Downregulation of OPA 1 alters mouse mitochondrial morphology , PTP function , and cardiac adaptation to pressure overload Running title : OPA 1 deficit and cardiac mitochondria

Aims: The optic atrophy 1 (OPA1) protein is an essential protein involved in the fusion of the mitochondrial inner membrane. Despite its high level of expression, the role of OPA1 in the heart is largely unknown. We investigated the role of this protein in Opa1 mice, having a 50% reduction in OPA1 protein expression in cardiac tissue. Methods and Results: In mutant mice, cardiac function assessed by echocardiography was not significantly different from that of the Opa1. Electron and fluorescence microscopy revealed altered morphology of the Opa1 mitochondrial network; unexpectedly, mitochondria were larger with the presence of clusters of fused mitochondria and altered cristae. In permeabilized mutant ventricular fibers, mitochondrial functional properties were maintained, but direct energy channeling between mitochondria and myofilaments was weakened. Importantly, the mitochondrial permeability transition pore (PTP) opening in isolated permeabilized cardiomyocytes and in isolated mitochondria was significantly less sensitive to mitochondrial calcium accumulation. Finally, 6 weeks after transversal aortic constriction (TAC), Opa1 hearts demonstrated hypertrophy almost two-fold higher (p<0.01) than in wild type mice with altered ejection fraction (decrease of 43% versus 22% in Opa1 mice, p<0.05). Conclusions: These results suggest that, in adult cardiomyocytes, OPA1 plays an important role in mitochondrial morphology and PTP functioning. These properties may be critical for cardiac function under conditions of chronic pressure overload. in se rm -0 08 71 86 5, v er si on 1 10 O ct 2 01 3 Author manuscript, published in "Cardiovasc Res 2012;94(3):408-17" DOI : 10.1093/cvr/cvs117