Akihiro Shirakabe1, Peiyong Zhai1, Yoshiyuki Ikeda1, Toshiro Saito1, Yasuhiro Maejima1, Chiao-Po Hsu1, Masatoshi Nomura1, Kensuke Egashira1, Beth Levine1, Junichi Sadoshima2. 1. From Department of Cell Biology and Molecular Medicine, Rutgers-New Jersey Medical School, Newark (A.S., P.Z., Y.I., T.S., Y.M., J.S.); Department of Cardiovascular Medicine and Hypertension, Graduate School of Medical and Dental Science, Kagoshima University, Japan (Y.I.); Department of Medicine and Bioregulatory Science, Kyushu University, Fukuoka, Japan (M.N.); Division of Cardiovascular Surgery, Department of Surgery, Veterans General Hospital, National Yang-Ming University School of Medicine, Taiwan (C.-P.H.); Department of Cardiovascular Medicine, Kyushu University Hospital, Fukuoka, Japan (K.E.); Department of Cardiovascular Research, Development, and Translational Medicine, Graduate School of Medical Science, Kyushu University Hospital, Fukuoka, Japan (K.E.); and Center for Autophagy Research, Department of Internal Medicine, and Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas (B.L.). 2. From Department of Cell Biology and Molecular Medicine, Rutgers-New Jersey Medical School, Newark (A.S., P.Z., Y.I., T.S., Y.M., J.S.); Department of Cardiovascular Medicine and Hypertension, Graduate School of Medical and Dental Science, Kagoshima University, Japan (Y.I.); Department of Medicine and Bioregulatory Science, Kyushu University, Fukuoka, Japan (M.N.); Division of Cardiovascular Surgery, Department of Surgery, Veterans General Hospital, National Yang-Ming University School of Medicine, Taiwan (C.-P.H.); Department of Cardiovascular Medicine, Kyushu University Hospital, Fukuoka, Japan (K.E.); Department of Cardiovascular Research, Development, and Translational Medicine, Graduate School of Medical Science, Kyushu University Hospital, Fukuoka, Japan (K.E.); and Center for Autophagy Research, Department of Internal Medicine, and Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas (B.L.). sadoshju@njms.rutgers.edu.
Abstract
BACKGROUND: Mitochondrial autophagy is an important mediator of mitochondrial quality control in cardiomyocytes. The occurrence of mitochondrial autophagy and its significance during cardiac hypertrophy are not well understood. METHODS AND RESULTS: Mice were subjected to transverse aortic constriction (TAC) and observed at multiple time points up to 30 days. Cardiac hypertrophy developed after 5 days, the ejection fraction was reduced after 14 days, and heart failure was observed 30 days after TAC. General autophagy was upregulated between 1 and 12 hours after TAC but was downregulated below physiological levels 5 days after TAC. Mitochondrial autophagy, evaluated by electron microscopy, mitochondrial content, and Keima with mitochondrial localization signal, was transiently activated at ≈3 to 7 days post-TAC, coinciding with mitochondrial translocation of Drp1. However, it was downregulated thereafter, followed by mitochondrial dysfunction. Haploinsufficiency of Drp1 abolished mitochondrial autophagy and exacerbated the development of both mitochondrial dysfunction and heart failure after TAC. Injection of Tat-Beclin 1, a potent inducer of autophagy, but not control peptide, on day 7 after TAC, partially rescued mitochondrial autophagy and attenuated mitochondrial dysfunction and heart failure induced by overload. Haploinsufficiency of either drp1 or beclin 1 prevented the rescue by Tat-Beclin 1, suggesting that its effect is mediated in part through autophagy, including mitochondrial autophagy. CONCLUSIONS: Mitochondrial autophagy is transiently activated and then downregulated in the mouse heart in response to pressure overload. Downregulation of mitochondrial autophagy plays an important role in mediating the development of mitochondrial dysfunction and heart failure, whereas restoration of mitochondrial autophagy attenuates dysfunction in the heart during pressure overload.
BACKGROUND: Mitochondrial autophagy is an important mediator of mitochondrial quality control in cardiomyocytes. The occurrence of mitochondrial autophagy and its significance during cardiac hypertrophy are not well understood. METHODS AND RESULTS:Mice were subjected to transverse aortic constriction (TAC) and observed at multiple time points up to 30 days. Cardiac hypertrophy developed after 5 days, the ejection fraction was reduced after 14 days, and heart failure was observed 30 days after TAC. General autophagy was upregulated between 1 and 12 hours after TAC but was downregulated below physiological levels 5 days after TAC. Mitochondrial autophagy, evaluated by electron microscopy, mitochondrial content, and Keima with mitochondrial localization signal, was transiently activated at ≈3 to 7 days post-TAC, coinciding with mitochondrial translocation of Drp1. However, it was downregulated thereafter, followed by mitochondrial dysfunction. Haploinsufficiency of Drp1 abolished mitochondrial autophagy and exacerbated the development of both mitochondrial dysfunction and heart failure after TAC. Injection of Tat-Beclin 1, a potent inducer of autophagy, but not control peptide, on day 7 after TAC, partially rescued mitochondrial autophagy and attenuated mitochondrial dysfunction and heart failure induced by overload. Haploinsufficiency of either drp1 or beclin 1 prevented the rescue by Tat-Beclin 1, suggesting that its effect is mediated in part through autophagy, including mitochondrial autophagy. CONCLUSIONS: Mitochondrial autophagy is transiently activated and then downregulated in the mouse heart in response to pressure overload. Downregulation of mitochondrial autophagy plays an important role in mediating the development of mitochondrial dysfunction and heart failure, whereas restoration of mitochondrial autophagy attenuates dysfunction in the heart during pressure overload.
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