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B. F. Godley, H. Xu, A. Havey, X. Zhong, H. Lin, M. E. Boulton; Mitochondrial DNA Repair Capacity Decreases With Progression of Age-Related Macular Degeneration. Invest. Ophthalmol. Vis. Sci. 2008;49(13):4548.
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We have previously demonstrated that the frequency of mitochondrial DNA (mtDNA) damage correlates with progression of age-related macular degeneration. We have extended this observation to determine whether macular RPE cells exhibit less mtDNA repair capability than peripheral RPE cells in the aged human population, and if dysfunctional repair is associated with age-related macular degeneration (AMD).
Macular and peripheral RPE cells were isolated and cultured from human donor eyes of different ages and from AMD patients graded according to the Minnesota Grading System. Confluent primary RPE cells were used to test the frequency of endogenous mtDNA damage by quantitative PCR. To test the mtDNA repair capacity, cultured RPE cells were allowed to recover after exposure to H2O2 (200 µM for 1hr) for up to 12 hours and repair assessed by quantitative PCR. The expression levels of enzymes associated with mtDNA repair were analyzed by Western Blot.
Macular RPE cells exhibited greater mtDNA damage than those of peripheral RPE cells and the degree of mtDNA damage increased with the severity of AMD. mtDNA repair capacity was 30% greater in RPE cells from young donors compared with old donors. RPE cells from peripheral retina show 25% greater mtDNA repair capacity compared with RPE cells from the macular region. The reduction in mtDNA repair capacity was significantly greater in macular RPE cells from AMD patients compared to their normal aged-matched counterparts (p<0.05). The mtDNA repair capacity negatively correlated with the progression of AMD. This decrease in mtDNA repair was associated with a reduction in the expression levels of a number of mtDNA repair enzymes including OGG1, DNA polymerase γ and DNA ligase III.
Mitochondrial DNA repair is impaired in AMD and this may be in part due to a loss of activity of key enzymes in the mtDNA repair pathway. The findings highlight the possibility that the mtDNA repair system may serve as a potential target for pharmaceutical intervention and gene therapy in AMD
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