Opposing effects of genetic variation in MTCH2 for obesity versus heart failure

• Published in: Human molecular genetics 2023-01, Vol.32 (1), p.15-29
• Main Authors: Fischer, Julie A, Monroe, Tanner O, Pesce, Lorenzo L, Sawicki, Konrad T, Quattrocelli, Mattia, Bauer, Rosemary, Kearns, Samuel D, Wolf, Matthew J, Puckelwartz, Megan J, McNally, Elizabeth M
• Format: Article
• Language: English
• Subjects: Adult; Animals; Drosophila; Drosophila Proteins; Fatty Acids - genetics; Fatty Acids - metabolism; Genetic Variation - genetics; Glucose - metabolism; Heart Failure - genetics; Heart Failure - metabolism; Humans; Lactates - metabolism; Mitochondrial Membrane Transport Proteins - genetics; Myocardium - metabolism; Obesity - genetics; Obesity - metabolism; Original
• ISSN: 0964-6906; 1460-2083; 1460-2083
• DOI: 10.1093/hmg/ddac176

Genetic variation in genes regulating metabolism may be advantageous in some settings but not others. The non-failing adult heart relies heavily on fatty acids as a fuel substrate and source of ATP. In contrast, the failing heart favors glucose as a fuel source. A bootstrap analysis for genes with deviant allele frequencies in cardiomyopathy cases versus controls identified the MTCH2 gene as having unusual variation. MTCH2 encodes an outer mitochondrial membrane protein, and prior genome-wide studies associated MTCH2 variants with body mass index, consistent with its role in metabolism. We identified the referent allele of rs1064608 (p.Pro290) as being overrepresented in cardiomyopathy cases compared to controls, and linkage disequilibrium analysis associated this variant with the MTCH2 cis eQTL rs10838738 and lower MTCH2 expression. To evaluate MTCH2, we knocked down Mtch in Drosophila heart tubes which produced a dilated and poorly functioning heart tube, reduced adiposity and shortened life span. Cardiac Mtch mutants generated more lactate at baseline, and they displayed impaired oxygen consumption in the presence of glucose but not palmitate. Treatment of cardiac Mtch mutants with dichloroacetate, a pyruvate dehydrogenase kinase inhibitor, reduced lactate and rescued lifespan. Deletion of MTCH2 in human cells similarly impaired oxygen consumption in the presence of glucose but not fatty acids. These data support a model in which MTCH2 reduction may be favorable when fatty acids are the major fuel source, favoring lean body mass. However, in settings like heart failure, where the heart shifts toward using more glucose, reduction of MTCH2 is maladaptive.