Journal
SCIENCE
Volume 331, Issue 6016, Pages 456-461Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1196371
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Funding
- CMG
- NIH [R01 DK080425, 1P01CA120964]
- National Cancer Institute [P30CA014195]
- American Cancer Society
- American Diabetes Association [1-08-JF-47]
- Howard Hughes Medical Institute
- NHBLI [K08]
- Burroughs Welcome Fund
- American Lebanese Syrian Association
- Agence Nationale de la Recherche (ANR)
- Ellison Medical Foundation
- Helmsley Charitable Trust
- [T32 CA009370]
- [5P30CA006516-43]
- [1P01CA120964-01A]
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Adenosine monophosphate-activated protein kinase (AMPK) is a conserved sensor of intracellular energy activated in response to low nutrient availability and environmental stress. In a screen for conserved substrates of AMPK, we identified ULK1 and ULK2, mammalian orthologs of the yeast protein kinase Atg1, which is required for autophagy. Genetic analysis of AMPK or ULK1 in mammalian liver and Caenorhabditis elegans revealed a requirement for these kinases in autophagy. In mammals, loss of AMPK or ULK1 resulted in aberrant accumulation of the autophagy adaptor p62 and defective mitophagy. Reconstitution of ULK1-deficient cells with a mutant ULK1 that cannot be phosphorylated by AMPK revealed that such phosphorylation is required for mitochondrial homeostasis and cell survival during starvation. These findings uncover a conserved biochemical mechanism coupling nutrient status with autophagy and cell survival.
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