Electron transfer between cytochrome c and p66Shc generates reactive oxygen species that trigger mitochondrial apoptosis
Electron transfer between cytochrome c and p66Shc generates reactive oxygen species that trigger mitochondrial apoptosis
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DOI：
10.1016/j.cell.2005.05.011
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发表时间：
2005-07-29
期刊：
影响因子：
64.5
通讯作者：
Pelicci, PG
中科院分区：
文献类型：
--
作者：
Giorgio, M;Migliaccio, E;Pelicci, PG
活性氧（ROS）是氧化损伤的强效诱导剂，并参与特定细胞功能的调节，包括细胞凋亡。在促凋亡信号出现后，线粒体ROS显著增加，尽管其生物学意义和潜在的分子机制仍未确定。p66(Shc)是哺乳动物寿命的一个遗传决定因素，它调节ROS代谢和细胞凋亡。我们在此报道，p66(Shc)是一种氧化还原酶，它产生线粒体ROS（过氧化氢）作为细胞凋亡的信号分子。为了实现这一功能，p66(Shc)通过细胞色素c的氧化利用线粒体电子传递链的还原当量。p66(Shc)的氧化还原缺陷型突变体无法在体外诱导线粒体ROS产生和肿胀，也无法在体内介导线粒体凋亡。这些数据证明了线粒体电子传递链存在其他氧化还原反应，这些反应是为了在应对特定应激信号时产生促凋亡的ROS而进化出来的。
Reactive oxygen species (ROS) are potent inducers of oxidative damage and have been implicated in the regulation of specific cellular functions, including apoptosis. Mitochondrial ROS increase markedly after proapoptotic signals, though the biological significance and the underlying molecular mechanisms remain undetermined. P66(Shc) is a genetic determinant of life span in mammals, which regulates ROS metabolism and apoptosis. We report here that p66(Shc) is a redox enzyme that generates mitochondrial ROS (hydrogen peroxide) as signaling molecules for apoptosis. For this function, p66(Shc) utilizes reducing equivalents of the mitochondrial electron transfer chain through the oxidation of cytochrome c. Redox-defective mutants of p66(Shc) are unable to induce mitochondrial ROS generation and swelling in vitro or to mediate mitochondrial apoptosis in vivo. These data demonstrate the existence of alternative redox reactions of the mitochondrial electron transfer chain, which evolved to generate proapoptotic ROS in response to specific stress signals.