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Phosphorylation of ULK1 by AMPK regulates translocation of ULK1 to mitochondria and mitophagy.

FEBS letters (2015-05-20)
Weili Tian, Wen Li, Yinqin Chen, Zeming Yan, Xia Huang, Haixia Zhuang, Wangtao Zhong, Yusen Chen, Wenxian Wu, Chunxia Lin, Hao Chen, Xiaoyan Hou, Liangqing Zhang, Senfang Sui, Bin Zhao, Zhe Hu, Longxuan Li, Du Feng
ABSTRACT

UNC-51 like kinase (ULK1) translocates to dysfunctional mitochondria and is involved in mitophagy, but the mechanisms responsible for ULK1 activation and translocation remain unclear. Here, we found that hypoxia induces phosphorylation of ULK1 at Serine-555 by Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK). Unlike wild-type ULK1, an ULK1 (S555A) mutant cannot translocate to mitochondria in response to hypoxia. Inhibition or knockdown of AMPK prevents ULK1 translocation and inhibits mitophagy. Finally, the phospho-mimic ULK1 (S555D) mutant, but not ULK1 (S555A), rescues mitophagy in AMPK-knockdown cells. Thus, we conclude that AMPK-dependent phosphorylation of ULK1 is critical for translocation of ULK1 to mitochondria and for mitophagy in response to hypoxic stress.

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