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

Abstract:

:An increasing body of evidence points to mitochondrial dysfunction as a contributor to the molecular pathogenesis of neurodegenerative diseases such as Parkinson's disease. 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. 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.

journal_name

Nature

journal_title

Nature

authors

Hasson SA,Kane LA,Yamano K,Huang CH,Sliter DA,Buehler E,Wang C,Heman-Ackah SM,Hessa T,Guha R,Martin SE,Youle RJ

doi

10.1038/nature12748

subject

Has Abstract

pub_date

2013-12-12 00:00:00

pages

291-5

issue

7479

eissn

0028-0836

issn

1476-4687

pii

nature12748

journal_volume

504

pub_type

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