title: ULK1 translocates to mitochondria and phosphorylates FUNDC1 to regulate mitophagy.
abstract: Autophagy eliminates dysfunctional mitochondria in an intricate process known as mitophagy. ULK1 is critical for the induction of autophagy, but its substrate(s) and mechanism of action in mitophagy remain unclear. Here, we show that ULK1 is upregulated and translocates to fragmented mitochondria upon mitophagy induction by either hypoxia or mitochondrial uncouplers. At mitochondria, ULK1 interacts with FUNDC1, phosphorylating it at serine 17, which enhances FUNDC1 binding to LC3. A ULK1-binding-deficient mutant of FUNDC1 prevents ULK1 translocation to mitochondria and inhibits mitophagy. Finally, kinase-active ULK1 and a phospho-mimicking mutant of FUNDC1 rescue mitophagy in ULK1-null cells. Thus, we conclude that FUNDC1 regulates ULK1 recruitment to damaged mitochondria, where FUNDC1 phosphorylation by ULK1 is crucial for mitophagy.
authors.affiliation: Institute of Neurology, Guangdong Key Laboratory of Age-related Cardiac-cerebral Vascular Disease, Affiliated Hospital of Guangdong Medical College, Zhanjiang Guangdong, China.
authors.forename: Wenxian
authors.initials: W
authors.lastname: Wu
authors.forename: Weili
authors.initials: W
authors.lastname: Tian
authors.forename: Zhe
authors.initials: Z
authors.lastname: Hu
authors.forename: Guo
authors.initials: G
authors.lastname: Chen
authors.forename: Lei
authors.initials: L
authors.lastname: Huang
authors.forename: Wen
authors.initials: W
authors.lastname: Li
authors.forename: Xingli
authors.initials: X
authors.lastname: Zhang
authors.forename: Peng
authors.initials: P
authors.lastname: Xue
authors.forename: Changqian
authors.initials: C
authors.lastname: Zhou
authors.forename: Lei
authors.initials: L
authors.lastname: Liu
authors.forename: Yushan
authors.initials: Y
authors.lastname: Zhu
authors.forename: Xingliang
authors.initials: X
authors.lastname: Zhang
authors.forename: Longxuan
authors.initials: L
authors.lastname: Li
authors.forename: Liangqing
authors.initials: L
authors.lastname: Zhang
authors.forename: Senfang
authors.initials: S
authors.lastname: Sui
authors.forename: Bin
authors.initials: B
authors.lastname: Zhao
authors.forename: Du
authors.initials: D
authors.lastname: Feng
mesh_terms: D000071189:Autophagy-Related Protein-1 Homolog; D015687:Cell Hypoxia; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008928:Mitochondria / Q000502:physiology; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D063306:Mitophagy / Q000502:physiology*; D009154:Mutation; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: C571016:FUNDC1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; C477012:MAP1LC3A protein, human; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D000071189:Autophagy-Related Protein-1 Homolog; D017346:Protein Serine-Threonine Kinases; C484754:ULK1 protein, human