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

Oncogene volume 21, pages 8149–8157 (2002)Cite this article

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 α (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.

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Abbreviations

ANT:

adenine nucleotide translocator

CCCP:

carbonyl cyanide m-chlorophenylhydrazone

CsA:

Cyclosporin A

DCF:

dichlorofluorescine

DCFDA:

dichlorofluorescine diacetate

DMEM:

Dulbecco's modified Eagle's medium

DNP:

2,4-p-dinitrophenol

DOG:

2-deoxiglucose

MTT:

3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

PTP:

permeability transition pore

Sts:

staurosporine

TFP:

trifluoropyrasine

TNF:

tumor necrosis factor α

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Acknowledgements

The authors wish to thank Professor YM Vasiliev for intellectual support and helpful discussions, Dr LV Domnina, Dr OY Ivanova and Ms N Korovkina for help in some experiments, Dr G Belov for cells lines, and Dr V Korobko for a sample of TNF. This work was supported by Ludwig Cancer Research Institute Grant ROB 0863 and by RFBR Grants No 00-04-48090, 01-04-06048; 99-04-49256, 00-15-97799, 01-04-48606.

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  1. AN Belozersky Institute, MV Lomonosov Moscow State University, 4 Khokhlova str., Bldg, A, 119992, Moscow, Russia

    Liarisa A Shchepina, Olga Y Pletjushkina, Armine V Avetisyan, Liora E Bakeeva, Elena K Fetisova, Denis S Izyumov, Valeria B Saprunova, Mikhail Y Vyssokikh, Boris V Chernyak & Vladimir P Skulachev

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  1. Liarisa A Shchepina
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Correspondence to Boris V Chernyak.

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Shchepina, L., Pletjushkina, O., Avetisyan, A. et al. Oligomycin, inhibitor of the F0 part of H+-ATP-synthase, suppresses the TNF-induced apoptosis. Oncogene 21, 8149–8157 (2002). https://doi.org/10.1038/sj.onc.1206053

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