MiR-499-5P/PACS2/TRPV1 Axis Maintains Mitochondrial Homeostasis and Left Ventricular Function after Extreme Cold Stress

Exposure to cold environments is physiologically challenging, with extreme cold stress (ECS) impairing the function of the left ventricle (LV) of the heart. We aimed to determine the role and mechanism of action of the miR-499-5p/phosphofurin acidic cluster sorting protein 2 (PACS2)/transient receptor potential cation channel subfamily V member 1 (TRPV1) axis in ECS-induced cardiomyocyte injury and LV dysfunction. Mice were placed in a -20 °C chamber to simulate an extremely cold environment. MiR-499-5p overexpression in the mice decreased PACS2 levels, and mitochondrial function was inhibited in vivo following ECS. Inhibiting miR-499-5p enhanced PACS2 expression, thereby reversing the structural and functional LV deficits caused by ECS. Cardiac-specific Pacs2 knock-in restored the decreases in mitophagy and mitochondrial energy metabolism caused by ECS via enhancing endoplasmic reticulum-mitochondrial calcium flux through TRPV1, a nonselective calcium channel. The findings indicate targets for preventing cardiac disease during exposure to extremely cold environments.