Lipid-induced NOX2 activation inhibits autophagic flux by impairing lysosomal enzyme activity

Area of Science:

• Cardiovascular Biology
• Cellular Metabolism
• Autophagy Research

Background:

• Autophagy is crucial for cellular homeostasis, but its role in obesity-related heart dysfunction is unclear.
• Obesity can adversely affect cardiac structure and function, with altered autophagy potentially contributing.

Purpose of the Study:

• To investigate the impact of fatty acid overload on cardiac autophagy in obesity.
• To elucidate the molecular mechanisms linking lipotoxicity to impaired autophagic flux in cardiomyocytes.

Main Methods:

• Utilized high-fat-fed murine hearts and palmitate-treated H9C2 cardiomyocytes.
• Assessed autophagosome clearance, NADPH oxidase 2 (Nox2) activation, lysosomal acidification, and enzyme activity.
• Investigated the role of protein kinase Cs (PKCs), specifically PKCβII, in palmitate-induced Nox2 activation.

Main Results:

• High-fat diet and palmitate treatment suppressed autophagosome clearance and activated Nox2 in cardiac cells.
• Impaired lysosomal acidification and enzyme activity, due to superoxide production, caused defective autophagosome clearance.
• Inhibition of Nox2 restored lysosomal function and reduced autophagosome accumulation.
• Palmitate-induced Nox2 activation was dependent on PKCβII activation.

Conclusions:

• Reveals a novel mechanism where lipotoxicity impairs cardiac autophagy via a PKCβ-Nox2-mediated pathway.
• This pathway disrupts pH-dependent lysosomal enzyme activity, diminishing autophagic turnover in cardiomyocytes.
• Findings highlight a potential therapeutic target for obesity-induced heart disease.