依赖动力相关蛋白1（Drp1）的线粒体自噬对压力超负荷诱导的线粒体功能障碍和心力衰竭起保护作用。
Drp1-Dependent Mitochondrial Autophagy Plays a Protective Role Against Pressure Overload-Induced Mitochondrial Dysfunction and Heart Failure.
作者信息
Shirakabe Akihiro, Zhai Peiyong, Ikeda Yoshiyuki, Saito Toshiro, Maejima Yasuhiro, Hsu Chiao-Po, Nomura Masatoshi, Egashira Kensuke, Levine Beth, Sadoshima Junichi
机构信息
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.).
出版信息
Circulation. 2016 Mar 29;133(13):1249-63. doi: 10.1161/CIRCULATIONAHA.115.020502. Epub 2016 Feb 25.
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.
背景
线粒体自噬是心肌细胞中线粒体质量控制的重要调节因子。目前对心脏肥大过程中线粒体自噬的发生及其意义尚不完全清楚。
方法与结果
对小鼠进行主动脉缩窄（TAC），并在长达30天的多个时间点进行观察。TAC术后5天出现心脏肥大，14天后射血分数降低，30天后出现心力衰竭。TAC术后1至12小时全身自噬上调，但TAC术后5天降至生理水平以下。通过电子显微镜、线粒体含量以及带有线粒体定位信号的Keima评估，线粒体自噬在TAC术后约3至7天短暂激活，与动力相关蛋白1（Drp1）的线粒体转位同时发生。然而，此后线粒体自噬下调，随后出现线粒体功能障碍。Drp1单倍体不足消除了线粒体自噬，并加剧了TAC术后线粒体功能障碍和心力衰竭的发展。在TAC术后第7天注射自噬强效诱导剂Tat-Beclin 1而非对照肽，可部分挽救线粒体自噬，并减轻由过载诱导的线粒体功能障碍和心力衰竭。Drp1或Beclin 1单倍体不足可阻止Tat-Beclin 1的挽救作用，提示其作用部分通过自噬介导，包括线粒体自噬。
结论
在压力过载的情况下，小鼠心脏中的线粒体自噬先短暂激活然后下调。线粒体自噬的下调在介导线粒体功能障碍和心力衰竭的发展中起重要作用，而恢复线粒体自噬可减轻压力过载期间心脏的功能障碍。
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