title: Type II diabetes increases mitochondrial DNA mutations in the left ventricle of the Goto-Kakizaki diabetic rat.
abstract: Mitochondrial dysfunction has a significant role in the development of diabetic cardiomyopathy. Mitochondrial oxidant stress has been accepted as the singular cause of mitochondrial DNA (mtDNA) damage as an underlying cause of mitochondrial dysfunction. However, separate from a direct effect on mtDNA integrity, diabetic-induced increases in oxidant stress alter mitochondrial topoisomerase function to propagate mtDNA mutations as a contributor to mitochondrial dysfunction. Both glucose-challenged neonatal cardiomyocytes and the diabetic Goto-Kakizaki (GK) rat were studied. In both the GK left ventricle (LV) and in cardiomyocytes, chronically elevated glucose presentation induced a significant increase in mtDNA damage that was accompanied by decreased mitochondrial function. TTGE analysis revealed a number of base pair substitutions in the 3' end of COX3 from GK LV mtDNA that significantly altered the protein sequence. Mitochondrial topoisomerase DNA cleavage activity in isolated mitochondria was significantly increased in the GK LV compared with Wistar controls. Both hydroxycamptothecin, a topoisomerase type 1 inhibitor, and doxorubicin, a topoisomerase type 2 inhibitor, significantly exacerbated the DNA cleavage activity of isolated mitochondrial extracts indicating the presence of multiple functional topoisomerases in the mitochondria. Mitochondrial topoisomerase function was significantly altered in the presence of H2O2 suggesting that separate from a direct effect on mtDNA, oxidant stress mediated type II diabetes-induced alterations of mitochondrial topoisomerase function. These findings are significant in that the activation/inhibition state of the mitochondrial topoisomerases will have important consequences for mtDNA integrity and the well being of the diabetic myocardium.
authors: Department of Physiology, New York Medical College, Valhalla, NY, USA.
authors: S
authors: S
authors: Hicks
authors: N
authors: N
authors: Labinskyy
authors: B
authors: B
authors: Piteo
authors: D
authors: D
authors: Laurent
authors: J E
authors: JE
authors: Mathew
authors: S A
authors: SA
authors: Gupte
authors: J G
authors: JG
authors: Edwards
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D004249:DNA Damage; D026942:DNA Topoisomerases / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000235:genetics / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006352:Heart Ventricles / Q000166:cytology / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008929:Mitochondria, Heart / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism; D009154:Mutation; D032383:Myocytes, Cardiac / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D051381:Rats; D017208:Rats, Wistar; D059003:Topoisomerase Inhibitors / Q000494:pharmacology; D020506:Untranslated Regions / Q000235:genetics
chemical_list: D004272:DNA, Mitochondrial; D024101:Mitochondrial Proteins; D059003:Topoisomerase Inhibitors; D020506:Untranslated Regions; D006861:Hydrogen Peroxide; D003576:Electron Transport Complex IV; D026942:DNA Topoisomerases; D005947:Glucose
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