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OPA1 mutation and late-onset cardiomyopathy: Mitochondrial dysfunction and mtDNA instability

Chen, L., Liu, T., Tran, A., Lu, X., Tomilov, A. A., Davies, V., Cortopassi, G., Chiamvimonvat, N, Bers, D. M., Votruba, Marcela and Knowlton, A. A. 2012. OPA1 mutation and late-onset cardiomyopathy: Mitochondrial dysfunction and mtDNA instability. Journal of the American Heart Association , e003012. 10.1161/JAHA.112.003012

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Optometry and Vision Sciences
Neuroscience and Mental Health Research Institute (NMHRI)
Subjects: R Medicine > RC Internal medicine
R Medicine > RE Ophthalmology
Additional Information: Pdf uploaded in accordance with publisher's policy at http://www.sherpa.ac.uk/romeo/issn/2047-9980/ (accessed 25/02/2014).
Publisher: American Heart Association
ISSN: 0041-008X
Date of First Compliant Deposit: 30 March 2016
Last Modified: 04 Jun 2017 04:44
URI: http://orca.cf.ac.uk/id/eprint/43741

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