Oxidative damage of mitochondrial DNA in diabetes and its protection by manganese superoxide dismutase.
Retinal mitochondria become dysfunctional in diabetes and the production of superoxide radicals is increased; over-expression of MnSOD abrogates mitochondrial dysfunction and prevents the development of diabetic retinopathy. The mitochondrial DNA (mtDNA) is particularly prone to oxidative damage. The aim of this study is to examine the role of MnSOD in the maintenance of mtDNA. The effect of MnSOD mimic, MnTBAP or over-expression of MnSOD on glucose-induced alterations in mtDNA homeostasis and its functional consequence was determined in retinal endothelial cells. Exposure of retinal endothelial cells to high glucose increased mtDNA damage and compromised the DNA repair machinery. The gene expressions of mitochondrial-encoded proteins of the electron transport chain complexes were decreased. Inhibition of superoxide radicals by either MnTBAP or by over-expression of MnSOD prevented mtDNA damage and protected mitochondrial-encoded genes. Thus, the protection of mtDNA from glucose-induced oxidative damage is one of the plausible mechanisms by which MnSOD ameliorates the development of diabetic retinopathy.
Madsen-Bouterse
Sally A
SA
Department of Ophthalmology, Kresge Eye Institute, Wayne State University, Detroit, MI 48201, USA.
Zhong
Qing
Q
Mohammad
Ghulam
G
Ho
Ye-Shih
YS
Kowluru
Renu A
RA
D000818:Animals; D002417:Cattle; D004249:DNA Damage; D004272:DNA, Mitochondrial / Q000378:metabolism*; D003920:Diabetes Mellitus / Q000201:enzymology* / Q000473:pathology; D003930:Diabetic Retinopathy / Q000201:enzymology* / Q000473:pathology; D042783:Endothelial Cells / Q000201:enzymology / Q000473:pathology; D015870:Gene Expression / Q000187:drug effects; D005947:Glucose / Q000633:toxicity; D008856:Microscopy, Fluorescence; D018384:Oxidative Stress / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013482:Superoxide Dismutase / Q000378:metabolism*
D004272:DNA, Mitochondrial; D013482:Superoxide Dismutase; D005947:Glucose