PINK1 is selectively stabilized on impaired mitochondria to activate Parkin.
PINK1 is selectively stabilized on impaired mitochondria to activate Parkin.
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PINK1在线粒体受损中有选择地稳定以激活帕金。
DOI：
10.1371/journal.pbio.1000298
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发表时间：
2010-01-26
期刊：
影响因子：
9.8
通讯作者：
Youle RJ
中科院分区：
文献类型：
--
作者：
Narendra DP;Jin SM;Tanaka A;Suen DF;Gautier CA;Shen J;Cookson MR;Youle RJ
PINK1或Parkin基因突变可导致家族性帕金森病。作者认为，PINK1和Parkin形成了一种途径，可以感知受损的线粒体，并选择性地靶向它们进行降解。PINK1和Parkin的功能丧失突变导致人类帕金森病和模式生物的线粒体功能障碍。帕金被选择性地从细胞质中招募到受损的线粒体，以触发它们的自噬。然而，帕金如何识别受损的线粒体尚不清楚。在这里，我们发现PINK1在单个线粒体上的表达受到电压依赖性蛋白水解的调节，以维持健康的、极化的线粒体上PINK1的低水平，同时促进PINK1在维持损伤的线粒体上的快速积累。PINK1在线粒体上的积累是Parkin向线粒体募集的必要条件和充分条件，PINK1和Parkin的致病突变在不同的步骤上破坏了Parkin募集和Parkin诱导的线粒体自噬。这些发现为果蝇PINK1和Parkin基因的遗传上位性提供了生化解释。此外，他们支持了受损线粒体负选择的新模型，其中PINK1向Parkin发出线粒体功能障碍信号，Parkin促进其消除。PINK1或帕金森氏基因的突变会导致遗传形式的帕金森氏病。了解这些基因的产物是如何工作的，可能会让我们更深入地了解这些患者和帕金森病的问题所在。先前对果蝇和小鼠以及人类细胞的研究表明，PINK1和Parkin是防止线粒体受损的共同途径的一部分；这些细胞器在健康时为细胞提供能量，但在受损时可以产生有害的活性氧。PINK1和Parkin究竟是如何共同保护线粒体免受损伤的，目前还不清楚。我们在本文中报道的发现提出了一种新的模型，其中PINK1和Parkin共同感知线粒体处于困境并选择性地靶向它们进行降解。在这个途径中，PINK1作为一个标志，在功能失调的线粒体上积累，然后向Parkin发出信号，Parkin标记这些线粒体进行破坏。由于PINK1或Parkin的致病突变破坏了这一途径，这些突变的患者可能无法清理受损的线粒体，从而导致帕金森病典型的神经元损伤。
Mutations in PINK1 or Parkin lead to familial parkinsonism. The authors suggest that PINK1 and Parkin form a pathway that senses damaged mitochondria and selectively targets them for degradation. Loss-of-function mutations in PINK1 and Parkin cause parkinsonism in humans and mitochondrial dysfunction in model organisms. Parkin is selectively recruited from the cytosol to damaged mitochondria to trigger their autophagy. How Parkin recognizes damaged mitochondria, however, is unknown. Here, we show that expression of PINK1 on individual mitochondria is regulated by voltage-dependent proteolysis to maintain low levels of PINK1 on healthy, polarized mitochondria, while facilitating the rapid accumulation of PINK1 on mitochondria that sustain damage. PINK1 accumulation on mitochondria is both necessary and sufficient for Parkin recruitment to mitochondria, and disease-causing mutations in PINK1 and Parkin disrupt Parkin recruitment and Parkin-induced mitophagy at distinct steps. These findings provide a biochemical explanation for the genetic epistasis between PINK1 and Parkin in Drosophila melanogaster. In addition, they support a novel model for the negative selection of damaged mitochondria, in which PINK1 signals mitochondrial dysfunction to Parkin, and Parkin promotes their elimination. Mutations in the PINK1 or Parkin genes lead to an inherited form of Parkinson disease. Understanding how the products of these genes work may give us insights into what goes wrong in these patients and in Parkinson disease more generally. Previous studies in flies and mice, and in human cells suggest that PINK1 and Parkin are part of a common pathway that protects against damaged mitochondria; these organelles power the cell when healthy but can produce harmful reactive oxygen species when damaged. Exactly how PINK1 and Parkin work together to protect against damaged mitochondria is unclear. The findings we report in this paper suggest a new model in which PINK1 and Parkin together sense mitochondria in distress and selectively target them for degradation. In this pathway, PINK1 acts as a flag that accumulates on dysfunctional mitochondria and then signals to Parkin, which tags these mitochondria for destruction. Since disease-causing mutations in PINK1 or Parkin disrupt this pathway, patients with these mutations may not be able to clean up their damaged mitochondria, leading to the neuronal damage typical of parkinsonism.
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影响因子：
11.2
作者：
Abou-Sleiman, Patrick M.;Muqit, Miratul M. K.;Wood, Nicholas W.
通讯作者：
Wood, Nicholas W.
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：
10.1073/pnas.93.10.4604
发表时间：
1996-05-14
影响因子：
11.1
作者：
Belshaw, PJ;Ho, SN;Schreiber, SL
通讯作者：
Schreiber, SL
ATG32是一种线粒体蛋白，在线粒体过程中赋予了选择性。
影响因子：
11.8
作者：
Kanki, Tomotake;Wang, Ke;Cao, Yang;Baba, Misuzu;Klionsky, Daniel J.
通讯作者：
Klionsky, Daniel J.
环手指（RBR）蛋白质家族之间的环。
影响因子：
12.3
作者：
Eisenhaber B;Chumak N;Eisenhaber F;Hauser MT
通讯作者：
Hauser MT