YAP rejuvenates cardiomyocytes by changing mitochondrial substrate utilization

Postnatal cardiomyocyte (CM) maturation, marked by a metabolic transition from glycolysis to fatty acid oxidation, impedes adult CM proliferation and heart regeneration. Our research reveals that Hippo-YAP signaling facilitates CM cell cycle re-entry by reducing lipid utilization in CMs, thereby preserving mitochondrial homeostasis, and promoting CM rejuvenation. On the other hand, overloaded fat by a maternal high-fat diet significantly enhances fatty acid oxidation and maturation in neonatal CMs, counteracting YAP-mediated rejuvenation effects. Through metabolomic and transcriptomic analyses, we discovered that YAP-induced mitochondrial substrate utilization change predominantly depends on reducing Cpt1b activity. Additionally, we identified Mef2 as a crucial activator for CM maturation, which is inhibited upon YAP overexpression, leading to decreased Cpt1b levels in CMs. Our results highlight the heterogeneity and adaptability of neonatal CM energy metabolism and establish YAP as a key regulator of CM substrate utilization. Furthermore, we elucidate a mechanistic framework by which YAP reverses metabolic maturation in cardiomyocytes, thereby facilitating heart regeneration. This insight advances our understanding of metabolic remodeling in heart regeneration and the therapeutic potential of YAP.