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Ian A. Trounce, Nicole Van Bergen, David Mackey, Lisa Kearns, Sandra Staffieri, Jonathan Crowston; Oxidative Phosphorylation Compensation May Preserve Vision In Opa-1-linked Autosomal Dominant Optic Atrophy. Invest. Ophthalmol. Vis. Sci. 2011;52(14):3326.
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© ARVO (1962-2015); The Authors (2016-present)
Patients with Autosomal dominant optic atrophy (ADOA) carrying mutations of the mitochondrial inner membrane fusion protein OPA-1 show large variations in the degree of vision loss. We hypothesized that variable impact on oxidative phosphorylation (OXPHOS) due to genetic modifiers may associate with the variation in clinical severity.
Patients from six large Australian pedigrees with OPA-1-linked ADOA were sampled. We established lymphoblast cell lines from blood lymphocytes from patients with very poor vision (VA less than 6/36, n=8), patients with normal vision (VA 6/9 or better, n=7) and non-OPA-1 mutation controls (n=20). Investigation of mitochondrial function included enzymology and western blotting of OXPHOS complexes, cell respiration and maximal ATP synthesis rates.
ATP synthesis rates were decreased by 49% in poor-vision ADOA patient cells compared with controls (p<0.05), while normal vision patients were not significantly lower than controls. Cell respiration was around 15% higher in normal vision patients compared with both poor vision (p<0.05). OXPHOS enzymology revealed higher activity of complex II+III activity in normal vision patients compared with controls (p<0.01) and trends for higher complex III and IV activities. Immunoblot analysis showed higher levels of complex IV subunits in normal vision patients compared with poor vision patients and controls (p<0.05).
These data suggest that OPA1 deficiency impairs OXPHOS efficiency, but compensation through increases in the distal complexes of the respiratory chain may preserve mitochondrial ATP production in patients who maintain normal vision. Identification of genetic variants that enable this response may provide novel therapeutic insights into OXPHOS compensation for the prevention of vision loss in optic neuropathies.
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