The mitochondria-associated membrane protein PACS2 promotes mitophagy and energy metabolism to maintain right cardiac function in hypobaric hypoxia exposure

Hypobaric hypoxia (HH) is the primary challenge at high altitude. Prolonged HH exposure impairs right cardiac function. Mitochondria-associated membrane (MAM) plays a principal role in regulating mitochondrial function under hypoxic conditions, but the mechanism remains poorly understood. In this study, proteomics analysis identified that PACS2, a key protein in MAM, and mitophagy were down-regulated in HH conditions. Metabolomics analysis indicated suppression of aerobic oxidation of glucose and fatty acids. Cardiomyocyte Pacs2 deficiency disrupted MAM formation and endoplasmic reticulum (ER)-mitochondria calcium flux further inhibiting mitophagy and mitochondrial energy metabolism during HH exposure. Overexpression of Pacs2 reversed these effects. Cardiac-specific knockout of Pacs2 exacerbated mitophagy inhibition, cardiomyocyte injury and right cardiac dysfunction induced by HH. Knock-in of Pacs2 recovered HH-induced RV structural and functional impairment. Thus, PACS2 is essential for protecting cardiomyocytes through mechanisms of ER-mitochondria calcium flux, mitophagy, and mitochondrial energy metabolism, thereby maintaining right cardiac function at high altitude.