| Damage to the Mitochondrial DNA Replication Machinery and the Development of Diabetic Retinopathy. | |
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MedLine Citation:
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PMID: 22229649 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Aim: In the pathogenesis of diabetic retinopathy, retinal mitochondria are damaged, superoxide levels are elevated and mitochondrial DNA (mtDNA) biogenesis is impaired. MtDNA has a non-coding region, D-loop, which has essential transcription and replication elements, and this region is highly vulnerable to oxidative damage. The aim of this study is to investigate the effect of diabetes on the D-loop damage and the mtDNA replication machinery. Methods: Using retina from wild-type (WT) and MnSOD transgenic (Tg) mice, we have investigated the effect of diabetes on retinal D-loop damage and on the replication system. The results were confirmed in the isolated retinal endothelial cells in which DNA polymerase gamma 1 (POLG1) function was genetically manipulated. Results: Diabetes damaged retinal mtDNA, and the damage was more at the D-loop region compared to cytochrome B region. Gene transcripts and mitochondrial accumulation of POLG1, POLG2 and Twinkle (mtDNA helicase), the enzymes that form replisome to bind/unwind and extend mtDNA, were also decreased in WT-diabetic mice compared to WT-normal mice. Tg-diabetic mice were protected from diabetes-induced damage to D-loop region. Overexpression of POLG1 prevented high glucose-induced D-loop damage. This was accompanied by decrease in mitochondrial superoxide levels. Innovation and Conclusions: Integrity of retinal D-loop region and the mtDNA replication play important role in the mtDNA damage experienced by the retina in diabetes, and these are under the control of superoxide. Thus, the regulation of mtDNA replication/repair machinery has potential to prevent mitochondrial dysfunction and the development of diabetic retinopathy. |
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Authors:
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Shikha Tewari; Julia M Santos; Renu Kowluru |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2012-1-9 |
Journal Detail:
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Title: Antioxidants & redox signaling Volume: - ISSN: 1557-7716 ISO Abbreviation: - Publication Date: 2012 Jan |
Date Detail:
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Created Date: 2012-1-10 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 100888899 Medline TA: Antioxid Redox Signal Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Detroit, United States; shiktewari@med.wayne.edu. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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