Mitochondrial Ca2+ cycle mediated by the palmitate-activated cyclosporin A-insensitive pore.
Earlier we found that in isolated rat liver mitochondria the reversible opening of the mitochondrial cyclosporin A-insensitive pore induced by low concentrations of palmitic acid (Pal) plus Ca(2+) results in the brief loss of Deltapsi [Mironova et al., J Bioenerg Biomembr (2004), 36:171-178]. Now we report that Pal and Ca(2+), increased to 30 and 70 nmol/mg protein respectively, induce a stable and prolonged (10 min) partial depolarization of the mitochondrial membrane, the release of Ca(2+) and the swelling of mitochondria. Inhibitors of the Ca(2+) uniporter, ruthenium red and La(3+), as well as EGTA added in 10 min after the Pal/Ca(2+)-activated pore opening, prevent the release of Ca(2+) and repolarize the membrane to initial level. Similar effects can be observed in the absence of exogeneous Pal, upon mitochondria accumulating high [Sr(2+)], which leads to the activation of phospholipase A(2) and appearance of endogenous fatty acids. The paper proposes a new model of the mitochondrial Ca(2+) cycle, in which Ca(2+) uptake is mediated by the Ca(2+) uniporter and Ca(2+) efflux occurs via a short-living Pal/Ca(2+)-activated pore.
Mironova
Galina D
GD
Institute of Theoretical and Experimental Biophysics RAS, Pushchino, Moscow Region 142290, Russia. mironova@iteb.ru
Belosludtsev
Konstantin N
KN
Belosludtseva
Natalia V
NV
Gritsenko
Elena N
EN
Khodorov
Boris I
BI
Saris
Nils-Erik L
NE
D000818:Animals; D002118:Calcium / Q000502:physiology*; D015220:Calcium Channels / Q000502:physiology*; D016572:Cyclosporine / Q000494:pharmacology*; D004533:Egtazic Acid / Q000494:pharmacology; D005227:Fatty Acids / Q000096:biosynthesis; D066298:In Vitro Techniques; D007811:Lanthanum / Q000494:pharmacology; D053078:Membrane Potential, Mitochondrial; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism*; D051336:Mitochondrial Membranes; D024101:Mitochondrial Proteins / Q000502:physiology*; D008933:Mitochondrial Swelling; D019308:Palmitic Acid / Q000494:pharmacology*; D064801:Phospholipase A2 Inhibitors; D051381:Rats; D017208:Rats, Wistar; D012430:Ruthenium Red / Q000494:pharmacology
D015220:Calcium Channels; D005227:Fatty Acids; D024101:Mitochondrial Proteins; D064801:Phospholipase A2 Inhibitors; C034703:mitochondrial calcium uniporter; D012430:Ruthenium Red; D019308:Palmitic Acid; D004533:Egtazic Acid; D007811:Lanthanum; D016572:Cyclosporine; D002118:Calcium