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J Am Heart Assoc. 2012 Oct;1(5):e003012. doi: 10.1161/JAHA.112.003012. Epub 2012 Oct 25.

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

Author information

1
Department of Medicine, University of California, Davis, CA 95616, USA.

Abstract

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.

KEYWORDS:

OPA1; ROS; cardiomyopathy; mitochondrial fusion; mtDNA

PMID:
23316298
PMCID:
PMC3541627
DOI:
10.1161/JAHA.112.003012
[Indexed for MEDLINE]
Free PMC Article

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