High-content genome-wide RNAi screens identify regulators of parkin upstream of mitophagy

被引：316

作者：

Hasson, Samuel A. ^{[1
,2
]}

Kane, Lesley A. ^{[1
]}

Yamano, Koji ^{[1
]}

Huang, Chiu-Hui ^{[1
]}

Sliter, Danielle A. ^{[1
]}

Buehler, Eugen ^{[2
]}

Wang, Chunxin ^{[1
]}

Heman-Ackah, Sabrina M. ^{[3
]}

Hessa, Tara ^{[1
]}

Guha, Rajarshi ^{[2
]}

Martin, Scott E. ^{[2
]}

Youle, Richard J. ^{[1
]}

机构：

[1] NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA

[2] NIH, Div Preclin Innovat, Natl Ctr Adv Translat Sci, Rockville, MD 20850 USA

[3] NIH, Ctr Regenerat Med, Bethesda, MD 20892 USA

来源：

NATURE | 2013年 / 504卷 / 7479期

关键词：

MITOCHONDRIA; RECRUITMENT; SENSITIVITY; ACTIVATION; MUTATIONS; PROMOTES; COMPLEX;

D O I：

10.1038/nature12748

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

An increasing body of evidence points to mitochondrial dysfunction as a contributor to the molecular pathogenesis of neurodegenerative diseases such as Parkinson's disease(1). Recent studies of the Parkinson's disease associated genes PINK1 (ref. 2) and parkin (PARK2, ref. 3) indicate that they may act in a quality control pathway preventing the accumulation of dysfunctional mitochondria(4-8). Here we elucidate regulators that have an impact on parkin translocation to damaged mitochondria with genome-wide small interfering RNA (siRNA) screens coupled to high-content microscopy. Screening yielded gene candidates involved in diverse cellular processes that were subsequently validated in low-throughput assays. This led to characterization of TOMM7 as essential for stabilizing PINK1 on the outer mitochondrial membrane following mitochondrial damage. We also discovered that HSPA1L (HSP70 family member) and BAG4 have mutually opposing roles in the regulation of parkin translocation. The screens revealed that SIAH3, found to localize to mitochondria, inhibits PINK1 accumulation after mitochondrial insult, reducing parkin translocation. Overall, our screens provide a rich resource to understand mitochondrial quality control.

引用

页码：291 / +

页数：18

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