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P. P. Karunadharma, C. L. Nordgaard, T. W. Olsen, D. A. Ferrington; Mitochondrial DNA Damage in Age-Related Macular Degeneration: Insight Into a Potential Pathologic Mechanism. Invest. Ophthalmol. Vis. Sci. 2010;51(13):4103.
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Increasing evidence suggests a central role for mitochondrial dysfunction in age-related macular degeneration (AMD). Our previous proteomic analysis of the retinal pigment epithelium (RPE) revealed significant mitochondrial protein changes indicative of mitochondrial DNA (mtDNA) defects and damage associated with AMD progression (Nordgaard et al., IOVS 2008). The current study tests the hypothesis that mtDNA damage increases with aging and AMD.
RPE genomic DNA was isolated from the macular region of human donor globes graded for stage of AMD (MGS 1-4). We evaluated region-specific mtDNA damage with normal aging in 45 control subjects (34-88 yrs, MGS 1) and AMD-associated damage in disease subjects compared to age-matched controls (n = 72). Lesions per 10kb in the mtDNA and nuclear DNA were measured using long extension polymerase chain reaction. The level of ‘common deletion’ with age and AMD was measured using quantitative real-time PCR. Amplification of a small 191 bp mtDNA fragment was used to normalize each sample to the total mtDNA content.
With aging, an increase in mtDNA damage was only observed in the ‘common deletion’ region of the mitochondrial genome. With AMD, mtDNA lesions increased significantly in all regions of the mt genome above levels found in age-matched controls. MtDNA was more susceptible to lesions; total damage of the mt genome was 7-fold higher compared to a nuclear gene.
Collectively our data indicates that mtDNA is preferentially damaged with AMD progression. These results suggest a potential mechanistic link between mitochondrial dysfunction, due to increased mtDNA lesions, and AMD pathology.
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