biostudies-literatureChen RKey Technologies Research and Development ProgramNational Natural Science Foundation of ChinaBeijing Natural Science Foundation18https://www.ebi.ac.uk/biostudies/studies/S-EPMC12876099biostudies-literatureUnknown19(1)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 decreasJournal of cardiovascular translational researchMiR-499-5P/PACS2/TRPV1 Axis Maintains Mitochondrial Homeostasis and Left Ventricular Function after Extreme Cold Stress.PMC12876099No. 922493012022YFC36024002022YFA1104500L241026Li HSun NMa YCao FChen SChen RQin CfalseMiR-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 decreas2026-01-01T00:00:00Z2026 Feb2026-07-16T09:40:28.708Z2026-07-09T10:47:09.632ZS-EPMC128760994164476410.1007/s12265-025-10742-8