Targeting mitochondrial oxidative stress through lipoic acid synthase: a novel strategy to manage diabetic cardiovascular disease.

ABSTRACT

Mitochondrial oxidative stress is a major etiological factor in the development of cardiovascular disease associated with type 2 diabetes. Hyperglycemia and insulin resistance contribute to the generation of excessive reactive oxygen species (ROS) which have damaging effects on various macromolecules within the mitochondria, leading to mitochondrial dysfunction. Mitochondrial damage within the endothelial cells lining the vasculature causes endothelial dysfunction, a critical event in atherosclerosis. In diabetes, deficiency of the antioxidant defense network prevents the generation of a robust response to counter the damaging effects of ROS. Since oxidative stress is the underlying factor for the damages inflicted by hyperglycemia, a logical therapeutic approach is to use antioxidants to quench ROS produced within the mitochondria. Lipoic acid (LA) is a potent mitochondrial antioxidant and an essential cofactor of α-ketoacid dehydrogenases. Clinical studies testing the effects of LA supplementation in diabetes and its complications have yielded promising results, especially with regard to management of diabetic neuropathy. Endogenously, LA is synthesized within the mitochondria by the enzyme, Lipoic acid synthase (LASY). This review describes a novel therapeutic approach which is aimed at increasing expression of LASY to enhance mitochondrial levels of LA. Such a strategy has the potential of improving mitochondrial function, reducing inflammation and insulin resistance, translating to better metabolic control in diabetes and preventing cardiovascular disease.