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

Area of Science:

• Cardiovascular Biology
• Cellular Metabolism
• Autophagy Research

Background:

• WIPI1, a WD-repeat protein, interacts with phosphoinositides and is vital for autophagy.
• Mitophagy, a selective form of autophagy, clears damaged mitochondria.
• Diabetic cardiomyopathy involves ventricular remodeling and dysfunction.

Purpose of the Study:

• To investigate the role of WIPI1-mediated mitophagy dysfunction in diabetic ventricular remodeling.
• To explore WIPI1's impact on cardiac function and mitochondrial health in diabetes.

Main Methods:

• Utilized a 32-week diabetic rat and mouse model.
• Employed AAV9-cTNT-WIPI1 vectors for myocardial WIPI1 overexpression.
• Assessed cardiac function (echocardiography), mitochondrial membrane potential (JC-1), and oxygen consumption (respirometry).

Main Results:

• Long-term diabetes induced decreased ejection fraction, fibrosis, and elevated fibrotic markers.
• Reduced autophagy markers (LC3b-II, SQSTM1) and impaired mitophagy (decreased PINK, Parkin) were observed.
• WIPI1 knockdown resulted in mitochondrial dysfunction, including loss of membrane potential and reduced respiratory capacity.

Conclusions:

• WIPI1 is essential for effective mitophagy.
• Downregulation of WIPI1 contributes to ventricular remodeling and dysfunction in diabetes.
• Targeting WIPI1 pathways may offer a therapeutic strategy for diabetic cardiomyopathy.