Abstract Body: Introduction: MTCH2 is an outer mitochondrial membrane protein insertase and variants in MTCH2 associate with human heart failure and obesity.

Hypothesis: Lower levels of MTCH2 predispose the heart to stress.

Methods and Results: Cardiomyocyte-specific Mtch2 KO (cMtch2 KO) mice were generated and develop systolic dysfunction accompanied by increased fibrosis and elevation of heart failure markers (n=6). Prior to the development of cardiac dysfunction male cMtch2 KO mice maintain a leaner body mass compared to controls, consistent with the idea that cardiac MTCH2 drives whole body energy utilization. We hypothesize the increased energetic demand of maintaining cardiac function in younger animals shifts energy expenditure and results in lower fat mass. We found that young, pre-cardiomyopathic cMtch2 KO mice were sensitized to stress. When young cMtch2 KO mice were challenged to an acute dosing regimen of isoproterenol, compared to controls, hearts from cMtch2 KO mice failed to respond with physiological hypertrophy and animals could not maintain body mass (n=7). We assessed mitochondrial function in cMtch2 KO mice. Isolated cMtch2 KO cardiomyocytes loaded with Mitotracker green and TMRE had reduced mitochondrial membrane potential compared to control (n=20 cells/mouse, 3 mice/group). In the presence of glucose, oxygen consumption rates were reduced in cMtch2 KO heart tissue (n=6), and targeted metabolomics of cMtch2 KO ventricle exhibited an accumulation of palmitate (n=4), indicating cMtch2 KO hearts do not efficiently utilize glucose and fatty acids. To identify changes in the mitochondrial proteome we performed mass spectrometry on isolated mitochondria from control and cMtch2 KO mice (n=4). Overall, proteins associated with fatty acid beta oxidation and pyruvate metabolism were reduced in abundance in cMtch2 KO hearts compared to control. Additionally, three potential insertase target proteins were reduced, confirming a critical role for MTCH2 in mitochondrial health.

Conclusion: MTCH2 is vital for maintaining normal mitochondrial function. Reduction of MTCH2 sensitizes the heart to stress, resulting in impaired mitochondrial, sarcomere, and global heart function with effects on body composition.