Project description: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.
Project description:The role of peroxisome proliferator-activated receptor M-NM-4 (PPARM-NM-4) activation on global gene expression and mitochondrial fuel utilization were investigated in human myotubes. Only 21 genes were up-regulated and 3 genes were down-regulated after activation by the PPARM-NM-4 agonist GW501516. Pathway analysis showed up-regulated mitochondrial fatty acid oxidation, TCA cycle and cholesterol biosynthesis. GW501516 increased oleic acid oxidation and mitochondrial oxidative capacity by 2-fold. Glucose uptake and oxidation were reduced, but total substrate oxidation was not affected, indicating a fuel switch from glucose to fatty acid. Cholesterol biosynthesis was increased, but lipid biosynthesis and mitochondrial content were not affected. This study confirmed that the principal effect of PPARM-NM-4 activation was to increase mitochondrial fatty acid oxidative capacity. Our results further suggest that PPARM-NM-4 activation reduced glucose utilization through a switch in mitochondrial substrate preference by up-regulating pyruvate dehydrogenase kinase isozyme 4 and genes involved in lipid metabolism and fatty acid oxidation. Keywords: Expression profiling by array Human myotubes from four donors were exposed to a PPARM-NM-4 agonist or control for 96 h after which gene expression was profiled.
Project description:The role of mitochondria dynamics and its molecular regulators remains largely unknown during naïve-to-primed pluripotent cell interconversion. Here we report that mitochondrial MTCH2 is a regulator of mitochondrial fusion, essential for the naïve-to-primed interconversion of murine embryonic stem cells (ESCs). During this interconversion, wild-type ESCs elongate their mitochondria and slightly alter their glutamine utilization. In contrast, MTCH2-/- ESCs fail to elongate their mitochondria and to alter their metabolism, maintaining high levels of histone acetylation and expression of naïve pluripotency markers. Importantly, enforced mitochondria elongation by the pro-fusion protein Mitofusin (MFN) 2 or by a dominant negative form of the pro-fission protein dynamin-related protein (DRP) 1 is sufficient to drive the exit from naïve pluripotency of both MTCH2-/- and wild-type ESCs. Taken together, our data indicate that mitochondria elongation, governed by MTCH2, plays a critical role and constitutes an early driving force in the naïve-to-primed pluripotency interconversion of murine ESCs.
