Modulating Mitochondrial Fission to Lower Diabetic Oxidative Stress

Abstract

Mitochondria are at the crossroads of energy metabolism, and they play a major role in the regulation of cell life and death. Mitochondrial oxidation of fat and glucose substrates generates a transmembrane electrochemical gradient, and this is used to synthesize adenosine triphosphate (ATP), the chemical fuel for cell and tissue functions. In the process, electron transfer through the mitochondrial respiratory chain is inevitably associated with production of reactive oxygen species (ROS). Several physiological roles have been described for ROS (1), but ROS generation in excess of antioxidant defenses is harmful and may cause oxidative stress with damage to DNA, lipids, proteins, and organelles (1,2). Hyperglycemia is a strong inducer of oxidative stress through enhanced ROS generation at mitochondrial as well as nonmitochondrial levels (2–4), and pathways activated by oxidative stress have a major role in the pathogenesis of diabetes complications (2,5). In addition, oxidative stress may contribute to hyperglycemia-induced impairment of β-cell insulin secretion (2), and excess mitochondrial ROS production has been shown to acutely and chronically cause muscle insulin resistance in some (6–8) but not all reports (9). Lowering oxidative stress in diabetes could therefore beneficially modulate pathogenic disease mechanisms, and it could potentially reduce morbidity and mortality by limiting tissue and cardiovascular complications. Understanding and modulating the pathways that regulate mitochondrial ROS production is particularly relevant, and novel approaches involving mitochondrial dynamics have been …