On the interactions of Ca2+ and cyclosporin A with a mitochondrial inner membrane pore: a study using cobaltammine complex inhibitors of the Ca2+ uniporter.
The mitochondrial inner membrane contains a Ca(2+)-activated pore of possible relevance to the pathogenesis of ischaemia/reperfusion injury which is inhibited by the immunosuppressant cyclosporin A (CSA). The present study employs a number of novel cobaltammine complex inhibitors of the Ca2+ uniporter (mediating Ca2+ uptake) to examine whether intramitochondrial Ca2+ influences the capacity of CSA to block the pore. Using dissipation of the inner membrane potential as a means of monitoring the state of the pore, it is shown that CSA blockade is facilitated as Ca2+ uptake is restricted. Ca2+ also depresses and reverses the binding of [3H]CSA to mitochondria, but Ca2+ is ineffective when its uptake is prevented. It is concluded that a high intramitochondrial Ca2+ concentration antagonizes pore inhibition by CSA. The significance of this is discussed.
Crompton
M
M
Department of Biochemistry and Molecular Biology, University College London, U.K.
Andreeva
L
L
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels; D002135:Calcium-Binding Proteins / Q000037:antagonists & inhibitors*; D003035:Cobalt / Q000737:chemistry / Q000494:pharmacology*; D016572:Cyclosporine / Q000378:metabolism / Q000494:pharmacology*; D007425:Intracellular Membranes / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D008297:Male; D008564:Membrane Potentials; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D000644:Quaternary Ammonium Compounds / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012430:Ruthenium Red / Q000494:pharmacology
D015220:Calcium Channels; D002135:Calcium-Binding Proteins; D000644:Quaternary Ammonium Compounds; C034703:mitochondrial calcium uniporter; D012430:Ruthenium Red; D003035:Cobalt; D016572:Cyclosporine; D002118:Calcium