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Elevated glucose compromises myocardial mitochondrial DNA (mtDNA) integrity by activation of mitochondrial topoisomerase activity.
Author(s) -
Edwards John G.,
Medikayala Sushma,
Piteo Brian,
Labinskyy Nazar
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.978.8
Subject(s) - mitochondrial dna , mitochondrion , cytochrome c oxidase , biology , oxidative stress , oxidative phosphorylation , dna damage , microbiology and biotechnology , biochemistry , dna , gene
Mitochondrial dysfunction has a significant role in the development and complications of diabetic cardiomyopathy. The goal of this study was to determine if chronically elevated glucose promoted a decline in mitochondrial DNA (mtDNA) integrity that contributed to mitochondrial dysfunction and identify the underlying basis for mtDNA damage. Functional tests of mitochondria (Complex I activity, cytochrome oxidase activity, and ATP generation) were significantly depressed by chronically elevated glucose, while AnnexinV binding (a marker of apoptosis) was significantly increased after 7 days. 13 days of elevated glucose significantly increased mtDNA damage both globally and across the region encoding for cytochrome oxidase. Using mitochondria isolated from H9c2 cells exposed to elevated glucose, we observed significant increases in mitochondrial topoisomerase‐linked DNA cleavage, and this was exacerbated by H2O2. We conclude that even mild increases in glucose presentation will compromise mitochondrial function as a function of mtDNA damage. Separate from a direct impact of oxidative stress on mtDNA, ROS‐induced alteration of mitochondrial topoisomerase activity appeared to propagate an increase in mtDNA damage. These findings indicate that the mitochondrial topoisomerase function may have a significant role in the development and complications of diabetic cardiomyopathy.