Role of oxidative mitochondrial DNA damage in fatty acid‐induced apoptosis

Abstract

Cardiovascular disease represents the primary cause of mortality in diabetic individuals. This is thought to be due to the development of congestive heart failure, which is likely caused in part by myocyte loss. According to an integrating paradigm known as the “unifying hypothesis”, diabetes may induce myocyte death via the overproduction of reactive oxygen species and their effects on mitochondrial DNA (mtDNA). Since diabetes is associated with elevated levels of fatty acids, and since fatty acids have been shown to induce oxidative stress, we hypothesized that fatty acid-induced oxidative mtDNA damage may underlie the development of diabetic complications in the heart. To investigate this possibility, isolated neonatal cardiomyocytes were exposed to levels of palmitate found in the plasma of the diabetic rat. The fatty acid-treated cells exhibited significant mtDNA damage and showed reduced levels of key electron transport proteins, whose levels were normalized by treatment with the antioxidant, Tiron. Moreover, Tiron blocked fatty acid-mediated cytochrome c release and apoptosis. To confirm that the apoptotic cascade was initiated by DNA damage, cells were transfected with the DNA repair enzyme, 8-oxoguanine glycosylase (hOgg1). Besides restoring DNA integrity, hOgg1-transfected cells were resistant to fatty acid-mediated cytochrome c release and apoptosis.