Suppression of Autophagy-Dependent Clearance Mitochondria in Type 2 Diabetes

 描述(申请人提供)：线粒体对能量产生是必不可少的，但如果受损，它们会成为活性氧物种(ROS)和促凋亡因子的主要来源。因此，通过自噬选择性去除功能障碍的线粒体是维持线粒体功能和保存细胞活力的重要机制。我们令人兴奋的初步数据表明，自噬受到抑制，受损的线粒体在糖尿病心脏中积累，这两者都有助于2型糖尿病心脏的心肌细胞凋亡和心功能不全。这一建议的中心假设是，在2型糖尿病心脏中，Sirtuin 1活性降低介导的FoxO1去乙酰化抑制了功能障碍的线粒体的自噬清除，通过p62依赖的caspase-8和/或线粒体ROS的激活加剧了心肌细胞的凋亡，从而导致心肌病。这一假设将通过在动物模型和培养细胞中使用功能增减策略来验证。目的1是确定依赖自噬的线粒体清除缺陷是否会导致糖尿病患者心脏结构和功能的损害，如果是的话，描述其作用机制。在这个目标中，我们将检验这一假说，即在2型糖尿病中，线粒体自噬缺陷通过激活p62依赖的caspase-8和/或线粒体ROS来增强心肌细胞的凋亡，从而导致心肌病。目的2阐明糖尿病心脏线粒体自噬是如何受损的。我们将确定糖尿病抑制的Sirtuin 1信号是否通过下调PINK1和Beclin1来抑制线粒体自噬。这些研究将为糖尿病如何引起心肌病提供新的见解，并通过刺激SIRT1-FoxO1信号调节自噬是预防或延缓糖尿病心肌病的治疗靶点。

 DESCRIPTION (provided by applicant): Mitochondria are essential for energy production, but, if damaged, they become a major source of reactive oxygen species (ROS) and proapoptotic factors. Selective removal of dysfunctional mitochondria via autophagy is therefore an important mechanism to maintain mitochondrial function and preserve cell viability. Our exciting preliminary data suggests that autophagy is suppressed and damaged mitochondria are accumulated in diabetic heart, both of which contribute to cardiomyocyte apoptosis and cardiac dysfunction in Type 2 diabetic hearts. The central hypothesis of this proposal is that reduced Sirtuin 1 activity -mediated deacetylation of FoxO1 in Type 2 diabetic hearts suppresses autophagic clearance of dysfunctional mitochondria, leading to cardiomyopathy by accentuating cardiomyocyte apoptosis through p62-dependent activation of caspase-8 and/or mitochondrial ROS. This hypothesis will be tested by using gain-/loss-of function strategies in both animal models and cultured cells. Aim 1 is to establish if defective autophagy-dependent mitochondrial clearance causes cardiac structural and functional damages in diabetes and if so, delineate the mechanism of action. In this Aim, we will test the hypothesis that defective mitochondrial autophagy causes cardiomyopathy by potentiating cardiomyocyte apoptosis through p62- dependent activation of caspase-8 and/or mitochondrial ROS in Type 2 diabetes. Aim 2 is to elucidate how mitochondrial autophagy becomes impaired in diabetic heart. We will determine whether diabetes-inhibited Sirtuin 1 signaling results in suppression of mitochondrial autophagy through down-regulation of PINK1 and Beclin1. The proposed studies will provide new insights into how diabetes induces cardiomyopathy and the modulation of autophagy via stimulation of SIRT1-FoxO1 signaling is a therapeutic target to prevent or delay cardiomyopathy in diabetes.