Journal
SCIENCE ADVANCES
Volume 7, Issue 15, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.abg4544
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Funding
- National Institute of Health (NIH) [R35CA220538, R01DK080425]
- Leona M. and Harry B. Helmsley Charitable Trust [2012-PG-MED002]
- AHA-Allen Foundation [P01CA120964]
- Salk Institute Pioneer Fund Fellowship
- Bruce Ford and Anne Smith Bundy Foundation
- NIH Cell and Molecular Genetics Training Program [5T32GM007240-35]
- Chapman Charitable Trust
- NIH T32 postdoctoral training grant [5T32CA009370-33]
- NIH postdoctoral fellowship [F32CA206400]
- Damon-Runyan Postdoctoral Fellowship
- Hewitt Foundation Fellowship
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Research shows that AMPK-dependent ULK1 phosphorylates specific sites in Parkin rapidly, promoting Parkin activation and initiating mitophagy. Deletion or inhibition of ULK1 delays Parkin activation, leading to defects in mitophagy function and events.
The serine/threonine kinase ULK1 mediates autophagy initiation in response to various cellular stresses, and genetic deletion of ULK1 leads to accumulation of damaged mitochondria. Here we identify Parkin, the core ubiquitin ligase in mitophagy, and PARK2 gene product mutated in familial Parkinson's disease, as a ULK1 substrate. Recent studies uncovered a nine residue (ACT) domain important for Parkin activation, and we demonstrate that AMPK-dependent ULK1 rapidly phosphorylates conserved serine108 in the ACT domain in response to mitochondrial stress. Phosphorylation of Parkin Ser108 occurs maximally within five minutes of mitochondrial damage, unlike activation of PINK1 and TBK1, which is observed thirty to sixty minutes later. Mutation of the ULK1 phosphorylation sites in Parkin, genetic AMPK or ULK1 depletion, or pharmacologic ULK1 inhibition, all lead to delays in Parkin activation and defects in assays of Parkin function and downstream mitophagy events. These findings reveal an unexpected first step in the mitophagy cascade.
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