"Wages of Fear": transient threefold decrease in intracellular ATP level imposes apoptosis
"Wages of Fear": transient threefold decrease in intracellular ATP level imposes apoptosis
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DOI：
10.1016/j.bbabio.2004.05.007
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发表时间：
2004-07-23
影响因子：
4.3
通讯作者：
Skulachev, VP
中科院分区：
文献类型：
--
作者：
Izyumov, DS;Avetisyan, AV;Skulachev, VP
在HeLa细胞中，完全抑制氧化磷酸化寡霉素，myxothiazol或FCCP结合部分抑制糖酵解DOG导致稳定的三倍降低细胞内ATP水平。当用高糖培养基代替含DOG培养基时，ATP水平恢复。在短暂（3小时）[ATP]降低后48小时，随后ATP水平恢复，大多数细胞通过凋亡自杀。如果单独加入DOG或氧化磷酸化抑制剂，则不会发生细胞死亡，处理导致[ATP]降低10-35%。凋亡伴随着Bax易位到线粒体，细胞色素c释放到细胞质中，半胱天冬酶激活，活性氧（ROS）的产生，以及染色质的重组和分解。细胞凋亡似乎是敏感的癌蛋白Bcl-2和pancaspase抑制剂zVADfcR。在后一种情况下，显示坏死而不是凋亡。细胞自杀对环孢菌素A、磷脂酶抑制剂三氟拉嗪、JNK和p38激酶抑制剂、寡霉素、N-乙酰半胱氨酸和mitoQ具有抗性，在这些方面不同于肿瘤坏死因子（TNF）和H2 O2诱导的细胞凋亡。这表明，细胞中的ATP浓度是由细胞内的“ATP-米”产生细胞自杀信号时，ATP降低，即使是暂时的，低于一些临界水平（约1毫米）。(C)2004 Elsevier B. V.保留所有权利。
In HeLa cells, complete inhibition of oxidative phosphorylation by oligomycin, myxothiazol or FCCP combined with partial inhibition of glycolysis by DOG resulted in a steady threefold decrease in the intracellular ATP level. The ATP level recovers when the DOG-containing medium was replaced by that with high glucose. In 48 h after a transient (3 h) [ATP] lowering followed by recovery of the ATP level, the majority of the cells commits suicide by means of apoptosis. The cell death does not occur if DOG or an oxidative phosphorylation inhibitor was added separately, treatments resulting in 10-35% lowering of [ATP]. Apoptosis is accompanied by Bax translocation to mitochondria, cytochrome c release into cytosol, caspase activation, reactive oxygen species (ROS) generation, and reorganization and decomposition of chromatin. Apoptosis appears to be sensitive to oncoprotein Bcl-2 and a pancaspase inhibitor zVADfmk. In the latter case, necrosis is shown to develop instead of apoptosis. The cell suicide is resistant to cyclosporine A, a phospholipase inhibitor trifluoroperazine, the JNK and p38 kinase inhibitors, oligomycin, N-acetyl cysteine and mitoQ, differing in these respects from the tumor necrosis factor (TNF)- and H2O2-induced apoptoses. It is suggested that the ATP concentration in the cell is monitored by intracellular "ATP-meter(s)" generating a cell suicide signal when ATP decreases, even temporarily, below some critical level (around 1 mM). (C) 2004 Elsevier B.V. All rights reserved.