title: 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.affiliation: Guangdong Key Laboratory of Age-related Cardiac-cerebral Vascular Disease, Institute of Neurology, Affiliated Hospital of Guangdong Medical College, Guangdong Medical College, Zhanjiang 524001, Guangdong, China.
authors.forename: Weili
authors.initials: W
authors.lastname: Tian
authors.affiliation: Guangdong Key Laboratory of Age-related Cardiac-cerebral Vascular Disease, Institute of Neurology, Affiliated Hospital of Guangdong Medical College, Guangdong Medical College, Zhanjiang 524001, Guangdong, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Vascular Surgery, Thyroid and Mammary Gland Surgery, Guangdong Medical College, Zhanjiang 524001, China.
authors.forename: Yinqin
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Interventional Radiology, Guangdong Medical College, Zhanjiang 524001, China.
authors.forename: Zeming
authors.initials: Z
authors.lastname: Yan
authors.affiliation: Department of Anesthesiology, Guangdong Medical College, Zhanjiang 524001, China.
authors.forename: Xia
authors.initials: X
authors.lastname: Huang
authors.affiliation: Department of Anesthesiology, Guangdong Medical College, Zhanjiang 524001, China.
authors.forename: Haixia
authors.initials: H
authors.lastname: Zhuang
authors.affiliation: Guangdong Key Laboratory of Age-related Cardiac-cerebral Vascular Disease, Institute of Neurology, Affiliated Hospital of Guangdong Medical College, Guangdong Medical College, Zhanjiang 524001, Guangdong, China.
authors.forename: Wangtao
authors.initials: W
authors.lastname: Zhong
authors.affiliation: Guangdong Key Laboratory of Age-related Cardiac-cerebral Vascular Disease, Institute of Neurology, Affiliated Hospital of Guangdong Medical College, Guangdong Medical College, Zhanjiang 524001, Guangdong, China.
authors.forename: Yusen
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Guangdong Key Laboratory of Age-related Cardiac-cerebral Vascular Disease, Institute of Neurology, Affiliated Hospital of Guangdong Medical College, Guangdong Medical College, Zhanjiang 524001, Guangdong, China.
authors.forename: Wenxian
authors.initials: W
authors.lastname: Wu
authors.affiliation: Guangdong Key Laboratory of Age-related Cardiac-cerebral Vascular Disease, Institute of Neurology, Affiliated Hospital of Guangdong Medical College, Guangdong Medical College, Zhanjiang 524001, Guangdong, China.
authors.forename: Chunxia
authors.initials: C
authors.lastname: Lin
authors.affiliation: Guangdong Key Laboratory of Age-related Cardiac-cerebral Vascular Disease, Institute of Neurology, Affiliated Hospital of Guangdong Medical College, Guangdong Medical College, Zhanjiang 524001, Guangdong, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Chen
authors.affiliation: Guangdong Key Laboratory of Age-related Cardiac-cerebral Vascular Disease, Institute of Neurology, Affiliated Hospital of Guangdong Medical College, Guangdong Medical College, Zhanjiang 524001, Guangdong, China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Hou
authors.affiliation: Department of Anesthesiology, Guangdong Medical College, Zhanjiang 524001, China.
authors.forename: Liangqing
authors.initials: L
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Senfang
authors.initials: S
authors.lastname: Sui
authors.affiliation: Guangdong Key Laboratory of Age-related Cardiac-cerebral Vascular Disease, Institute of Neurology, Affiliated Hospital of Guangdong Medical College, Guangdong Medical College, Zhanjiang 524001, Guangdong, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhao
authors.affiliation: Department of Anesthesiology, Guangdong Medical College, Zhanjiang 524001, China. Electronic address: biohuzhe@hotmail.com.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Hu
authors.affiliation: Department of Neurology, Gongli Hospital, Pudong New Area, Shanghai 200135, China. Electronic address: longxuanlee2006@yahoo.com.
authors.forename: Longxuan
authors.initials: L
authors.lastname: Li
authors.affiliation: Guangdong Key Laboratory of Age-related Cardiac-cerebral Vascular Disease, Institute of Neurology, Affiliated Hospital of Guangdong Medical College, Guangdong Medical College, Zhanjiang 524001, Guangdong, China. Electronic address: feng_du@foxmail.com.
authors.forename: Du
authors.initials: D
authors.lastname: Feng
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism*; D000818:Animals; D000071189:Autophagy-Related Protein-1 Homolog; D002478:Cells, Cultured; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism*; D063306:Mitophagy; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D021381:Protein Transport
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D000071189:Autophagy-Related Protein-1 Homolog; D017346:Protein Serine-Threonine Kinases; C484754:ULK1 protein, human; D000263:Adenylate Kinase
keywords: Adenosine 5′-monophosphate (AMP)-activated protein kinase; Autophagy; Hypoxia; Mitochondria; Mitophagy; UNC-51 like kinase