Oligomycin strengthens the effect of cyclosporin A on mitochondrial permeability transition by inducing phosphate uptake.
The purpose of this work was to assess the effect of oligomycin on the mitochondrial membrane permeability transition. The antibiotic was found to strengthen cyclosporin A (CSA)-induced protection of non-specific permeability, which is triggered by a matrix Ca2+ load in the absence of ADP. Oligomycin also reinforced the protective effect of CSA on carboxyatractyloside-induced pore opening in the absence of ADP, but failed to do so in mitochondria incubated under anaerobic conditions or after addition of CCCP. Analyzing the efflux of matrix Ca2+, we found that mitochondrial swelling and the collapse of the transmembrane electric gradient coincided with membrane leakage. The effects of the antibiotic were observed in phosphate-containing media but not in the presence of acetate. Furthermore, N-ethylmaleimide hindered the protective effect of oligomycin-CSA. In addition, the matrix phosphate concentration increased concurrently with a diminution in the matrix-free fraction of Ca2+. We concluded that oligomycin increases phosphate uptake by stimulating the phosphate-/OH- exchange reaction.
Departamento de Bioquímica, Instituto Nacional de Cardiología, Ignacio Chávez, México, D.F. 014080, México. echavez@mail.ssa.gob.mx
Edmundo
E
Chávez
José S
JS
Rodríguez
Gerardo
G
García
Noemí
N
García
Francisco
F
Correa
D000085:Acetates / Q000378:metabolism; D000818:Animals; D001278:Atractyloside / Q000031:analogs & derivatives / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology*; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005033:Ethylmaleimide / Q000494:pharmacology; D007425:Intracellular Membranes / Q000187:drug effects / Q000378:metabolism; D007668:Kidney / Q000378:metabolism* / Q000502:physiology; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D008933:Mitochondrial Swelling / Q000187:drug effects; D009840:Oligomycins / Q000494:pharmacology*; D010539:Permeability / Q000187:drug effects; D010710:Phosphates / Q000378:metabolism; D051381:Rats; D014475:Uncoupling Agents / Q000494:pharmacology
D000085:Acetates; D004791:Enzyme Inhibitors; D009840:Oligomycins; D010710:Phosphates; D014475:Uncoupling Agents; D001278:Atractyloside; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone; D016572:Cyclosporine; D005033:Ethylmaleimide; C003853:carboxyatractyloside; D002118:Calcium