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

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.

• Authors: 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
• Journal: FEBS letters (FEBS Lett) Vol. 589 Issue 15 Pg. 1847-54 (Jul 08 2015) ISSN: 1873-3468 [Electronic] England
• PMID: 25980607 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Chemical References

• Intracellular Signaling Peptides and Proteins
• Autophagy-Related Protein-1 Homolog
• Protein Serine-Threonine Kinases
• ULK1 protein, human
• Adenylate Kinase

Topics

• Adenylate Kinase (metabolism)
• Animals
• Autophagy-Related Protein-1 Homolog
• Cells, Cultured
• HeLa Cells
• Humans
• Intracellular Signaling Peptides and Proteins (metabolism)
• Mice
• Microscopy, Fluorescence
• Mitochondria (enzymology, metabolism)
• Mitophagy
• Phosphorylation
• Protein Serine-Threonine Kinases (metabolism)
• Protein Transport