Inhibition by cyclosporin A of a Ca2+-dependent pore in heart mitochondria activated by inorganic phosphate and oxidative stress.
The capacity of cyclosporin A to inhibit opening of a Ca2+-dependent pore in the inner membrane of heart mitochondria was investigated. Whereas in the presence of 25 nmol of Ca2+/mg of mitochondrial protein and 5 mM-Pi mitochondria were unable to maintain accumulated Ca2+, inner-membrane potential and sucrose impermeability, all three parameters were preserved when cyclosporin was included. Pore opening was assayed directly by [14C]sucrose entry and entrapment in the matrix space. [14C]Sucrose entry induced by both Ca2+ plus Pi and Ca2+ plus t-butyl hydroperoxide was almost completely inhibited by 60 pmol of cyclosporin/mg of mitochondrial protein. It is concluded that cyclosporin A is a potent inhibitor of the pore.
Crompton
M
M
Department of Biochemistry, University College London, U.K.
Ellinger
H
H
Costi
A
A
D000818:Animals; D002118:Calcium / Q000494:pharmacology*; D002463:Cell Membrane Permeability / Q000187:drug effects; D003524:Cyclosporins / Q000494:pharmacology*; D005260:Female; D007425:Intracellular Membranes / Q000187:drug effects / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism*; D010084:Oxidation-Reduction; D010545:Peroxides / Q000494:pharmacology; D010710:Phosphates / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013395:Sucrose / Q000493:pharmacokinetics; D020122:tert-Butylhydroperoxide
D003524:Cyclosporins; D010545:Peroxides; D010710:Phosphates; D013395:Sucrose; D020122:tert-Butylhydroperoxide; D002118:Calcium