The mitochondrial permeability transition is required for tumor necrosis factor alpha-mediated apoptosis and cytochrome c release
The mitochondrial permeability transition is required for tumor necrosis factor alpha-mediated apoptosis and cytochrome c release
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DOI：
10.1128/mcb.18.11.6353
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发表时间：
1998-11-01
影响因子：
5.3
通讯作者：
Lemasters, JJ
中科院分区：
文献类型：
--
作者：
Bradham, CA;Qian, T;Lemasters, JJ
在表达I κ B超抑制因子的原代大鼠肝细胞中，肿瘤坏死因子α (TNF α)通过核形态、DNA阶梯形成和caspase 3激活诱导细胞凋亡。共聚焦显微镜显示TNF α诱导MPT和线粒体去极化开始于TNF α治疗后9小时。最初，去极化和MPT只发生在线粒体的一个子集中；然而，在TNF α治疗12小时后，几乎所有线粒体都受到影响，环孢素A (CsA)，一种MPT抑制剂，阻断TNF α介导的细胞凋亡和细胞色素c的释放。MPT发作后可诱导Caspase 3活化、细胞色素c释放和凋亡核形态改变，CsA可阻止这些变化。在表达Delta FADD （fas相关蛋白死亡结构域（FADD）的显性负突变体）或crmA （caspases的天然丝氨酸抑制剂）的肝细胞中，去极化和MPT的发生被阻断。相反，caspase 3的抑制剂Asp-Glu-Val-Asp-cho不能阻断TNF α诱导的去极化或MPT的发生，尽管它完全抑制了Fell死亡。综上所述，MPT是TNF α诱导肝细胞凋亡信号通路中的重要组成部分，是细胞色素c释放和细胞死亡所必需的，其功能位于FADD和crmA的下游，但位于caspase 3的上游。
This study assesses the controversial role of the mitochondrial permeability transition (MPT) in apoptosis, In primary rat hepatocytes expressing an I kappa B superrepressor, tumor necrosis factor alpha (TNF alpha) induced apoptosis as shown by nuclear morphology, DNA ladder formation, and caspase 3 activation. Confocal microscopy showed that TNF alpha induced onset of the MPT and mitochondrial depolarization beginning 9 h after TNF alpha treatment. Initially, depolarization and the MPT occurred in only a subset of mitochondria; however, by 12 h after TNF alpha treatment, virtually all mitochondria were affected, Cyclosporin A (CsA), an inhibitor of the MPT, blocked TNF alpha-mediated apoptosis and cytochrome c release. Caspase 3 activation, cytochrome c release, and apoptotic nuclear morphological changes were induced after onset of the MPT and were prevented by CsA. Depolarization and onset of the MPT were blocked in hepatocytes expressing Delta FADD, a dominant negative mutant of Fas-associated protein with death domain (FADD), or crmA, a natural serpin inhibitor of caspases, In contrast, Asp-Glu-Val-Asp-cho, an inhibitor of caspase 3, did not block depolarization or onset of the MPT induced by TNF alpha, although it inhibited Fell death completely. In conclusion, the MPT is an essential component in the signaling pathway for TNF alpha-induced apoptosis in hepatocytes which is required for both cytochrome c release and cell death and functions downstream of FADD and crmA but upstream of caspase 3.