Parkin Sensitizes toward Apoptosis Induced by Mitochondrial Depolarization through Promoting Degradation of Mcl-1
Parkin Sensitizes toward Apoptosis Induced by Mitochondrial Depolarization through Promoting Degradation of Mcl-1
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DOI：
10.1016/j.celrep.2014.10.046
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发表时间：
2014-11-20
期刊：
影响因子：
8.8
通讯作者：
Martin, Seamus J.
中科院分区：
文献类型：
--
作者：
Carroll, Richard G.;Hollville, Emilie;Martin, Seamus J.
线粒体去极化促进依赖于Parkin和PTEN诱导的蛋白1(PINK1)的多种蛋白质在线粒体外膜上的多泛素化，从而通过有丝分裂去除有缺陷的线粒体。由于帕金森氏症中会出现帕金森突变，这种情况与中脑多巴胺能神经元的死亡有关，因此野生型帕金森氏症被认为可以促进神经元的存活。然而，我们在这里表明，野生型Parkin对线粒体去极化诱导的细胞凋亡非常敏感，但不能通过未能激活Parkin的促凋亡刺激来诱导。依赖Parkin的细胞凋亡需要PINK1，并可被Bcl2家族的存活成员或Bax和Bak基因的敲除有效地阻断。在线粒体去极化后，Bcl2家族成员Mcl-1经历了依赖Parkin和PINK1的多泛素化和降解，并通过开放Bax/Bak通道而敏化细胞凋亡。这些数据表明，与其他细胞应激感受器，如p53，Parkin有细胞保护(有丝分裂)或细胞毒性(凋亡)模式，这取决于线粒体损伤的程度。
Mitochondrial depolarization promotes Parkin-and PTEN-induced kinase 1 (PINK1)-dependent polyubiquitination of multiple proteins on mitochondrial outer membranes, resulting in the removal of defective mitochondria via mitophagy. Because Parkin mutations occur in Parkinson's disease, a condition associated with the death of dopaminergic neurons in the midbrain, wild-type Parkin is thought to promote neuronal survival. However, here we show that wild-type Parkin greatly sensitized toward apoptosis induced by mitochondrial depolarization but not by proapoptotic stimuli that failed to activate Parkin. Parkin-dependent apoptosis required PINK1 and was efficiently blocked by prosurvival members of the Bcl-2 family or knockdown of Bax and Bak. Upon mitochondrial depolarization, the Bcl-2 family member Mcl-1 underwent rapid Parkin-and PINK1-dependent polyubiquitination and degradation, which sensitized toward apoptosis via opening of the Bax/Bak channel. These data suggest that similar to other sensors of cell stress, such as p53, Parkin has cytoprotective (mitophagy) or cytotoxic modes (apoptosis), depending on the degree of mitochondrial damage.