Oxidative stress and calcium dysregulation by palmitate in type 2 diabetes

Free fatty acids (FFAs) are important substrates for mitochondrial oxidative metabolism and ATP synthesis but also cause serious stress to various tissues, contributing to the development of metabolic diseases. CD36 is a major mediator of cellular FFA uptake. Inside the cell, saturated FFAs are able to induce the production of cytosolic and mitochondrial reactive oxygen species (ROS), which can be prevented by co-exposure to unsaturated FFAs. There are close connections between oxidative stress and organellar Ca2+ homeostasis. Highly oxidative conditions induced by palmitate trigger aberrant endoplasmic reticulum (ER) Ca2+ release and thereby deplete ER Ca2+ stores. The resulting ER Ca2+ deficiency impairs chaperones of the protein folding machinery, leading to the accumulation of misfolded proteins. This ER stress may further aggravate oxidative stress by augmenting ER ROS production. Secondary to ER Ca2+ release, cytosolic and mitochondrial matrix Ca2+ concentrations can also be altered. In addition, plasmalemmal ion channels operated by ER Ca2+ depletion mediate persistent Ca2+ influx, further impairing cytosolic and mitochondrial Ca2+ homeostasis. Mitochondrial Ca2+ overload causes superoxide production and functional impairment, culminating in apoptosis. This vicious cycle of lipotoxicity occurs in multiple tissues, resulting in β-cell failure and insulin resistance in target tissues, and further aggravates diabetic complications. High levels of the fatty acid palmitate cause cell death and exacerbate the complications of type 2 diabetes. Kyu-Sang Park at Yonsei University Wonju College of Medicine and colleagues review the molecular mechanisms responsible for palmitate-induced toxicity. The transmembrane protein CD36 mediates the uptake of palmitate into cells where it triggers the production of reactive oxygen species (ROS). Overproduction of ROS interferes with the cell's protein-processing organelle, the endoplasmic reticulum (ER), leading to damaged misfolded proteins and to ER calcium loss. This loss further damages protein folding and increases ROS production. Moreover, it causes an influx of calcium into mitochondria, the cell's power plants, and ultimately results in cell death. Therapeutic agents that inhibit CD36, reduce ROS production or prevent ER calcium loss could break this toxic cycle and contribute to the treatment of type 2 diabetes.