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.
Diabetes is devasating disease with severe complications in hearts. In this application, we have proposed a multidisciplinary, integrative and translational approach to validate the hypothesis that defective autophagy-dependent mitochondrial clearance is critical in diabetic cardiomyopathy and to demonstrate that specific modulation of autophagy by stimulating the Sirtuin 1-FoxO1 signaling pathway is a novel approach to prevent heart failure in type 2 diabetic patients.
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