title: The BCL2L1 and PGAM5 axis defines hypoxia-induced receptor-mediated mitophagy.
abstract: Receptor-mediated mitophagy is one of the major mechanisms of mitochondrial quality control essential for cell survival. We previously have identified FUNDC1 as a mitophagy receptor for selectively removing damaged mitochondria in mammalian systems. A critical unanswered question is how receptor-mediated mitophagy is regulated in response to cellular and environmental cues. Here, we report the striking finding that BCL2L1/Bcl-xL, but not BCL2, suppresses mitophagy mediated by FUNDC1 through its BH3 domain. Mechanistically, we demonstrate that BCL2L1, but not BCL2, interacts with and inhibits PGAM5, a mitochondrially localized phosphatase, to prevent the dephosphorylation of FUNDC1 at serine 13 (Ser13), which activates hypoxia-induced mitophagy. Our results showed that the BCL2L1-PGAM5-FUNDC1 axis is critical for receptor-mediated mitophagy in response to hypoxia and that BCL2L1 possesses unique functions distinct from BCL2.
authors.affiliation: State Key Laboratory of Biomembrane and Membrane Biotechnology; Institute of Zoology; Chinese Academy of Sciences; Beijing, China; University of Chinese Academy of Sciences; Beijing, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Biomembrane and Membrane Biotechnology; Institute of Zoology; Chinese Academy of Sciences; Beijing, China; School of Life Science; Anhui University; Hefei, Anhui China.
authors.forename: Danfeng
authors.initials: D
authors.lastname: Xue
authors.affiliation: Tianjin Key Laboratory of Protein Science; College of Life Sciences; Nankai University; Tianjin, China.
authors.forename: Guo
authors.initials: G
authors.lastname: Chen
authors.affiliation: Tianjin Key Laboratory of Protein Science; College of Life Sciences; Nankai University; Tianjin, China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Han
authors.affiliation: State Key Laboratory of Biomembrane and Membrane Biotechnology; Institute of Zoology; Chinese Academy of Sciences; Beijing, China; University of Chinese Academy of Sciences; Beijing, China.
authors.forename: Li
authors.initials: L
authors.lastname: Huang
authors.affiliation: State Key Laboratory of Biomembrane and Membrane Biotechnology; Institute of Zoology; Chinese Academy of Sciences; Beijing, China; University of Chinese Academy of Sciences; Beijing, China.
authors.forename: Chongzhuo
authors.initials: C
authors.lastname: Zhu
authors.affiliation: State Key Laboratory of Biomembrane and Membrane Biotechnology; Institute of Zoology; Chinese Academy of Sciences; Beijing, China.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Biomembrane and Membrane Biotechnology; Institute of Zoology; Chinese Academy of Sciences; Beijing, China.
authors.forename: Haijing
authors.initials: H
authors.lastname: Jin
authors.affiliation: State Key Laboratory of Biomembrane and Membrane Biotechnology; Institute of Zoology; Chinese Academy of Sciences; Beijing, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.affiliation: Tianjin Key Laboratory of Protein Science; College of Life Sciences; Nankai University; Tianjin, China.
authors.forename: Yushan
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: State Key Laboratory of Biomembrane and Membrane Biotechnology; Institute of Zoology; Chinese Academy of Sciences; Beijing, China; University of Chinese Academy of Sciences; Beijing, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Biomembrane and Membrane Biotechnology; Institute of Zoology; Chinese Academy of Sciences; Beijing, China; University of Chinese Academy of Sciences; Beijing, China; Tianjin Key Laboratory of Protein Science; College of Life Sciences; Nankai University; Tianjin, China.
authors.forename: Quan
authors.initials: Q
authors.lastname: Chen
mesh_terms: D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D000071186:Beclin-1; D002352:Carrier Proteins / Q000378:metabolism*; D015687:Cell Hypoxia; D006367:HeLa Cells; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism*; D063306:Mitophagy; D008954:Models, Biological; D010749:Phosphoprotein Phosphatases; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D012694:Serine / Q000378:metabolism; D013329:Structure-Activity Relationship; D051020:bcl-X Protein / Q000737:chemistry / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; C494811:BCL2L1 protein, human; C491997:BECN1 protein, human; D000071186:Beclin-1; D002352:Carrier Proteins; C571016:FUNDC1 protein, human; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D051020:bcl-X Protein; D012694:Serine; C529563:PGAM5 protein, human; D010749:Phosphoprotein Phosphatases
keywords: BCL2L1/Bcl-xL; FUNDC1; PGAM5 phosphatase; hypoxia; mitophagy