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R. A. Kowluru, S. A. Madsen-Bouterse; Diabetic Retinopathy and Mitochondrial Genome Instability of the Retina. Invest. Ophthalmol. Vis. Sci. 2009;50(13):4803.
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In the pathogenesis of diabetic retinopathy retinal mitochondria are dysfunctional and superoxide levels are elevated, and these abnormalities continue to persist after cessation of hyperglycemia. The mitochondrial genome (mtDNA) is highly sensitive to oxidative damage. The aim is to investigate the effect of diabetes on retinal mtDNA damage and repair.
Retina was analyzed from rats maintained in poor glycemic control (PC) for 7 months (glycated hemoglobin>11%). To investigate the effect of reversal of hyperglycemia on mtDNA, retina was also obtained from rats in PC for 5 months followed by good control (GHb<7%; PC-GC) for 2 additional months. Mitochondrial DNA damage was determined using genome specific quantitative extended length PCR. DNA repair was evaluated by measuring retinal transcripts of DNA glycosylases, 8-oxoguanine DNA glycosylase (OGG1) and MutY homolog (MYH), and their mitochondrial protein expressions.
Amplification of mtDNA was reduced by 60% in PC rats compared to the age-matched normal rats, indicating increased damage. Although the gene transcripts of the repair enzymes in the retina were increased by about 4 fold in PC group, the mitochondrial protein expressions of OGG1 and MYH remained subnormal. Two months of GC following 5 months of PC had no significant effect on mtDNA damage.
The retinal mitochondrial genome becomes highly susceptible to damage in diabetes. The retina attempts to initiate repair by making more transcripts for glycosylases, but the mitochondrial repair mechanism remains ineffective. Thus, this inefficiency of mtDNA maintenance could be, in part, responsible for mitochondrial dysfunction and increased superoxide that are implicated in the development and progression of diabetic retinopathy.
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