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Shikha Tewari, Qing Zhong, Renu Kowluru; Mitochondrial DNA Replication And The Metabolic Memory Phenomenon Associated With Diabetic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2011;52(14):4453. doi: https://doi.org/.
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Diabetic retinopathy continues to progress after the hyperglycemic insult is terminated, suggesting a metabolic memory phenomenon. We have shown that retinal mitochondria continue to be dysfunctional with its DNA (mtDNA) damaged even after reversal of hyperglycemia in rats. Integrity of mtDNA is maintained by DNA- repair and replication machinery which includes the DNA polymerase gamma (POLG) and the mtDNA helicase (Twinkle). POLG, a holoenzyme with its two subunits, POLG 1 (catalytic unit) and POLG 2 (DNA-binding unit), works with Twinkle to replicate mitochondrial genome. The aim of this study is to investigate the role of mtDNA replication machinery in the metabolic memory phenomenon associated with diabetic retinopathy.
Diabetes was induced in Wistar rats by streptozotocin, and a group of diabetic rats were maintained in poor glycemic control (PC, glycated hemoglobin-GHb >11%) for 2 months followed by good glycemic control (GC, GHb <5.5%) for 2 additional months (PC-GC). The rats maintained in PC or GC or remained normal for the entire duration served as controls. Gene expression of POLG1, POLG2 and Twinkle helicase was analyzed in the retina by quantitative real time PCR, and their protein expression was quantified by western blot technique.
Transcripts of POLG1 and Twinkle were decreased by about 25-60% in the retina obtained from rats in PC group, but that of POLG2 were significantly increased. This was accompanied by similar alterations in the protein expressions. Re-institution of GC after a period of PC (PC-GC) had no effect on retinal DNA replication machinery, and the gene and protein expression remain similar to those obtained from the PC group. Institution of good control immediately after induction of diabetes, however, protected any alterations in these enzymes, and the values were not different from those obtained from age-matched normal rats.
Continued alterations in retinal POLGs and Twinkle helicase after reversal of hyperglycemia suggests that the mtDNA replication machinery remains compromised and has a significant role in the metabolic memory phenomenon associated with the progression of diabetic retinopathy. Thus, regulation of DNA replication system presents a possible therapeutic target for diabetic retinopathy.
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