Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Aurovertins / pharmacology
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Cyclosporine / pharmacology
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Cytochrome c Group / metabolism*
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Cytosol / enzymology
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Deoxyglucose / pharmacology
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Emetine / pharmacology
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Enzyme Inhibitors / pharmacology*
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Genes, bcl-2
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HeLa Cells / drug effects
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HeLa Cells / enzymology
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Humans
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Ion Channels / drug effects
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Ion Channels / physiology
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Membrane Potentials / drug effects
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Mitochondria / drug effects*
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Mitochondria / enzymology
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Mitochondrial Membrane Transport Proteins
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Mitochondrial Permeability Transition Pore
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Neoplasm Proteins / antagonists & inhibitors
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Oligomycins / pharmacology*
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Proto-Oncogene Proteins c-bcl-2 / physiology
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Proton-Translocating ATPases / antagonists & inhibitors*
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Proton-Translocating ATPases / physiology
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Recombinant Fusion Proteins / physiology
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Recombinant Proteins / pharmacology
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Staurosporine / pharmacology
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Transfection
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Tumor Necrosis Factor-alpha / antagonists & inhibitors*
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Tumor Necrosis Factor-alpha / pharmacology
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Uncoupling Agents / pharmacology
Substances
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Aurovertins
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Cytochrome c Group
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Enzyme Inhibitors
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Ion Channels
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Mitochondrial Membrane Transport Proteins
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Mitochondrial Permeability Transition Pore
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Neoplasm Proteins
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Oligomycins
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Proto-Oncogene Proteins c-bcl-2
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Recombinant Fusion Proteins
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Recombinant Proteins
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Tumor Necrosis Factor-alpha
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Uncoupling Agents
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aurovertin B
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Cyclosporine
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Deoxyglucose
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Proton-Translocating ATPases
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Staurosporine
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Emetine