title: Mitochondrial outer-membrane protein FUNDC1 mediates hypoxia-induced mitophagy in mammalian cells.
abstract: Accumulating evidence has shown that dysfunctional mitochondria can be selectively removed by mitophagy. Dysregulation of mitophagy is implicated in the development of neurodegenerative disease and metabolic disorders. How individual mitochondria are recognized for removal and how this process is regulated remain poorly understood. Here we report that FUNDC1, an integral mitochondrial outer-membrane protein, is a receptor for hypoxia-induced mitophagy. FUNDC1 interacted with LC3 through its typical LC3-binding motif Y(18)xxL(21), and mutation of the LC3-interaction region impaired its interaction with LC3 and the subsequent induction of mitophagy. Knockdown of endogenous FUNDC1 significantly prevented hypoxia-induced mitophagy, which could be reversed by the expression of wild-type FUNDC1, but not LC3-interaction-deficient FUNDC1 mutants. Mechanistic studies further revealed that hypoxia induced dephosphorylation of FUNDC1 and enhanced its interaction with LC3 for selective mitophagy. Our findings thus offer insights into mitochondrial quality control in mammalian cells.
authors.affiliation: The State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Liu
authors.forename: Du
authors.initials: D
authors.lastname: Feng
authors.forename: Guo
authors.initials: G
authors.lastname: Chen
authors.forename: Ming
authors.initials: M
authors.lastname: Chen
authors.forename: Qiaoxia
authors.initials: Q
authors.lastname: Zheng
authors.forename: Pingping
authors.initials: P
authors.lastname: Song
authors.forename: Qi
authors.initials: Q
authors.lastname: Ma
authors.forename: Chongzhuo
authors.initials: C
authors.lastname: Zhu
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
authors.forename: Wanjun
authors.initials: W
authors.lastname: Qi
authors.forename: Lei
authors.initials: L
authors.lastname: Huang
authors.forename: Peng
authors.initials: P
authors.lastname: Xue
authors.forename: Baowei
authors.initials: B
authors.lastname: Li
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Wang
authors.forename: Haijing
authors.initials: H
authors.lastname: Jin
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.forename: Fuquan
authors.initials: F
authors.lastname: Yang
authors.forename: Pingsheng
authors.initials: P
authors.lastname: Liu
authors.forename: Yushan
authors.initials: Y
authors.lastname: Zhu
authors.forename: Senfang
authors.initials: S
authors.lastname: Sui
authors.forename: Quan
authors.initials: Q
authors.lastname: Chen
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001343:Autophagy; D001665:Binding Sites / Q000235:genetics; D015153:Blotting, Western; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D016253:Microscopy, Immunoelectron; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism* / Q000648:ultrastructure; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009154:Mutation; D010766:Phosphorylation; D011485:Protein Binding; D034622:RNA Interference; D017386:Sequence Homology, Amino Acid
chemical_list: C571016:FUNDC1 protein, human; C477012:MAP1LC3A protein, human; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D049452:Green Fluorescent Proteins