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OPA1 mutations cause cytochrome c oxidase deficiency due to loss of wild-type mtDNA molecules

Lookup NU author(s): Dr Patrick Yu Wai Man, Kamil Sitarz, Dr David Samuels, Philip Griffiths, Dr Amy Reeve, Professor Rita HorvathORCiD, Professor Patrick Chinnery


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Pathogenic OPA1 mutations cause autosomal dominant optic atrophy (DOA),a condition characterized by the preferential loss of retinal ganglion cells and progressive optic nerve degeneration. Approximately 20% of affected patients will also develop more severe neuromuscular complications, an important disease subgroup known as DOA(+). Cytochrome c oxidase (COX)-negative fibres and multiple mitochondrial DNA (mtDNA) deletions have been identified in skeletal muscle biopsies from patients manifesting both the pure and syndromal variants, raising the possibility that the accumulation of somatic mtDNA defects contribute to the disease process. In this study, we investigated the mtDNA changes induced by OPA1 mutations in skeletal muscle biopsies from 15 patients with both pure DOA and DOA(+) phenotypes. We observed a 2-to 4-fold increase in mtDNA copy number at the single-fibre level, and patients with DOA(+) features had significantly greater mtDNA proliferation in their COX-negative skeletal muscle fibres compared with patients with isolated optic neuropathy. Low levels of wild-type mtDNA molecules were present in COX-deficient muscle fibres from both pure DOA and DOA(+) patients, implicating haplo-insufficiency as the mechanism responsible for the biochemical defect. Our findings are consistent with the 'maintenance of wild-type' hypothesis, the secondary mtDNA deletions induced by OPA1 mutations triggering a compensatory mitochondrial proliferative response in order to maintain an optimal level of wild-type mtDNA genomes. However, when deletion levels reach a critical level, further mitochondrial proliferation leads to replication of the mutant species at the expense of wild-type mtDNA, resulting in the loss of respiratory chain COX activity.

Publication metadata

Author(s): Yu-Wai-Man P, Sitarz KS, Samuels DC, Griffiths PG, Reeve AK, Bindoff LA, Horvath R, Chinnery PF

Publication type: Article

Publication status: Published

Journal: Human Molecular Genetics

Year: 2010

Volume: 19

Issue: 15

Pages: 3043-3052

Print publication date: 18/05/2010

ISSN (print): 0964-6906

ISSN (electronic): 1460-2083

Publisher: Oxford University Press


DOI: 10.1093/hmg/ddq209


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Funder referenceFunder name
Helse Vest (RHF)
Medical Research Council Translational Muscle Centre
Norwegian Research Council
Parkinson's Disease Society (UK)
Academy of Medical Sciences
UK NIHR Biomedical Research Centre in Ageing and Age related disease
Wellcome Trust
G0701386Clinical Research Fellowship
HO 2505/2-1Deutsche Forschungsgemeinschaft