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 ORCID: https://orcid.org/0000-0002-7680-9135 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:	12 May 2023 21:23
URI:	https://orca.cardiff.ac.uk/id/eprint/43741

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