Abstract 261: Evaluating MTCH2 as a Modifier of Cardiomyopathy

Abstract

Background: Cardiomyopathy is a highly heritable disorder that carries a significant risk for heart failure and arrhythmias. The onset, severity, and progression of cardiomyopathy is influenced by genetic variation, with the most common form of inheritance in familial cases being autosomal dominant. All inherited cardiomyopathies are characterized by variable penetrance and expressivity, which in part arises from additional genetic variation, known as genetic modifiers. Methods and Results: Broad genomic profiling of human cardiomyopathy cases identified enriched genetic variation in the gene MTCH2. Specifically, a loss of function variant was found to be enriched in patients with cardiomyopathy. MTCH2 single nucleotide polymorphisms have also been linked to obesity, underscoring a critical role for MTCH2 in metabolic regulation. MTCH2 encodes a mitochondrial carrier protein that has a role in regulating oxidative phosphorylation. In order to investigate fundamental mechanisms by which MTCH2 contributes to cardiac and metabolic phenotypes, we generated a knockdown model of the Drosophila MTCH2 ortholog, Mtch. This knockdown model mimics what is seen in human carriers with the heterozygous loss of function allele. In the Drosophila model, Mtch RNA was reduced by approximately half. We found that cardiac-specific Mtch deficiency in flies produced heart tube dilated and reduced function as well as a shortened life span, documenting a clear role for cardiac Mtch. Cardiac deficiency of Mtch increased circulating lactate levels in flies. Oxygen consumption was reduced in cardiac Mtch deficiency flies in the presence of glucose, but not palmitate. Thus, loss of Mtch2 alters oxygen consumption in a substrate dependent manner. Conclusions: We identified MTCH2 as a modifier of the cardiomyopathy phenotype in humans. Reduction of Mtch in flies resulted in impaired cardiac function and reduced oxygen consumption under certain metabolic condition. As 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.