The Role of Peroxidation of Mitochondrial Membrane Phospholipids in Pancreatic u0001-Cell Failure

摘要

Type 2 diabetes (T2D) is characterized by peripheral insulin resistance and pancreatic islet u0001-cell failure. Ac-ncumulating evidence indicates that mitochondrial dysfunction is a central contributor to u0001-cell failure in the pathogenesis nof T2D. This review focuses on mechanisms whereby reactive oxygen species (ROS) produced by u0001-cell in response to nmetabolic stress affect mitochondrial structure and function and lead to u0001-cell failure. Specifically, ROS oxidize mito-nchondrial membrane phospholipids such as cardiolipin, which impairs membrane integrity and leads to cytochrome c re-nlease and apoptosis. In addition, ROS activate UCP2 via peroxidation of the mitochondrial membrane phospholipids, nwhich results in proton leak leading to reduced ATP synthesis and content in u0001-cells — critical parameters in the regula-ntion of glucose-stimulated insulin secretion. Group VIA Phospholipase A2 (iPLA2u0001) appears to be a component of a nmechanism for repairing mitochondrial phospholipids that contain oxidized fatty acid substituents, and genetic or acquired niPLA2u0001-deficiency increases u0001-cell mitochondrial susceptibility to injury from ROS and predisposes to development of nT2D. Interventions that attenuate the adverse effects of ROS on u0001-cell mitochondrial phospholipids may prevent or retard nthe development of T2D.