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Ian A. Trounce, Nicole Van Bergen, George Kong, Vicki Chrysostomou, Carl A. Pinkert, Jonathan G. Crowston; Increased Neuro-retinal Injury After Intraocular Pressure Elevation In Xenomitochondrial Mice And Compensation By Oxphos Complex IV. Invest. Ophthalmol. Vis. Sci. 2012;53(14):6571.
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© ARVO (1962-2015); The Authors (2016-present)
To characterise age-related mitochondrial dysfunction in the retina of the xenomitochondrial mouse and determine how this renders retinal ganglion cells (RGCs) more vulnerable to injury induced by acute eye pressure elevation.
Mice harbouring an interspecific mtDNA (Xeno-mito mice) on a C57BL6 background and strain-matched controls were subjected to full-field (ganzfeld) scotopic electroretinogram (ERG) to assess retinal function at baseline and during IOP stress (50mm Hg for 30 minutes, n>8 mice). Retinal and brain mitochondrial respiration (n=6) was measured by high resolution respirometer. Retinas (n=6) were examined by western blotting for oxidative phosphorylation (OXPHOS) complex protein levels. RT-PCR was used to measure mtDNA encoded transcripts, and Blue Native PAGE to examine OXPHOS complex assembly.
The Xeno-mito mice showed no baseline impairment on ERG. In response to IOP stress, Xeno-mito mice showed a 91% loss of ganglion cell function one week post injury compared with a 46% reduction in controls (p<0.05). Complex I driven mitochondrial respiration in the retina was decreased by 18% in 12 month Xeno mice (p=0.019) and by 16% in 18+ month Xeno mice (p=0.020). We found an age related decrease in complex I expression in xeno retinas, with a 46% decrease by 18 months (P<0.05), and 58% by 24 months (P<0.001). In both the retina and the brain we found significant increases in complex IV expression, activity and assembly in younger xeno animals which may be a compensation for the impaired complex I. The levels of complex IV decreased more than in WT mice with age, suggesting loss of this compensation with aging. RT-PCR showed 3-fold increased cytochrome oxidase subunit II transcript levels in 3 month old animals (p<0.001) that decreased to WT levels by 12 months of age.
Xeno-mito mice provide insight into the in vivo effects mtDNA-linked OXPHOS defects on neural retinal function. The Xeno-mito mice have defective complex I in the retina and brain. This defect manifests when the neural retina is exposed to aging and IOP stress. Upregulation of complex IV may compensate age-related decline of complex I.
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