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
Naturejournal_title
Natureauthors
Hasson SA,Kane LA,Yamano K,Huang CH,Sliter DA,Buehler E,Wang C,Heman-Ackah SM,Hessa T,Guha R,Martin SE,Youle RJdoi
10.1038/nature12748subject
Has Abstractpub_date
2013-12-12 00:00:00pages
291-5issue
7479eissn
0028-0836issn
1476-4687pii
nature12748journal_volume
504pub_type
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