Calpain activation after mitochondrial permeability transition in microcystin-induced cell death in rat hepatocytes
Calpain activation after mitochondrial permeability transition in microcystin-induced cell death in rat hepatocytes
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DOI：
10.1006/bbrc.2002.6453
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发表时间：
2002-02-22
影响因子：
3.1
通讯作者：
Ong, CN
中科院分区：
文献类型：
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作者：
Ding, WX;Shen, HM;Ong, CN
微囊藻毒素-LR（MLR）是一种特异性肝毒素，可诱导培养大鼠肝细胞线粒体通透性转换（MPT）和细胞凋亡。在这里，我们试图研究MLR处理的肝细胞中MPT发生后的下游事件。各种线粒体电子传递链（ETC）抑制剂有效地阻止了MPT的发生，表明线粒体ETC在MLR诱导的MPT中起着重要作用。MLR还诱导线粒体细胞色素c释放，这可以通过特定的MPT抑制剂（环孢菌素A，CsA）和各种ETC抑制剂来预防。有趣的是，细胞色素c的释放并没有激活caspase-9和-3，参与细胞凋亡的主要caspase。相反，MLR激活大鼠肝细胞中的钙蛋白酶，可能是通过增加细胞内的Ca 2+释放的线粒体。ALLN和ALLM，两种钙蛋白酶抑制剂，显着阻断MLR诱导的钙蛋白酶激活和随后的细胞死亡。CsA还阻止了MLR诱导的钙蛋白酶激活和细胞死亡，这表明钙蛋白酶的激活可能是线粒体后事件。这些数据首次表明，钙蛋白酶，而不是半胱天冬酶在MLR诱导的细胞凋亡中起着重要作用。(C)2002 Elsevier Science（美国）。
Previous studies have shown that microcystin-LR (MLR), a specific hepatotoxin, induces onset of mitochondrial permeability transition (MPT) and apoptosis in cultured rat hepatocytes. Here we attempted to investigate the downstream events after the onset of MPT in MLR-treated hepatocytes. Various mitochondrial electron transport chain (ETC) inhibitors effectively prevented the onset of MPT, suggesting that the mitochondrial ETC plays an important role in MLR-induced MPT. MLR also induced mitochondrial cytochrome c release, which can be prevented by a specific MPT inhibitor (cyclosporin A, CsA), and by various ETC inhibitors. Interestingly, the release of cytochrome c did not activate caspase-9 and -3, the main caspases involved in apoptosis. Instead, MLR activated calpain in rat hepatocytes, probably through the increase of intracellular Ca2+ released from mitochondria. Both ALLN and ALLM, two calpain inhibitors, significantly blocked MLR-induced calpain activation and subsequent cell death. CsA also prevented MLR-induced calpain activation and cell death, suggesting that the activation of calpain may be a post-mitochondrial event. These data demonstrate for the first time that calpain rather than caspases plays an important role in MLR-induced apoptosis. (C) 2002 Elsevier Science (USA).