Mitochondrial Quality Control Mediated by PINK1 and Parkin: Links to Parkinsonism
Mitochondrial Quality Control Mediated by PINK1 and Parkin: Links to Parkinsonism
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DOI：
10.1101/cshperspect.a011338
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发表时间：
2012-11-01
影响因子：
7.2
通讯作者：
Youle, Richard
中科院分区：
文献类型：
--
作者：
Narendra, Derek;Walker, John E.;Youle, Richard
Parkin 或 PINK1 突变是隐性家族性帕金森病的最常见原因。最近的研究表明，PINK1 和 Parkin 形成了线粒体质量控制途径，可识别功能失调的线粒体，将其从线粒体网络中分离出来，并通过自噬促进其降解。在此通路中，线粒体激酶 PINK1 感知线粒体保真度，并选择性地将 Parkin 招募到失去膜电位的线粒体。 Parkin 是一种 E3 连接酶，随后泛素化线粒体外膜蛋白，特别是丝裂融合素和 Miro，并诱导受损细胞器的自噬消除。在这里，我们回顾了最近在理解 PINK1 和 Parkin 介导的线粒体自噬的分子机制以及 Parkin 底物的鉴定方面取得的快速进展，这些底物表明线粒体裂变和运输是如何参与的。我们还讨论了线粒体自噬缺陷如何与帕金森病相关。
Mutations in Parkin or PINK1 are the most common cause of recessive familial parkinsonism. Recent studies suggest that PINK1 and Parkin form a mitochondria quality control pathway that identifies dysfunctional mitochondria, isolates them from the mitochondrial network, and promotes their degradation by autophagy. In this pathway the mitochondrial kinase PINK1 senses mitochondrial fidelity and recruits Parkin selectively to mitochondria that lose membrane potential. Parkin, an E3 ligase, subsequently ubiquitinates outer mitochondrial membrane proteins, notably the mitofusins and Miro, and induces autophagic elimination of the impaired organelles. Here we review the recent rapid progress in understanding the molecular mechanisms of PINK1- and Parkin-mediated mitophagy and the identification of Parkin substrates suggesting how mitochondrial fission and trafficking are involved. We also discuss how defects in mitophagy may be linked to Parkinson's disease.