Mitochondrial Topoisomerase Dysfunction Contributes to Myocardial Mitochondrial Dysfunction and Mitochondrial DNA (mtDNA) Degradation

Mitochondrial dysfunction has a significant role in the development of many different cardiomyopathies. Mitochondrial dysfunction and mtDNA mutations are also associated with other nonmyocardial diseases including cancer and neurodegenerative diseases such as Leigh Syndrome. One pathophysiologic response includes a decline in mtDNA integrity. Although it is widely accepted that mitochondrial‐derived oxidant stress is the sole cause of mtDNA damage, our work in models of diabetes and alcoholism has found involvement of the mitochondrial topoisomerases. To date, three unique mitochondrial topoisomerases have been identified in the myocardium. In models of type II diabetes or alcoholism we have observed a significant decreased in left ventricle cytochrome oxidase activity as an indicator of mitochondrial dysfunction, concomitant with significant increases in mtDNA damage. Using purified myocardial mitochondria, we observed significant increases in mitochondrial topoisomerase dependent DNA cleavage in response to diabetes or alcoholism. Mitochondrial topoisomerase is regulated at different levels and we found that DNA cleavage was significantly exacerbated by acute exposure to H 2 O 2 as well as the topoisomerase inhibitor sobuzoxane to significantly increase DNA damage. Separate from a direct impact of oxidative stress on mtDNA, our studies find that alteration of mitochondrial topoisomerase reaction mechanism accelerates and propagates an increase in mtDNA damage. These findings indicate that the functional state of the mitochondrial topoisomerases have important consequences for the myocardium and participate in the pathophysiology leading to the development of cardiomyopathy.