title: FUNDC1 regulates mitochondrial dynamics at the ER-mitochondrial contact site under hypoxic conditions.
abstract: In hypoxic cells, dysfunctional mitochondria are selectively removed by a specialized autophagic process called mitophagy. The ER-mitochondrial contact site (MAM) is essential for fission of mitochondria prior to engulfment, and the outer mitochondrial membrane protein FUNDC1 interacts with LC3 to recruit autophagosomes, but the mechanisms integrating these processes are poorly understood. Here, we describe a new pathway mediating mitochondrial fission and subsequent mitophagy under hypoxic conditions. FUNDC1 accumulates at the MAM by associating with the ER membrane protein calnexin. As mitophagy proceeds, FUNDC1/calnexin association attenuates and the exposed cytosolic loop of FUNDC1 interacts with DRP1 instead. DRP1 is thereby recruited to the MAM, and mitochondrial fission then occurs. Knockdown of FUNDC1, DRP1, or calnexin prevents fission and mitophagy under hypoxic conditions. Thus, FUNDC1 integrates mitochondrial fission and mitophagy at the interface of the MAM by working in concert with DRP1 and calnexin under hypoxic conditions in mammalian cells.
authors.affiliation: Guangdong Key Laboratory of Age-related Cardiac-cerebral Vascular Disease, Department of Neurology, Institute of Neurology, The Affiliated Hospital of Guangdong Medical University, Guangdong Medical University, Zhanjiang, China.
authors.forename: Wenxian
authors.initials: W
authors.lastname: Wu
authors.affiliation: Guangdong Key Laboratory of Age-related Cardiac-cerebral Vascular Disease, Department of Neurology, Institute of Neurology, The Affiliated Hospital of Guangdong Medical University, Guangdong Medical University, Zhanjiang, China.
authors.forename: Chunxia
authors.initials: C
authors.lastname: Lin
authors.affiliation: Department of Cardiovasology, The Affiliated Hospital of Guangdong Medical University, Zhanjiang, China.
authors.forename: Keng
authors.initials: K
authors.lastname: Wu
authors.affiliation: Guangdong Key Laboratory of Age-related Cardiac-cerebral Vascular Disease, Department of Neurology, Institute of Neurology, The Affiliated Hospital of Guangdong Medical University, Guangdong Medical University, Zhanjiang, China Guangdong General Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Jiang
authors.affiliation: Guangdong Key Laboratory of Age-related Cardiac-cerebral Vascular Disease, Department of Neurology, Institute of Neurology, The Affiliated Hospital of Guangdong Medical University, Guangdong Medical University, Zhanjiang, China College of Life Science and Technology, Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Wang
authors.affiliation: Guangdong Key Laboratory of Age-related Cardiac-cerebral Vascular Disease, Department of Neurology, Institute of Neurology, The Affiliated Hospital of Guangdong Medical University, Guangdong Medical University, Zhanjiang, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Anesthesiology, Guangdong Medical University, Zhanjiang, China.
authors.forename: Haixia
authors.initials: H
authors.lastname: Zhuang
authors.affiliation: Department of Pediatrics, Guangdong Medical University, Zhanjiang, China.
authors.forename: Xingliang
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Guangdong Key Laboratory of Age-related Cardiac-cerebral Vascular Disease, Department of Neurology, Institute of Neurology, The Affiliated Hospital of Guangdong Medical University, Guangdong Medical University, Zhanjiang, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Chen
authors.affiliation: Guangdong Key Laboratory of Age-related Cardiac-cerebral Vascular Disease, Department of Neurology, Institute of Neurology, The Affiliated Hospital of Guangdong Medical University, Guangdong Medical University, Zhanjiang, China.
authors.forename: Shupeng
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Anesthesiology, Guangdong Medical University, Zhanjiang, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Anesthesiology, Guangdong Medical University, Zhanjiang, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Anesthesiology, Guangdong Medical University, Zhanjiang, China.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Laboratory of Hepatobiliary Surgery, Zhanjiang Key Laboratory of Hepatobiliary Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China.
authors.forename: Runzhi
authors.initials: R
authors.lastname: Zhu
authors.affiliation: Department of Anesthesiology, Guangdong Medical University, Zhanjiang, 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, China.
authors.forename: Senfang
authors.initials: S
authors.lastname: Sui
authors.affiliation: Guangdong General Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Tan
authors.affiliation: Guangdong Key Laboratory of Age-related Cardiac-cerebral Vascular Disease, Department of Neurology, Institute of Neurology, The Affiliated Hospital of Guangdong Medical University, Guangdong Medical University, Zhanjiang, China binzhaoe@163.com jingjing.zhang@live.com longxuanlee2006@yahoo.com feng_du@foxmail.com.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhao
authors.affiliation: Guangdong Key Laboratory of Age-related Cardiac-cerebral Vascular Disease, Department of Neurology, Institute of Neurology, The Affiliated Hospital of Guangdong Medical University, Guangdong Medical University, Zhanjiang, China binzhaoe@163.com jingjing.zhang@live.com longxuanlee2006@yahoo.com feng_du@foxmail.com.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Neurology, Gongli Hospital, Pudong New Area, Shanghai, China binzhaoe@163.com jingjing.zhang@live.com longxuanlee2006@yahoo.com feng_du@foxmail.com.
authors.forename: Longxuan
authors.initials: L
authors.lastname: Li
authors.affiliation: Guangdong Key Laboratory of Age-related Cardiac-cerebral Vascular Disease, Department of Neurology, Institute of Neurology, The Affiliated Hospital of Guangdong Medical University, Guangdong Medical University, Zhanjiang, China Department of Developmental Biology, Harvard School of Dental Medicine, Harvard Medical School, Boston, MA, USA binzhaoe@163.com jingjing.zhang@live.com longxuanlee2006@yahoo.com feng_du@foxmail.com.
authors.forename: Du
authors.identifier: 0000-0002-2489-4702
authors.initials: D
authors.lastname: Feng
mesh_terms: D037281:Calnexin / Q000378:metabolism*; D002478:Cells, Cultured; D034281:Dynamins; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D020558:GTP Phosphohydrolases / Q000378:metabolism*; D006801:Humans; D000860:Hypoxia; D008565:Membrane Proteins / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D063154:Mitochondrial Dynamics; D024101:Mitochondrial Proteins / Q000378:metabolism*; D063306:Mitophagy; D011485:Protein Binding
chemical_list: C571016:FUNDC1 protein, human; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D037281:Calnexin; D020558:GTP Phosphohydrolases; C110768:DNM1L protein, human; D034281:Dynamins
keywords: ER–mitochondrial contact site; MAM; autophagy; mitochondrial fission; mitophagy