PINK1 stabilized by mitochondrial depolarization recruits Parkin to damaged mitochondria and activates latent Parkin for mitophagy.
PINK1 stabilized by mitochondrial depolarization recruits Parkin to damaged mitochondria and activates latent Parkin for mitophagy.
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DOI：
10.1083/jcb.200910140
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发表时间：
2010-04-19
期刊：
影响因子：
--
通讯作者：
Tanaka K
中科院分区：
文献类型：
--
作者：
Matsuda N;Sato S;Shiba K;Okatsu K;Saisho K;Gautier CA;Sou YS;Saiki S;Kawajiri S;Sato F;Kimura M;Komatsu M;Hattori N;Tanaka K
线粒体质量控制缺陷被证明是某些形式帕金森病神经退行性变的一种机制。
帕金森病（PD）是一种常见的神经退行性疾病。近期对与家族性帕金森病相关基因（如帕金和PINK1，即PTEN诱导的假定激酶1）的鉴定表明，泛素化和线粒体完整性是疾病发病机制中的关键因素。然而，帕金催化的泛素化与PINK1调控的线粒体质量控制之间功能相互作用的确切机制仍然是个谜。在这项研究中，我们发现PINK1在稳态条件下以一种依赖线粒体膜电位的方式迅速且持续地降解，并且线粒体膜电位的丧失会稳定PINK1在线粒体中的积累。此外，PINK1将细胞质中的帕金招募到膜电位较低的线粒体，以启动受损线粒体的自噬降解。有趣的是，在稳态条件下，帕金的泛素连接酶活性在细胞质中受到抑制；然而，PINK1依赖的线粒体定位释放了帕金潜在的酶活性。PINK1和帕金的一些致病性突变会干扰上述事件，这表明其病因学重要性。这些结果为帕金森病的致病机制提供了关键的见解。
Defective mitochondrial quality control is shown to be a mechanism for neurodegeneration in some forms of Parkinson's disease. Parkinson's disease (PD) is a prevalent neurodegenerative disorder. Recent identification of genes linked to familial forms of PD such as Parkin and PINK1 (PTEN-induced putative kinase 1) has revealed that ubiquitylation and mitochondrial integrity are key factors in disease pathogenesis. However, the exact mechanism underlying the functional interplay between Parkin-catalyzed ubiquitylation and PINK1-regulated mitochondrial quality control remains an enigma. In this study, we show that PINK1 is rapidly and constitutively degraded under steady-state conditions in a mitochondrial membrane potential–dependent manner and that a loss in mitochondrial membrane potential stabilizes PINK1 mitochondrial accumulation. Furthermore, PINK1 recruits Parkin from the cytoplasm to mitochondria with low membrane potential to initiate the autophagic degradation of damaged mitochondria. Interestingly, the ubiquitin ligase activity of Parkin is repressed in the cytoplasm under steady-state conditions; however, PINK1-dependent mitochondrial localization liberates the latent enzymatic activity of Parkin. Some pathogenic mutations of PINK1 and Parkin interfere with the aforementioned events, suggesting an etiological importance. These results provide crucial insight into the pathogenic mechanisms of PD.
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影响因子：
2.5
作者：
Takatori, Sho;Ito, Genta;Iwatsubo, Takeshi
通讯作者：
Iwatsubo, Takeshi
影响因子：
3.5
作者：
Silvestri, L;Caputo, V;Casari, G
通讯作者：
Casari, G
影响因子：
4.8
作者：
Hristova, Ventzislava A.;Beasley, Steven A.;Shaw, Gary S.
通讯作者：
Shaw, Gary S.
DOI：
10.1083/jcb.200412022
发表时间：
2005-05-09
期刊：
The Journal of cell biology
影响因子：
--
作者：
Komatsu M;Waguri S;Ueno T;Iwata J;Murata S;Tanida I;Ezaki J;Mizushima N;Ohsumi Y;Uchiyama Y;Kominami E;Tanaka K;Chiba T
通讯作者：
Chiba T
DOI：
10.1083/jcb.200809125
发表时间：
2008-12-01
期刊：
The Journal of cell biology
影响因子：
--
作者：
Narendra D;Tanaka A;Suen DF;Youle RJ
通讯作者：
Youle RJ