| Title | Central Role of Mitofusin 2 in Autophagosome-Lysosome Fusion in Cardiomyocytes |
| Authors | Zhao, Ting Huang, Xiaohu Han, Liang Wang, Xianhua Cheng, Hongqiang Zhao, Yungang Chen, Quan Chen, Ju Cheng, Heping Xiao, Ruiping Zheng, Ming |
| Affiliation | Peking Univ, Inst Mol Med, State Key Lab Biomembrane & Membrane Biotechnol, Peking Tsinghua Ctr Life Sci, Beijing 100871, Peoples R China. Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA. Chinese Acad Sci, Inst Zool, Beijing 100101, Peoples R China. |
| Keywords | MUSCLE-CELL APOPTOSIS MITOCHONDRIAL FUSION ENDOPLASMIC-RETICULUM ISCHEMIA/REPERFUSION INJURY OXIDATIVE STRESS MAMMALIAN-CELLS HEART-MUSCLE MUTATIONS PROTEIN GTPASE |
| Issue Date | 2012 |
| Publisher | journal of biological chemistry |
| Citation | JOURNAL OF BIOLOGICAL CHEMISTRY.2012,287,(28),23615-23625. |
| 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 knockout 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. |
| URI | http://hdl.handle.net/20.500.11897/343393 |
| ISSN | 0021-9258 |
| DOI | 10.1074/jbc.M112.379164 |
| Indexed | SCI(E) EI PubMed |
| Appears in Collections: | 分子医学研究所 |
