title: Hypoxic mitophagy regulates mitochondrial quality and platelet activation and determines severity of I/R heart injury.
abstract: Mitochondrial dysfunction underlies many prevalent diseases including heart disease arising from acute ischemia/reperfusion (I/R) injury. Here, we demonstrate that mitophagy, which selectively removes damaged or unwanted mitochondria, regulated mitochondrial quality and quantityin vivo. Hypoxia induced extensive mitochondrial degradation in a FUNDC1-dependent manner in platelets, and this was blocked byin vivoadministration of a cell-penetrating peptide encompassing the LIR motif of FUNDC1 only in wild-type mice. Genetic ablation of Fundc1 impaired mitochondrial quality and increased mitochondrial mass in platelets and rendered the platelets insensitive to hypoxia and the peptide. Moreover, hypoxic mitophagy in platelets protected the heart from worsening of I/R injury. This represents a new mechanism of the hypoxic preconditioning effect which reduces I/R injury. Our results demonstrate a critical role of mitophagy in mitochondrial quality control and platelet activation, and suggest that manipulation of mitophagy by hypoxia or pharmacological approaches may be a novel strategy for cardioprotection.
authors.affiliation: The State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
authors.forename: Weilin
authors.initials: W
authors.lastname: Zhang
authors.affiliation: The Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking University, Beijing, China.
authors.forename: He
authors.initials: H
authors.lastname: Ren
authors.affiliation: Department of Physiology, Peking University School of Basic Medical Sciences, Peking University, Beijing, China.
authors.forename: Chunling
authors.initials: C
authors.lastname: Xu
authors.affiliation: The State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
authors.forename: Chongzhuo
authors.initials: C
authors.lastname: Zhu
authors.affiliation: The State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Wu
authors.affiliation: The State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
authors.forename: Dong
authors.initials: D
authors.lastname: Liu
authors.affiliation: The State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.affiliation: The State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Liu
authors.affiliation: Center for Medical Genetics, Beijing Children's Hospital, Capital Medical University, Beijing, China.|Beijing Pediatric Research Institute, Beijing, China.|MOE Key Laboratory of Major Diseases in Children, Beijing, China.
authors.forename: Wei
authors.identifier: 0000-0001-7430-6019
authors.initials: W
authors.lastname: Li
authors.affiliation: The State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.|The Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking University, Beijing, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Ma
authors.affiliation: The State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Du
authors.affiliation: Department of Physiology, Peking University School of Basic Medical Sciences, Peking University, Beijing, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Zheng
authors.affiliation: The Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking University, Beijing, China.
authors.forename: Chuanmao
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiaotong University, Shanghai, China.
authors.forename: Junling
authors.initials: J
authors.lastname: Liu
authors.affiliation: The State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.|Tianjin Key Laboratory of Protein Science, College of Life Sciences, Nankai University, Tianjin, China.
authors.forename: Quan
authors.identifier: 0000-0001-7539-8728
authors.initials: Q
authors.lastname: Chen
mesh_terms: D000818:Animals; D000860:Hypoxia / Q000473:pathology* / Q000503:physiopathology*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008810:Mice, Inbred C57BL; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D063306:Mitophagy; D015428:Myocardial Reperfusion Injury / Q000473:pathology* / Q000503:physiopathology*; D015539:Platelet Activation
chemical_list: C000588786:FUNDC1 protein, mouse; D008565:Membrane Proteins; D024101:Mitochondrial Proteins
keywords: cell biology; human biology; hypoxia; ischemia/reperfusion injury; medicine; mitochondrial quality control; mitophagy receptor; mouse; platelet activation