Disruption of mitochondrial function during apoptosis is mediated by caspase cleavage of the p75 subunit of complex I of the electron transport chain
Disruption of mitochondrial function during apoptosis is mediated by caspase cleavage of the p75 subunit of complex I of the electron transport chain
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DOI：
10.1016/j.cell.2004.05.008
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发表时间：
2004-06-11
期刊：
影响因子：
64.5
通讯作者：
Green, DR
中科院分区：
文献类型：
--
作者：
Ricci, JE;Mu単oz-Pinedo, C;Green, DR
线粒体外膜透化和细胞色素c的释放通过切割细胞中特定的caspase底物促进caspase活化和凋亡的执行。活化的半胱天冬酶的第一个靶点是透化的线粒体本身，导致电子传递的破坏、线粒体跨膜电位（Deltapsim）的损失、ATP水平的下降、活性氧（ROS）的产生和线粒体结构完整性的损失。在这里，我们确定NDUFS1，呼吸复合物1的75 kDa亚基，作为线粒体中的一个关键的半胱天冬酶底物。表达p75的不可裂解突变体的细胞在凋亡期间维持Deltapsim和ATP水平，并且响应于凋亡刺激的ROS产生被抑制。虽然细胞色素c的释放和DNA片段不受不可裂解的p75突变体的影响，但死亡细胞的线粒体形态得以维持，质膜完整性的丧失得以延迟。因此，NDUFS1的半胱天冬酶裂解是与细胞凋亡相关的几种线粒体变化所必需的。
Mitochondrial outer membrane permeabilization and cytochrome c release promote caspase activation and execution of apoptosis through cleavage of specific caspase substrates in the cell. Among the first targets of activated caspases are the permeabilized mitochondria themselves, leading to disruption of electron transport, loss of mitochondrial transmembrane potential (Deltapsim), decline in ATP levels, production of reactive oxygen species (ROS), and loss of mitochondrial structural integrity. Here, we identify NDUFS1, the 75 kDa subunit of respiratory complex 1, as a critical caspase substrate in the mitochondria. Cells expressing a noncleavable mutant of p75 sustain Deltapsim and ATP levels during apoptosis, and ROS production in response to apoptotic stimuli is dampened. While cytochrome c release and DNA fragmentation are unaffected by the noncleavable p75 mutant, mitochondrial morphology of dying cells is maintained, and loss of plasma membrane integrity is delayed. Therefore, caspase cleavage of NDUFS1 is required for several mitochondrial changes associated with apoptosis.