OPA1 mediates cardiac function and metabolism: in silico and in vivo evidence

Abstract OPA1 is an inner mitochondrial membrane protein that mediates diverse signaling processes. OPA1 is important for cardiac function and protects against cardiac insults such as ischemia reperfusion injury. We sought to further assess OPA1 in human and mouse cardiac pathologies, hypothesizing that OPA1 may also function in a protective manner in chronic heart failure. Bioinformatic analyses of histological and transcript data from the GTEx database indicated that OPA1 expression levels vary in the human heart, where elevated OPA1 transcript levels were correlated with fatty acid, branch chain amino acid and contractile gene signatures. To experimentally assess these correlations, mice with a 1.5-fold whole body OPA1 overexpression (OPA1-OE) were subjected to transverse aortic constriction surgery and displayed improved 2D and 4D cardiac functional parameters compared to WT mice. OPA1-OE mice had no induction of fibrotic transcript markers and displayed sustained transcript levels of fatty acid, branch chain amino acid and contractile markers. Maximal oxidative capacity was sustained in both WT and OPA1-OE cardiac myofibers post-TAC. These results further demonstrate the important role of OPA1 in mediating cardiac function and highlight protective signaling pathways.