An 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 overload and doxorubicin treatment, preventing mitochondrial dysfunction. Accordingly, the treatment with the lipid oxidation inhibitor Trimetazidine concomitantly with stressful stimuli limits ROS accumulation and prevents long-term heart dysfunction. These findings disclose a physiologic mechanism of metabolic regulation in the heart and demonstrate that a timely restriction of lipid metabolism represents a potential therapeutic strategy to improve cardiac resilience to stress. Synopsis FAO is catalyzed by the mitochondrial trifunctional protein (MTP) and, if overloaded, generates ROS. ROS are boosted during stressful events, favoring cardiac maladaptive remodeling. Melusin is a muscle-specific chaperone able to sustain heart resilience during a wide variety of stressful insults. Melusin interacts and inhibits the MTP, restraining FAO and ROS generation in the myocardium. Heart resilience depends on the rate of FAO during stressful events occurrence. Inhibiting lipid metabolism in a timely manner during stress protects the heart from dysfunction and prolongs the survival in preclinical models. FAO is catalyzed by the mitochondrial trifunctional protein (MTP) and, if overloaded, generates ROS. ROS are boosted during stressful events, favoring cardiac maladaptive remodeling. Melusin is a muscle-specific chaperone able to sustain heart resilience during a wide variety of stressful insults.