The life span determinant p66Shc localizes to mitochondria where it associates with mitochondrial heat shock protein 70 and regulates trans-membrane potential
The life span determinant p66Shc localizes to mitochondria where it associates with mitochondrial heat shock protein 70 and regulates trans-membrane potential
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DOI：
10.1074/jbc.m401844200
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发表时间：
2004-06-11
影响因子：
4.8
通讯作者：
Pelicci, PG
中科院分区：
文献类型：
--
作者：
Orsini, F;Migliaccio, E;Pelicci, PG
P66 Shc调节哺乳动物的寿命，是氧化应激的凋亡反应的关键组成部分。它作为肿瘤抑制因子p53的下游靶点发挥作用，并且对于氧化应激激活的p53诱导细胞凋亡的能力是必不可少的。p66Shc致突变作用的分子机制尚不清楚。在这里，我们报告以下三个发现。(i)在p66Shc不存在的情况下，只有提供纯化的细胞色素c，才能在体外适当地激活线粒体。(ii)在p66Shc不存在的情况下，氧化信号后细胞色素c的释放受损。(iii)p66 Shc诱导氧化应激后线粒体跨膜电位的崩溃。此外，我们发现，一部分细胞质p66Shc定位在线粒体内，它与线粒体Hsp70形成复合物。用紫外线辐射处理细胞诱导该复合物的解离和单体p66Shc的释放。我们建议，p66 Shc调节线粒体途径的细胞凋亡诱导线粒体损伤后，从抑制性蛋白复合物解离。遗传和生化证据表明，线粒体通过影响能量代谢来调节寿命（线粒体衰老理论）。我们的数据表明，线粒体调节细胞凋亡也可能有助于寿命的决定。
P66Shc regulates life span in mammals and is a critical component of the apoptotic response to oxidative stress. It functions as a downstream target of the tumor suppressor p53 and is indispensable for the ability of oxidative stress-activated p53 to induce apoptosis. The molecular mechanisms underlying the apoptogenic effect of p66Shc are unknown. Here we report the following three findings. (i) The apoptosome can be properly activated in vitro in the absence of p66Shc only if purified cytochrome c is supplied. (ii) Cytochrome c release after oxidative signals is impaired in the absence of p66Shc. (iii) p66Shc induces the collapse of the mitochondrial trans-membrane potential after oxidative stress. Furthermore, we showed that a fraction of cytosolic p66Shc localizes within mitochondria where it forms a complex with mitochondrial Hsp70. Treatment of cells with ultraviolet radiation induced the dissociation of this complex and the release of monomeric p66Shc. We propose that p66Shc regulates the mitochondrial pathway of apoptosis by inducing mitochondrial damage after dissociation from an inhibitory protein complex. Genetic and biochemical evidence suggests that mitochondria regulate life span through their effects on the energetic metabolism (mitochondrial theory of aging). Our data suggest that mitochondrial regulation of apoptosis might also contribute to life span determination.