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Nicole J. Van Bergen, George Kong, Vicki Chrysostomou, Ian Trounce, Jonathon Crowston; Mice With A mtDNA-linked Respiratory Chain Defect Show Increased Neuronal Injury Consequent To IOP Stress. Invest. Ophthalmol. Vis. Sci. 2011;52(14):2439.
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Our previous work has demonstrated that retinal ganglion cells of old mice (12 and 18-month) have increased vulnerability to short term IOP elevation compared to young (3-month) mice. To determine whether age-associated mitochondrial dysfunction might contribute to this increased vulnerability, we here investigated whether a novel mouse with impairment in mitochondrial OXPHOS also has increased the susceptibility to IOP elevation.
Mice harbouring interspecific mtDNA mutations (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 elevation (50mm Hg for 30 minutes, n>8 mice). To characterize the mitochondrial defect in the retina and brain of these mice, we measured retinal and brain mitochondrial respiration (n=6) with the Oroboros Oxygraph 2k. We also quantified OXPHOS protein levels by western blotting.
Xeno-mito (n>6) mice showed a 52% greater loss of ganglion cell function, in response to IOP stress, and a delayed recovery compared to age-matched wild type mice. (p<0.05) which persisted at one week and was associated with increased oxidative stress, demonstrated by elevated HO-1. Detailed investigation of OXPHOS in the retina and brain demonstrated a significant decrease in complex I driven ATP production with mitochondrial respiration decreased by 18% in 12 month Xenos (p=0.019) and by 16% in 18+ month Xenos (p=0.020). There was also a 55% decreased complex I expression (p<0.05) in the retina. Other complexes were not significantly altered, with the exception of complex IV which appeared upregulated in the xeno-mito mice.
Defective OXPHOS complex-1 impairs retinal function in these mice and increases vulnerability to IOP elevation. The Xeno-mito mice provide insight into the in vivo effects mtDNA-linked OXPHOS defects on neural retinal function and may provide further mechanistic insight into how age-related mitochondrial failure may contribute to ganglion cell vulnerability to IOP elevation.
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