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Dysfunctional mitochondrial topoisomerases mediates diabetic induced myocardial mitochondrial DNA damage.
Author(s) -
Edwards John G.,
Hicks Steven,
Piteo Brian,
Laurent Dimitri,
Mathew Jamie,
Labinskyy Nazar
Publication year - 2012
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.26.1_supplement.1057.1
Subject(s) - mitochondrial dna , mitochondrion , topoisomerase , cytochrome c oxidase , biology , microbiology and biotechnology , biochemistry , dna , gene
We have reported previously that chronically elevated glucose induced mtDNA damage that was linked to dysfunctional mitochondrial topoisomerase activity. The present study extends those observations to the type 2 diabetic Goto‐Kakizaki (GK) rat. Diabetes significantly decreased cytochrome oxidase activity in GK LV compared to Wistar LV. Mitochondrial dysfunction was associated with significantly increased mtDNA damage without a change in mitochondrial copy number. TTGE analysis of the Cytochrome Oxidase Subunit 3 identified several different nucleotide substitutions in the GK LV that altered the primary protein sequence; none were observed in Wistar LV. In isolated mitochondria, diabetes significantly increased mitochondrial dependent DNA cleavage. Immunoprecipitation with a mitochondrial topoisomerase I antibody partially blocked mitochondrial dependent DNA cleavage indicating a functional role for this enzyme. Incubation of mitochondrial extracts with 50 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. These findings indicate a significant role for mitochondrial topoisomerase function in the development and complications of diabetic cardiomyopathy.