uptake by mitochondria and thus modulate the excitation-relaxation cycles of cytoplasmic free calcium.
Rottenberg
H
H
Pathology Department, Hahnemann University, Philadelphia, PA 19102.
Marbach
M
M
D000227:Adenine Nucleotides / Q000502:physiology*; D000818:Animals; D001278:Atractyloside / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D001865:Bongkrekic Acid / Q000494:pharmacology; D001921:Brain / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D003524:Cyclosporins / Q000494:pharmacology; D066298:In Vitro Techniques; D007700:Kinetics; D008274:Magnesium / Q000494:pharmacology; D008297:Male; D008928:Mitochondria / Q000378:metabolism*; D000226:Mitochondrial ADP, ATP Translocases / Q000037:antagonists & inhibitors; D008956:Models, Chemical; D010539:Permeability / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains
D000227:Adenine Nucleotides; D003524:Cyclosporins; D001865:Bongkrekic Acid; D001278:Atractyloside; D000226:Mitochondrial ADP, ATP Translocases; D008274:Magnesium; D002118:Calcium