OPA1 mutation and late-onset cardiomyopathy: mitochondrial dysfunction and mtDNA instability.

Mitochondrial fusion protein mutations are a cause of inherited neuropathies such as charcot-marie-tooth disease and dominant optic atrophy. previously we reported that the fusion protein optic atrophy 1 (opa1) is decreased in heart failure. we investigated cardiac function,mitochondrial function,and mtdna stability in a mouse model of the disease with opa1 mutation. the homozygous mutation is embryonic lethal. heterozygous opa(+/-) mice exhibit reduced mtdna copy number and decreased expression of nuclear antioxidant genes at 3 to 4 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. in addition to small fragmented mitochondria,aged opa1(+/-) mice had impaired cardiac mitochondrial function compared with wild-type littermates. opa1 mutation leads to deficiency in antioxidant transcripts,increased reactive oxygen species,mitochondrial dysfunction,and late-onset cardiomyopathy.