Abstract 12935: Age Related Cardiac Dysfunction and Pancreatic β-cell Function in Diabetes Were Improved by P53 Inhibition Through Parkin-mediated Mitophagy

Abstract

Previous studies have demonstrated mitochondrial dysfunction has roles in the progression of several diseases and tumor suppressor p53 has a boarder role that extends to the modulation of mitochondrial homeostasis. Here we show that cytosolic p53 impairs autophagic degradation of damaged mitochondria and facilitates mitochondrial dysfunction during the development of heart failure and diabetes, and that cytosolic p53 binds to Parkin and disturbs its translocation to damaged mitochondria and their subsequent clearance by mitophagy. In heart, prevalence and induction of mitochondrial autophagy is attenuated by senescence or doxorubicin (DOX) treatment. And p53-deficient mice show less decline of mitochondrial integrity and cardiac function reserve with increasing age or after treatment with DOX. And, overexpression of Parkin improves the functional decline in aged heart, and is accompanied by decreased senescence-associated β-galactosidase activity and proinflammatory phenotypes. Furthermore, regarding diabetes, p53 deficiency protects against the development of diabetes in streptozotocin (STZ)-induced type 1 and db/db mouse models of type 2 diabetes. Glucolipotoxicity stimulates NADPH oxidase via RAGE and TLR4. This oxidative stress induces the accumulation of p53 in the cytosolic compartment of pancreatic β cells in concert with ER stress. The occurrence of mitophagy is maintained in STZ-treated p53–/– mice that exhibit preserved glucose oxidation capacity and subsequent insulin secretion signaling, leading to better glucose tolerance. These protective effects are not observed when Parkin is deleted. Besides, pifithrin-α improves mitochondrial dysfunction and glucose intolerance in both STZ-treated and db/db mice. Thus, p53-mediated inhibition of mitophagy modulates dysfunction of heart and islet, raising the possibility that therapeutic activation of mitophagy by inhibiting cytosolic p53 may ameliorate heart failure and diabetes.