Cyclosporin A blocks 6-hydroxydopamine-induced efflux of Ca2+ from mitochondria without inactivating the mitochondrial inner-membrane pore.
Oxidative stress causes Ca(2+)-loaded mitochondria to release Ca2+. The mechanism of this efflux is unclear, but it appears to be associated with the opening of a pore in the mitochondrial inner membrane. Pore opening depolarizes the mitochondria, letting solutes enter the mitochondrial matrix, causing swelling. Cyclosporin A (CsA) prevents opening of this pore. The neurotoxin 6-hydroxydopamine (6HD) autoxidizes, producing free radicals, which cause oxidative stress. In this paper it is shown that 6HD-induced efflux from Ca(2+)-loaded mitochondria was prevented by CsA. The 6HD-induced Ca2+ efflux was not accompanied by mitochondrial swelling, depolarization of the mitochondrial inner membrane or movement of radiolabelled sucrose into the mitochondrial matrix. In agreement with others [Schlegel, Schweizer and Richter (1992) Biochem. J. 285, 65-69], these findings suggest that the mitochondrial pore remained closed during pro-oxidant-induced Ca2+ efflux. However, the implication that CsA blocks pro-oxidant-induced Ca2+ efflux by some mechanism other than inactivating the mitochondrial pore, suggests that the interaction of CsA with mitochondria may be more complex than is currently supposed.
Reichman
N
N
Department of Biochemistry, University of Otago, Dunedin, New Zealand.
Porteous
C M
CM
Murphy
M P
MP
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D016572:Cyclosporine / Q000494:pharmacology*; D004533:Egtazic Acid / Q000494:pharmacology; D005260:Female; D007425:Intracellular Membranes / Q000502:physiology* / Q000648:ultrastructure; D008564:Membrane Potentials / Q000187:drug effects; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D008933:Mitochondrial Swelling / Q000187:drug effects; D016627:Oxidopamine / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
D004533:Egtazic Acid; D016572:Cyclosporine; D016627:Oxidopamine; D002118:Calcium