biostudies-literatureSorge MAssociazione Italiana per la Ricerca sul CancroProgetto di Ricerca Nazionale 2022 PNRRNIDDK NIH HHSProgetto di Ricerca di Interesse Nazionale 2015NHLBI NIH HHSHHS | NIH | National Heart, Lung, and Blood InstituteCompagnia di San Paolo (CSP)Compagnia di San Paolo2450-2484https://www.ebi.ac.uk/biostudies/studies/S-EPMC11473679biostudies-literatureUnknown16(10)Defining the molecular mechanisms underlying cardiac resilience is crucial to find effective approaches to protect the heart. A physiologic level of ROS is produced in the heart by fatty acid oxidation, but stressful events can boost ROS and cause mitochondrial dysfunction and cardiac functional impairment. Melusin is a muscle specific chaperone required for myocardial compensatory remodeling during stress. Here we report that Melusin localizes in mitochondria where it binds the mitochondrial trifunctional protein, a key enzyme in fatty acid oxidation, and decreases it activity. Studying both mice and human induced pluripotent stem cell-derived cardiomyocytes, we found that Melusin reduces lipid oxidation in the myocardium and limits ROS generation in steady state and during pressure overlEMBO molecular medicineAn intrinsic mechanism of metabolic tuning promotes cardiac resilience to stress.PMC11473679IG29250CSTO165798P30 DK017047IG21408R01 HL1497342015EASE8ZP20225EMBTPenna CSorge MRaimondi ATacchetti CRiganti CBertero ANattenberg GMoiso ERaffaelli NGallo AGhigo ATarone GHirsch ESbroggio MTurco ESavore GZamporlini FBrancaccio MCorsetto PPagliaro PVelasco SStefania RFemmino SBalmas EAltruda FPinton PSniadecki NJSilengo LAcquarone DMorciano GRizzo AMfalseAn intrinsic mechanism of metabolic tuning promotes cardiac resilience to stress.Defining the molecular mechanisms underlying cardiac resilience is crucial to find effective approaches to protect the heart. A physiologic level of ROS is produced in the heart by fatty acid oxidation, but stressful events can boost ROS and cause mitochondrial dysfunction and cardiac functional impairment. Melusin is a muscle specific chaperone required for myocardial compensatory remodeling during stress. Here we report that Melusin localizes in mitochondria where it binds the mitochondrial trifunctional protein, a key enzyme in fatty acid oxidation, and decreases it activity. Studying both mice and human induced pluripotent stem cell-derived cardiomyocytes, we found that Melusin reduces lipid oxidation in the myocardium and limits ROS generation in steady state and during pressure overl2024-01-01T00:00:00Z2024 Oct2026-07-15T05:33:40.51Z2025-04-04T08:21:24.087ZS-EPMC114736793927195910.1038/s44321-024-00132-z