Premium
Type II diabetes increases myocardial mitochondrial DNA (mtDNA) damage by altered mitochondrial topoisomerase function
Author(s) -
Edwards John Grenville,
Piteo Brian,
Laurent Dimitri,
Mitry Maria,
Hicks Steven
Publication year - 2013
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.27.1_supplement.1154.21
Subject(s) - mitochondrial dna , mitochondrion , cytochrome c oxidase , topoisomerase , biology , diabetic cardiomyopathy , oxidative stress , microbiology and biotechnology , medicine , endocrinology , biochemistry , cardiomyopathy , dna , gene , heart failure
Mitochondrial dysfunction has a significant role in the development of diabetic cardiomyopathy. Using neonatal cardiomyocytes and the Goto‐Kakizaki (GK) rat as models of type II diabetes, we investigated if mitochondrial topoisomerases contributed to mitochondrial dysfunction. In cardiomyocytes elevated glucose significantly decreased ATP production and cytochrome oxidase (COX) activity. Diabetes significantly decreased cytochrome oxidase activity in GK left ventricle (LV). Diabetes significantly increased mtDNA damage, in both glucose‐challenged cardiomyocytes and GK LV. TTGE analysis of COX3 identified nucleotide substitutions in the GK LV mtDNA that altered the primary protein sequence. In isolated mitochondria, diabetes increased DNA cleavage activity and incubation with topoisomerase inhibitors significantly altered this response. Immunoprecipitation with a mtTOP1 antibody partially blocked DNA cleavage. The presence of 60 μM H2O2 increased mitochondrial topoisomerase dependent DNA cleavage: implicating ROS as a modifier of topoisomerase function. Separate from a direct impact of oxidative stress on mtDNA, ROS‐induced alteration of mitochondrial topoisomerase function propagated mtDNA damage. Our findings suggest that mitochondrial topoisomerase dysfunction contributes to the development and complications of diabetic cardiomyopathy. Supported in part by NIH HD065551.