Abstract P397: MTCH2 As A Modifier Of Cardiomyopathy

Background: Cardiomyopathy is a highly heritable disorder that carries a significant risk for heart failure and arrhythmias. Most inherited cardiomyopathies are characterized by variable penetrance and expressivity, which in part arises from additional genetic variation, known as genetic modifiers. Methods and Results: Genomic profiling of human cardiomyopathy cases identified enriched genetic variation in the gene MTCH2. Specifically, a truncating variant was found to be overrepresented in patients with cardiomyopathy compared to controls. MTCH2 encodes a mitochondrial carrier protein that has a role in regulating oxidative phosphorylation. To investigate fundamental mechanisms by which MTCH2 contributes to cardiac and metabolic phenotypes, we generated a knockdown model of the Drosophila MTCH2 ortholog, Mtch. We found that cardiac-specific Mtch reduction in flies produced heart tube dilation and reduced function as well as a shortened life span, documenting a clear role Mtch in the myocardium. Metabolomic profiling demonstrated cardiac deficiency of Mtch lowered the flux of glucose-derived metabolites to the citric acid cycle associated with reduced downstream oxygen consumption and ATP synthesis, causing an energy deficit. We generated a deletion of MTCH2 using gene editing in HEK293 cells. Similar to the fly model, these cells demonstrated reduced oxygen consumption in the presence of glucose, but not fatty acids, and had a higher level of inhibitory phosphorylation of pyruvate dehydrogenase, a critical regulator of glucose metabolism. These data suggest MTCH2 influences the efficiency of glucose oxidation and substrate usage, an important mode of cardiac energy generation, especially in the setting of heart failure. Conclusions: We identified MTCH2 as a modifier of the cardiomyopathy phenotype in humans. Reduction of MTCH2 resulted in impaired cardiac function with reduced oxygen consumption and increased glycolysis in a substrate dependent manner. Since failed hearts are more dependent on glycolysis, these data support that reduction of MTCH2 promotes heart failure and provides a mechanism by which MTCH2 acts as a deleterious genetic modifier in heart failure.