Cardiac regulation of heart failure and obesity

Northwestern University At Chicago, Evanston IL

Investigators

Abstract

PROJECT SUMMARY/ABSTRACT Heart failure impacts over 5 million Americans annually. Obesity increases risk factors associated with heart failure. The gene MTCH2 has genetic variants that associate with both cardiomyopathy and obesity. The human genetic data support that reduction of MTCH2 protein increases the risk for cardiomyopathy and promotes a reduction in body mass. MTCH2 encodes an outer mitochondrial membrane protein important for mitochondrial dynamics and metabolism, and MTCH2 protein was recently identified as an insertase for outer mitochondrial membrane proteins. To study the role of cardiac Mtch2 in the heart, we created cardiomyocyte- specific Mtch2 KO mice (cMtch2 KO). cMtch2 KO mice develop decreased systolic function in males earlier than female mice. Male cMtch2 KO mice have reduced fat mass compared to controls prior to systolic dysfunction. cMtch2 KO mice fail to hypertrophy their hearts in response to isoproterenol challenge, and instead lose function and lose a large percentage of their body mass compared to controls. These data support the idea that deletion of cardiac Mtch2 induces mitochondrial dysfunction and increases energetics to maintain cardiac contraction at the cost of body fat. When challenged by a stressor, such as aging or isoproterenol, the damaged mitochondria can no longer increase energetics required to maintain function. To explore the mechanism by which reduced MTCH2 protein results in damaged mitochondria, we performed mass spectrometry on mitochondria isolated from cMtch2 KO hearts revealing a significant decrease in FUNDC2, a potential target of Mtch2’s insertase function. FUNDC2 is linked to mitochondrial dynamics, apoptosis/autophagy, and activation of the transcription factor SREBP1. I hypothesize that reduction of MTCH2 sensitizes the heart to diet-induced cardiomyopathy due to mis-insertion of FUNDC2. In Aim 1 of this proposal, I will overexpress FUNDC2 in cMtch2 KO mice and determine if restoring FUNDC2 to the mitochondria rescues both the development of cardiomyopathy and impaired body composition. In Aim 2, I will measure how MTCH2 influences mitochondrial interactions with the sarcoplasmic reticulum and sarcomere. In Aim 3, I will test if globally reducing Mtch2 leads to cardiomyopathy when sensitized by high fat diet. The data gathered from these aims will elucidate the mechanism by which removal or reduction of MTCH2 from the mitochondrial outer membrane induces mitochondrial dysfunction, sarcomere dysfunction, and ultimately, impaired heart function.