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
AN Belozersky Institute, MV Lomonosov Moscow State University, 4 Khokhlova str., Bldg, A, Moscow 119992, Russia.
Oncogene. 2002 Nov 21;21(53):8149-57. 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.
细胞色素c从线粒体膜间隙释放到细胞质中是凋亡性细胞死亡的关键事件之一。在本研究中，结果表明，在HeLa细胞中，细胞色素c的释放以及由肿瘤坏死因子α（TNF）诱导的凋亡可被以下因素抑制：（i）癌蛋白Bcl-2的过表达；（ii）环孢菌素A，一种线粒体通透性转换孔（PTP）抑制剂；或（iii）寡霉素，一种H⁺-ATP合酶抑制剂。星形孢菌素诱导的凋亡对Bcl-2敏感，但对环孢菌素A和寡霉素不敏感。寡霉素的作用并非由于线粒体膜电位的改变或ATP合成/水解的抑制，因为（a）使膜电位去极化的解偶联剂（CCCP、DNP）未能消除寡霉素的保护作用，且（b）金担子素B（另一种H⁺-ATP合酶抑制剂，影响其F1组分）不影响凋亡。提示H⁺-ATP合酶的寡霉素敏感F0组分在TNF诱导的PTP开放和凋亡中起作用。
