Abstract P230: Orchestration of Cardiac Mitochondrial Biogenesis by Mitofusin2

Mitochondria generate energy and play central roles governing cell signaling and programmed death. As an energy dependant tissue, the heart is more affected by mitochondrial dysfunction than other tissues. Mitochondrial fusion and fission are essential for normal morphology and function. Mitofusins Mfn1 and Mfn2 are the key components to process mitochondrial fusion. Previous data shows that Mfn1 and Mfn2 are functional redundant in skeletal muscle and the drosophila heart tube. But the role for the mitochondrial fusion proteins in mammalian cardiac myocytes is unknown. The functional role of mitofusins in the mammalian heart was investigated by conditional gene deletion of Mfn1 and Mfn2 in mice. Mice with myh6Cre-directed inactivation of Mfn1 exhibited normal cardiac structure and function. In contrast, ablation of Mfn2 in mouse heart caused progressive dilated cardiomyopathy. At 6 weeks old, the cardiac structure and function were normal, but at 16 weeks old, Mfn2 null mice developed severe cardiac dilation and impaired contractile performance at baseline and in response to β-adrenergic stimulation without induction of programmed cell death. Cardiomyocytes from young Mfn2 null mice had normal excitation-contraction coupling, whereas older cardiomyocytes showed decreased fractional shortening with normal calcium cycling. mRNA resequencing of Mfn2 null hearts revealed that cardiac dysfunction was associated with induction of nuclear-encoded mitochondrial genes. Mfn2 deficient cardiac mitochondria displayed normal function of the mitochondrial permeability transition, respiration and expression of respiration chain complexes, but increased mitochondrial oxidant stress. Remarkably, the development of cardiomyopathy paralleled dramatic (60-80%) loss of mitochondria, measured both as the ratio of mitochondrial DNA to nuclear DNA, and as μg protein/mg cardiac protein. Conclusion: 1. Mfn1 and Mfn2 are not redundant in the heart.Mfn1 is dispensable for normal cardiac development and function. 2. Mfn2 deficiency reacts in a dilated cariomyopathy caused not by a failure of mitochondrial function, but by a crisis of mitochondrial biogenesis.