Mitochondrial Ca2+ influx targets cardiolipin to disintegrate respiratory chain complex II for cell death induction
Mitochondrial Ca2+ influx targets cardiolipin to disintegrate respiratory chain complex II for cell death induction
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DOI：
10.1038/cdd.2014.84
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发表时间：
2014-11-01
影响因子：
12.4
通讯作者：
Grimm, S.
中科院分区：
文献类型：
--
作者：
Hwang, M-S;Schwall, C. T.;Grimm, S.
大量的Ca2+流入线粒体是细胞死亡诱导的关键，但这是未知的如何激活细胞器的细胞破坏。使用多种方法，包括亚细胞分级分离，FRET在完整的细胞，并在体外重建，我们表明，线粒体Ca2+内流提示呼吸链的复合物II解体，从而释放酶活性的子复合物，产生过量的活性氧（ROS）诱导细胞死亡。这种钙离子依赖性的解离复合物II也观察到在模型膜系统，但不是当心磷脂被替换的脂质缺乏钙离子结合。已知心磷脂与复合物II相关，并且在Ca2+结合后聚结成单独的同型簇。当复合物II被剥夺这种脂质时，它分解形成ROS和细胞死亡。我们的研究结果表明，钙结合心磷脂复合物II解体的氧化应激和细胞死亡诱导的关键步骤。
Massive Ca2+ influx into mitochondria is critically involved in cell death induction but it is unknown how this activates the organelle for cell destruction. Using multiple approaches including subcellular fractionation, FRET in intact cells, and in vitro reconstitutions, we show that mitochondrial Ca2+ influx prompts complex II of the respiratory chain to disintegrate, thereby releasing an enzymatically competent sub-complex that generates excessive reactive oxygen species (ROS) for cell death induction. This Ca2+-dependent dissociation of complex II is also observed in model membrane systems, but not when cardiolipin is replaced with a lipid devoid of Ca2+ binding. Cardiolipin is known to associate with complex II and upon Ca2+ binding coalesces into separate homotypic clusters. When complex II is deprived of this lipid, it disintegrates for ROS formation and cell death. Our results reveal Ca2+ binding to cardiolipin for complex II disintegration as a pivotal step for oxidative stress and cell death induction.