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18th World Congress on Heart Disease



Anne A. Knowlton, M.D., University of California, Davis, CA, USA


Mitochondrial fusion and fission are essential processes for preservation of normal mitochondrial function. OPA1, a mitochondrial fusion protein, is decreased in both human and rat failing hearts. A number of inherited neuropathies are associated with mutation of fission/fusion proteins, including Charcot-Marie-Tooth (CMT) disease. We hypothesized that mutation of OPA1, one cause of CMT type 2, would lead to cardiac dysfunction via impaired mitochondrial function in the mouse heart. The homozygote mutation B6;C3-Opa1(Q285STOP) mouse, which models autosomal dominant optic atrophy, is embryonic lethal. The heterozygote has a 50% reduction in OPA1 transcript and protein in the heart and was used for our studies. Reduced mtDNA copy number and decreased expression of nuclear antioxidant genes at 3-4 months occurred at 3 months. Although initial cardiac function was normal, at 12 months the OPA1+/- mouse hearts had decreased fractional shortening, cardiac output and myocyte contraction. This coincided with the onset of blindness. Besides small fragmented mitochondria, aged OPA1+/- mouse had impaired cardiac mitochondrial function compared to wild type littermates. In conclusion, OPA1 mutation leads to deficiency in antioxidant transcripts, increased ROS, mitochondrial dysfunction and late onset cardiomyopathy. This has implications for the clinical care of patients with inherited optic neuropathies and raises possibility of OPA1 mutation as cause of idiopathic dilated cardiomyopathy.




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