Alternative Mitophagy Protects the Heart Against Obesity-Associated Cardiomyopathy
Alternative Mitophagy Protects the Heart Against Obesity-Associated Cardiomyopathy
复制标题
DOI：
10.1161/circresaha.121.319377
复制
发表时间：
2021-11
影响因子：
20.1
通讯作者：
Mingming Tong;Toshiro Saito;P. Zhai;S. Oka;Wataru Mizushima;Michinari Nakamura;Shohei Ikeda;A. Shirakabe;J. Sadoshima
中科院分区：
文献类型：
--
作者：
Mingming Tong;Toshiro Saito;P. Zhai;S. Oka;Wataru Mizushima;Michinari Nakamura;Shohei Ikeda;A. Shirakabe;J. Sadoshima
补充数字内容可在正文中找到。理论基础：以肥大和线粒体功能障碍为特征的肥胖相关心肌病。线粒体质量控制机制，包括有丝分裂，对于肥胖相关心肌病的心脏功能的维持是必不可少的。然而，自噬通量在摄入高脂饮食(HFD)约6周时达到峰值，此后下降。目的：研究在肥胖相关心肌病(肥胖型心肌病)的慢性期，在全身自噬下调后是否激活了有丝分裂吞噬，如果是的话，其潜在的机制和功能意义是什么。方法和结果：给小鼠喂普通饲料或高脂饲料(60kcal%脂肪)。用Mito-Keima评估的有丝分裂吞噬作用在服用HFD 3周后增加，在传统的自噬机制被灭活后继续增加，至少持续到24周。HFD的摄入呈时间依赖性地上调线粒体部分中Ser555磷酸化的Ulk1(UNC-51 like kinase1)和Rab9(RAS相关蛋白Rab-9)。在摄入HFD 20周后，分离的小鼠心肌细胞中的线粒体被Rab9阳性的环状结构隔离，这与交替有丝分裂激活是一致的。在心脏特异的ulk1基因敲除小鼠心脏中，摄入20周的HFD诱导的有丝分裂增加被取消，其中舒张期和收缩期功能障碍都加剧。Rab9 S179A敲入小鼠体内选择性抑制了选择性的有丝分裂吞噬功能，在摄入HFD 20周后，表现出有丝分裂吞噬功能受损和更严重的心功能障碍。在服用HFD期间，在心脏中过表达Rab9可增加有丝分裂并保护心脏免受心脏功能障碍的影响。HFD诱导的Rab9依赖的有丝分裂激活伴随着转录因子结合IGHM增强子3(TFE3)的上调，TFE3在有丝分裂的转录激活中起重要作用。结论：Ulk1-Rab9依赖的选择性有丝分裂在HFD消费的慢性期被激活，并作为一种基本的线粒体质量控制机制，从而保护心脏免受肥胖性心肌病的影响。
Supplemental Digital Content is available in the text. Rationale: Obesity-associated cardiomyopathy characterized by hypertrophy and mitochondrial dysfunction. Mitochondrial quality control mechanisms, including mitophagy, are essential for the maintenance of cardiac function in obesity-associated cardiomyopathy. However, autophagic flux peaks at around 6 weeks of high-fat diet (HFD) consumption and declines thereafter. Objective: We investigated whether mitophagy is activated during the chronic phase of cardiomyopathy associated with obesity (obesity cardiomyopathy) after general autophagy is downregulated and, if so, what the underlying mechanism and the functional significance are. Methods and Results: Mice were fed either a normal diet or a HFD (60 kcal% fat). Mitophagy, evaluated using Mito-Keima, was increased after 3 weeks of HFD consumption and continued to increase after conventional mechanisms of autophagy were inactivated, at least until 24 weeks. HFD consumption time-dependently upregulated both Ser555-phosphorylated Ulk1 (unc-51 like kinase 1) and Rab9 (Ras-related protein Rab-9) in the mitochondrial fraction. Mitochondria were sequestrated by Rab9-positive ring-like structures in cardiomyocytes isolated from mice after 20 weeks of HFD consumption, consistent with the activation of alternative mitophagy. Increases in mitophagy induced by HFD consumption for 20 weeks were abolished in cardiac-specific ulk1 knockout mouse hearts, in which both diastolic and systolic dysfunction were exacerbated. Rab9 S179A knock-in mice, in which alternative mitophagy is selectively suppressed, exhibited impaired mitophagy and more severe cardiac dysfunction than control mice following HFD consumption for 20 weeks. Overexpression of Rab9 in the heart increased mitophagy and protected against cardiac dysfunction during HFD consumption. HFD-induced activation of Rab9-dependent mitophagy was accompanied by upregulation of TFE3 (transcription factor binding to IGHM enhancer 3), which plays an essential role in transcriptional activation of mitophagy. Conclusions: Ulk1-Rab9-dependent alternative mitophagy is activated during the chronic phase of HFD consumption and serves as an essential mitochondrial quality control mechanism, thereby protecting the heart against obesity cardiomyopathy.