Cyclophilin D-dependent mitochondrial permeability transition regulates some necrotic but not apoptotic cell death
Cyclophilin D-dependent mitochondrial permeability transition regulates some necrotic but not apoptotic cell death
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DOI：
10.1038/nature03317
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发表时间：
2005-03-31
期刊：
影响因子：
64.8
通讯作者：
Tsujimoto, Y
中科院分区：
文献类型：
--
作者：
Nakagawa, T;Shimizu, S;Tsujimoto, Y
线粒体在能量产生、Ca 2+稳态和细胞死亡中起重要作用。近年来，线粒体在细胞凋亡和坏死性细胞死亡中的作用引起了广泛关注（1，2）。在细胞凋亡和坏死中，线粒体通透性转换（mPT），导致线粒体膜的破坏和线粒体功能障碍，被认为是关键事件之一，尽管其在细胞死亡中的确切作用仍然难以捉摸。因此，我们创造了缺乏亲环素D（CypD）的小鼠，这种蛋白质被认为参与mPT，以分析其在细胞死亡中的作用。CypD缺陷小鼠发育正常，没有表现出明显的异常，但CypD缺陷的线粒体没有经历环孢菌素A敏感的mPT。CypD缺陷细胞在各种凋亡刺激下正常死亡，但对活性氧和Ca 2+超载诱导的坏死性细胞死亡表现出抗性。此外，CypD缺陷小鼠对缺血/再灌注诱导的心脏损伤表现出高水平的抵抗力。我们的研究结果表明，CypD依赖的mPT调节某些形式的坏死性死亡，但不凋亡性死亡。
Mitochondria play an important role in energy production, Ca2+ homeostasis and cell death. In recent years, the role of the mitochondria in apoptotic and necrotic cell death has attracted much attention(1,2). In apoptosis and necrosis, the mitochondrial permeability transition (mPT), which leads to disruption of the mitochondrial membranes and mitochondrial dysfunction, is considered to be one of the key events, although its exact role in cell death remains elusive. We therefore created mice lacking cyclophilin D (CypD), a protein considered to be involved in the mPT, to analyse its role in cell death. CypD-deficient mice were developmentally normal and showed no apparent anomalies, but CypD-deficient mitochondria did not undergo the cyclosporin A-sensitive mPT. CypD-deficient cells died normally in response to various apoptotic stimuli, but showed resistance to necrotic cell death induced by reactive oxygen species and Ca2+ overload. In addition, CypD-deficient mice showed a high level of resistance to ischaemia/reperfusion-induced cardiac injury. Our results indicate that the CypD-dependent mPT regulates some forms of necrotic death, but not apoptotic death.