WIPI1-mediated mitophagy dysfunction in ventricular remodeling associated with long-term diabetes mellitus

WIPI1 is a member of the WD-repeat protein family that interacts with phosphoinositides and plays a crucial role in autophagy. This study investigated how WIPI1-mediated mitophagy dysfunction contributes to ventricular remodeling in rat and mouse models of diabetes mellitus.

The study utilized a 32-weeks diabetic animal model to simulate long-term diabetic conditions. AAV9-cTNT-WIPI1 vectors were employed to overexpress WIPI1 in the myocardium. Cardiac function was assessed by echocardiography. Mitochondrial membrane potential was assessed using JC-1 dye. Oxygen consumption rates were quantified using an Oxygraph-O2K high-resolution respirometry.

Long-term diabetes led to decreased ejection fraction and fractional shortening associated with a marked increase in ventricular fibrosis and elevated expression of fibrotic markers such as collagen type I and periostin. Expression of autophagy markers such as LC3b-II and SQSTM1 was reduced, and colocalization with mitochondria was disrupted, suggesting failures in autophagosome formation and maturation. This impairment was further supported by decreased levels of mitophagy-related proteins (PINK and Parkin), indicating impaired mitophagy. WIPI1 knockdown led to mitochondrial dysfunction, characterized by loss of membrane potential and reduced respiratory capacity.

WIPI1 is essential for proper mitophagy function. Its downregulation produces ventricular remodeling and dysfunction. These findings suggest that targeting WIPI1-mediated pathways could be a potential therapeutic strategy for treating diabetic cardiomyopathy by improving mitochondrial health and mitophagic processes.