Superoxide Flashes EARLY MITOCHONDRIAL SIGNALS FOR OXIDATIVE STRESS-INDUCED APOPTOSIS
Superoxide Flashes EARLY MITOCHONDRIAL SIGNALS FOR OXIDATIVE STRESS-INDUCED APOPTOSIS
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DOI：
10.1074/jbc.m111.241794
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发表时间：
2011-08-05
影响因子：
4.8
通讯作者：
Cheng, Heping
中科院分区：
文献类型：
--
作者：
Ma, Qi;Fang, Huaqiang;Cheng, Heping
不可逆的线粒体渗透性转变和由此产生的细胞色素c释放标志着细胞走向凋亡死亡。然而，由于线粒体渗透性转换孔的闪烁开放，瞬时MPT（tMPT）的作用仍然难以捉摸。在这里，我们表明，tMPT和相关的超氧化物闪光（即tMPT/超氧化物闪光）构成氧化应激诱导的细胞凋亡过程中的早期线粒体信号。亚硒酸盐（ROS依赖的侮辱），但不是staurosporine（ROS独立的侮辱）刺激早期和持续增加的tMPT/超氧化物闪光活性之前，线粒体片段化和全球活性氧上升，独立的Bax易位和细胞色素c的释放。通过操纵亲环素D表达或清除线粒体ROS来选择性靶向tMPT/超氧化物闪光活性，显著影响亚硒酸盐诱导的细胞凋亡的进展，而对总体ROS反应几乎没有影响。此外，tMPT/超氧化物闪光充当亲环素D和Bcl-2蛋白介导的促凋亡和抗凋亡调节的汇聚点。这些结果表明，tMPT/超氧化物闪光作为早期线粒体信号介导的氧化应激过程中的细胞凋亡反应，并提供了第一次证明高度有效的本地线粒体ROS信号在决定细胞命运。
Irreversible mitochondrial permeability transition and the resultant cytochrome c release signify the commitment of a cell to apoptotic death. However, the role of transient MPT (tMPT) because of flickering opening of the mitochondrial permeability transition pore remains elusive. Here we show that tMPT and the associated superoxide flashes (i.e. tMPT/superoxide flashes) constitute early mitochondrial signals during oxidative stress-induced apoptosis. Selenite (a ROS-dependent insult) but not staurosporine (a ROS-independent insult) stimulated an early and persistent increase in tMPT/superoxide flash activity prior to mitochondrial fragmentation and a global ROS rise, independently of Bax translocation and cytochrome c release. Selectively targeting tMPT/superoxide flash activity by manipulating cyclophilin D expression or scavenging mitochondrial ROS markedly impacted the progression of selenite-induced apoptosis while exerting little effect on the global ROS response. Furthermore, the tMPT/superoxide flash served as a convergence point for pro-and anti-apoptotic regulation mediated by cyclophilin D and Bcl-2 proteins. These results indicate that tMPT/superoxide flashes act as early mitochondrial signals mediating the apoptotic response during oxidative stress, and provide the first demonstration of highly efficacious local mitochondrial ROS signaling in deciding cell fate.