Oligomycin, inhibitor of the F0 part of H+-ATP-synthase, suppresses the TNF-induced apoptosis

• Published in: Oncogene Vol. 21; no. 53; pp. 8149 - 8157
• Main Authors: Shchepina, Liarisa A, Pletjushkina, Olga Y, Avetisyan, Armine V, Bakeeva, Liora E, Fetisova, Elena K, Izyumov, Denis S, Saprunova, Valeria B, Vyssokikh, Mikhail Y, Chernyak, Boris V, Skulachev, Vladimir P
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 21-11-2002
• Subjects: Apoptosis; Aurovertins - pharmacology; Bcl-2 protein; Cancer; Cell death; Cyclosporin A; Cyclosporine - pharmacology; Cytochrome; Cytochrome c; Cytochrome c Group - metabolism; Cytosol; Cytosol - enzymology; Deoxyglucose - pharmacology; Emetine - pharmacology; Enzyme Inhibitors - pharmacology; Genes, bcl-2; Genetic aspects; Health aspects; HeLa Cells - drug effects; HeLa Cells - enzymology; Humans; Hydrogen; Ion Channels - drug effects; Ion Channels - physiology; Kinases; Macrolide antibiotics; Membrane permeability; Membrane potential; Membrane potentials; Membrane Potentials - drug effects; Mitochondria; Mitochondria - drug effects; Mitochondria - enzymology; Mitochondrial Membrane Transport Proteins; Mitochondrial permeability transition pore; Neoplasm Proteins - antagonists & inhibitors; Oligomycin; Oligomycins - pharmacology; Permeability; Phosphorylation; Physiological aspects; Proteins; Proto-Oncogene Proteins c-bcl-2 - physiology; Proton-Translocating ATPases - antagonists & inhibitors; Proton-Translocating ATPases - physiology; Recombinant Fusion Proteins - physiology; Recombinant Proteins - pharmacology; Staurosporine; Staurosporine - pharmacology; Transfection; Tumor necrosis factor; Tumor Necrosis Factor-alpha - antagonists & inhibitors; Tumor Necrosis Factor-alpha - pharmacology; Tumor necrosis factor-TNF; Tumor necrosis factor-α; Uncouplers; Uncoupling Agents - pharmacology; Russia
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1206053

The release of cytochrome c from the intermembrane space of mitochondria into the cytosol is one of the critical events in apoptotic cell death. In the present study, it is shown that release of cytochrome c and apoptosis induced by tumor necrosis factor alpha (TNF) in HeLa cells can be inhibited by (i) overexpression of an oncoprotein Bcl-2, (ii) Cyclosporin A, an inhibitor of the mitochondrial permeability transition pore (PTP) or (iii) oligomycin, an inhibitor of H+- ATP-synthase. Staurosporine-induced apoptosis is sensitive to Bcl-2 but insensitive to Cyclosporin A and oligomycin. The effect of oligomycin is not due to changes in mitochondrial membrane potential or to inhibition of ATP synthesis/hydrolysis since (a) uncouplers (CCCP, DNP) which discharge the membrane potential fail to abolish the protective action of oligomycin and (b) aurovertin B (another inhibitor of H+-ATP-synthase, affecting its F1 component) do not affect apoptosis. A role of oligomycin-sensitive F0 component of H+-ATP-synthase in the TNF-induced PTP opening and apoptosis is suggested.