Journal
JOURNAL OF THE AMERICAN HEART ASSOCIATION
Volume 1, Issue 5, Pages -Publisher
WILEY
DOI: 10.1161/JAHA.112.003012
Keywords
cardiomyopathy; mitochondrial fusion; mtDNA; OPA1; ROS
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Funding
- National Institutes of Health [HL077281, HL079071]
- Veterans Affairs Merit Award
- Medical Research Council [G108/523, G0700949] Funding Source: researchfish
- MRC [G0700949, G108/523] Funding Source: UKRI
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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.
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