Document Detail


Central role of mitofusin 2 in autophagosome-lysosome fusion in cardiomyocytes.
MedLine Citation:
PMID:  22619176     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Ting Zhao; Xiaohu Huang; Liang Han; Xianhua Wang; Hongqiang Cheng; Yungang Zhao; Quan Chen; Ju Chen; Heping Cheng; Ruiping Xiao; Ming Zheng
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-05-22
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  287     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2012 Jul 
Date Detail:
Created Date:  2012-07-09     Completed Date:  2012-10-09     Revised Date:  2013-07-12    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  23615-25     Citation Subset:  IM    
Affiliation:
Institute of Molecular Medicine, State Key Laboratory of Biomembrane and Membrane Biotechnology, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China.
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MeSH Terms
Descriptor/Qualifier:
Animals
Animals, Newborn
Autophagy / physiology*
Blotting, Western
Cells, Cultured
DNA, Mitochondrial / genetics
Echocardiography
GTP Phosphohydrolases / deficiency*,  genetics,  metabolism
Heart / physiopathology
Immunoprecipitation
Lysosomes / metabolism
Membrane Fusion / physiology*
Mice
Mice, Knockout
Microscopy, Electron, Transmission
Mitochondria, Heart / genetics,  metabolism,  ultrastructure
Myocardium / metabolism,  pathology,  ultrastructure
Myocytes, Cardiac / enzymology,  physiology*
Phagosomes / metabolism
Protein Binding
RNA Interference
Reperfusion Injury / physiopathology
rab GTP-Binding Proteins / metabolism
Chemical
Reg. No./Substance:
0/DNA, Mitochondrial; 152989-05-4/rab7 protein; EC 3.6.1.-/GTP Phosphohydrolases; EC 3.6.1.-/Mfn2 protein, mouse; EC 3.6.1.-/rab GTP-Binding Proteins
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