Myocardial mitochondrial topoisomerase function is altered by hyperglycemia to promote mitochondrial DNA (mtDNA) damage

Diabetic cardiomyopathy (DCM) manifests initially as diastolic dysfunction, but evolves into decompensated eccentric hypertrophy. Mitochondrial dysfunction has a significant role in the complications of diabetic cardiomyopathy. We examined the impact of elevated glucose on accelerated mtDNA damage and identified the underlying cause of this damage. 13 days of elevated glucose in H9c2 cells or resulted in significant mitochondrial dysfunction. Concomitant with this, 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 topoisomerase‐linked DNA cleavage. We conclude increases in glucose presentation will compromise mitochondrial function as a function of mtDNA integrity. Separate from a direct impact of oxidative stress on mtDNA, ROS‐induced alteration of topoisomerase function propagated mtDNA damage. These findings indicate that the mitochondrial topoisomerase function may have a significant role in the development and complications of diabetic cardiomyopathy.