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Shikha Tewari, Renu Kowluru; Regulation Of Mitochondrial DNA Damage And POLG In Diabetic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2012;53(14):5422.
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© ARVO (1962-2015); The Authors (2016-present)
In the pathogenesis of diabetic retinopathy, increased superoxide levels precede mitochondria dysfunction and capillary cell apoptosis, mitochondrial DNA (mtDNA) is damaged, and the damage is selectively higher at the D-loop region, the regulatory region of the mtDNA. Mitochondria are equipped with an efficient DNA replication system consisting of DNA polymerase gamma (POLG) and mtDNA helicase (Twinkle). The aim of this study is to investigate temporal relationship between increased mtDNA damage and the mtDNA regulating enzyme POLG.
Damage to the D-loop region of mtDNA and POLG was measured in the retina of streptozotocin-induced diabetic rats at 15 days (a duration when superoxide levels are increased but the mitochondria remain intact) to 6 months (dysfunctional mitochondria) after induction of diabetes. Mitochondrial level of the replication enzyme was measured by western blot technique. The results were confirmed in the retinal endothelial cells, the site of histopathology of diabetic retinopathy, exposed to high (20mM) glucose for 6 hours to 8 days.
In the early stages of diabetes (15 days), despite increased superoxide levels in the retina, the D-loop region of mtDNA was not damaged, but POLG was significantly increased. At two months of diabetes, superoxide levels remained significantly elevated but POLG levels became normal. After 4 months of diabetes, the D-loop region was damaged, however, this damage was accompanied by decreased POLG, and similar damage to the D-loop and decrease in POLG was observed at 6 months of diabetes. Consistent with the in vivo data, exposure of retinal endothelial cells to high glucose for 6 hours increased oxidative stress and POLG, but after 48 hours of glucose exposure, POLG levels became normal. However, 4 days of high glucose insult damaged the D-loop region and decreased the POLG, and the process continued for up to 8 days of high glucose exposure.
In the initial stages of hyperglycemic insult, POLG is upregulated to protect the damage to the mtDNA induced by increased superoxide. But chronic exposure to superoxide radicals overwhelms the replication/repair system of the retina and the damaged mtDNA propagates the vicious cycle, and mitochondria become dysfunctional initiating the apoptotic machinery. This further strengthens the importance of early and sustained glycemic control for a diabetic patient to prevent/inhibit the development of diabetic retinopathy.
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