OPA1 Mutation and Late‐Onset Cardiomyopathy: Mitochondrial Dysfunction and mtDNA Instability

• Published in: Journal of the American Heart Association 2012-10, Vol.1 (5), p.e003012-n/a
• Main Authors: Chen, Le, Liu, Tingting, Tran, Alice, Lu, Xiyuan, Tomilov, Alexey A., Davies, Vanessa, Cortopassi, Gino, Chiamvimonvat, Nipavan, Bers, Donald M., Votruba, Marcela, Knowlton, Anne A.
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Blotting, Western; Cardiomyopathies - genetics; cardiomyopathy; Disease Models, Animal; DNA, Mitochondrial - genetics; Genomic Instability; GTP Phosphohydrolases - genetics; Mice; Mitochondria - genetics; mitochondrial fusion; mtDNA; Mutation; OPA1; Original Research; Polymerase Chain Reaction; Reactive Oxygen Species; ROS
• ISSN: 2047-9980; 2047-9980
• DOI: 10.1161/JAHA.112.003012

Background 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. Methods and Results 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. Conclusions OPA1 mutation leads to deficiency in antioxidant transcripts, increased reactive oxygen species, mitochondrial dysfunction, and late‐onset cardiomyopathy.