Mitochondrial DNA (mtDNA) damage in diabetic heart: 4-hydroxy-2-nonenal (4HNE) inhibits mtDNA repair enzyme, 8-oxoguanine glycosylase 1

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Conference Proceeding

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J Mol Cell Cardiol


Background: Diabetes mellitus (DM) affects a variety of organs including myocardium. 8-oxoguanine glycosylase 1 (OGG-1) repairs mitochondrial DNA (mtDNA) by base excision repair process. We hypothesize that DM mediated 4-hydroxy-2-nonenal (4HNE) contributes to mtDNA damage by forming adducts with mtOGG-1 and thus inhibiting its activity and thereby contributing to cardiac dysfunction in the diabetic heart. Methods and results: First of all, we treated 4HNE (1, 10 and 100 μM) directly to recombinant OGG-1, analyzed the 4HNE adduction on specific amino acids in OGG-1 and measured its activity, in vitro. 4HNE dose-dependently inhibited the activity of OGG-1 by forming adducts. We identified that several amino acids on OGG-1 such as Cys241, His237, Lys238, Cys163, His282, and Lys249 were 4HNE adducted. A type-2 diabetic model, db/db mice were sacrificed at six months when they exhibit cardiac dysfunction. We found a decrease in myocardial OGG-1 activity in db/db mouse hearts compared to db/dm hearts. We observed an increase in 4HNE adducts on OGG-1 in db/db mouse hearts. We also found increased mtDNA damage. The activity of aldehyde dehydrogenase (ALDH) 2 which detoxifies 4HNE was decreased in db/db mouse hearts which may have led to increases in the 4HNE levels. Before the 4HNE challenge, pre-incubation with recombinant ALDH2 decreased the 4HNE-mediated reduction in OGG-1 activity, in vitro. Therefore, we treated db/db mice with Alda-1, an ALDH2 activator and found a decrease in 4HNE adducts and thus decreased mtDNA damage along with improved cardiac function. Conclusion: Increased 4HNE formed adducts with OGG-1 and inhibited its activity and thus led to mtDNA damage in a type-2 diabetic heart. ALDH2 decreased the 4HNE adduction on OGG-1 and thereby improved mtDNA repair and cardiac function.



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