title: Central role of mitofusin 2 in autophagosome-lysosome fusion in cardiomyocytes.
abstract: In the heart, autophagy has been implicated in cardioprotection and ischemia-reperfusion tolerance, and the dysregulation of autophagy is associated with the development of heart failure. Mitochondrial dynamic proteins are profoundly involved in autophagic processes, especially the initiation and formation of autophagosomes, but it is not clear whether they play any role in cardiac autophagy. We previously reported that mitofusin 2 (MFN2), a mitochondrial outer membrane protein, serves as a major determinant of cardiomyocyte apoptosis mediated by oxidative stress. Here, we reveal a novel and essential role of MFN2 in mediating cardiac autophagy. We found that specific deletion of MFN2 in cardiomyocytes caused extensive accumulation of autophagosomes. In particular, the fusion of autophagosomes with lysosomes, a critical step in autophagic degradation, was markedly retarded without altering the formation of autophagosomes and lysosomes in response to ischemia-reperfusion stress. Importantly, MFN2 co-immunoprecipitated with RAB7 in the heart, and starvation further increased it. Knockdown of MFN2 by shRNA prevented, whereas re-expression of MFN2 restored, the autophagosome-lysosome fusion in neonatal cardiomyocytes. Hearts from cardiac-specific MFN2 knock-out mice had abnormal mitochondrial and cellular metabolism and were vulnerable to ischemia-reperfusion challenge. Our study defined a novel and essential role of MFN2 in the cardiac autophagic process by mediating the maturation of autophagy at the phase of autophagosome-lysosome fusion; deficiency of MFN2 caused multiple molecular and functional defects that undermined cardiac reserve and gradually led to cardiac vulnerability and dysfunction.
authors.affiliation: Institute of Molecular Medicine, State Key Laboratory of Biomembrane and Membrane Biotechnology, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Zhao
authors.forename: Xiaohu
authors.initials: X
authors.lastname: Huang
authors.forename: Liang
authors.initials: L
authors.lastname: Han
authors.forename: Xianhua
authors.initials: X
authors.lastname: Wang
authors.forename: Hongqiang
authors.initials: H
authors.lastname: Cheng
authors.forename: Yungang
authors.initials: Y
authors.lastname: Zhao
authors.forename: Quan
authors.initials: Q
authors.lastname: Chen
authors.forename: Ju
authors.initials: J
authors.lastname: Chen
authors.forename: Heping
authors.initials: H
authors.lastname: Cheng
authors.forename: Ruiping
authors.initials: R
authors.lastname: Xiao
authors.forename: Ming
authors.initials: M
authors.lastname: Zheng
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001343:Autophagy / Q000502:physiology*; D015153:Blotting, Western; D002478:Cells, Cultured; D004272:DNA, Mitochondrial / Q000235:genetics; D004452:Echocardiography; D020558:GTP Phosphohydrolases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D006321:Heart / Q000503:physiopathology; D047468:Immunoprecipitation; D008247:Lysosomes / Q000378:metabolism; D008561:Membrane Fusion / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D008929:Mitochondria, Heart / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D009206:Myocardium / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D032383:Myocytes, Cardiac / Q000201:enzymology / Q000502:physiology*; D010588:Phagosomes / Q000378:metabolism; D011485:Protein Binding; D034622:RNA Interference; D015427:Reperfusion Injury / Q000503:physiopathology; D020691:rab GTP-Binding Proteins / Q000378:metabolism; D000090802:rab7 GTP-Binding Proteins
chemical_list: D004272:DNA, Mitochondrial; D000090802:rab7 GTP-Binding Proteins; C000716465:rab7 GTP-binding proteins, mouse; D020558:GTP Phosphohydrolases; C488751:Mfn2 protein, mouse; D020691:rab GTP-Binding Proteins