Mechanisms and implications of reactive oxygen species generation during the unfolded protein response: roles of endoplasmic reticulum oxidoreductases, mitochondrial electron transport, and NADPH oxidase.

Abstract Cellular mechanisms governing redox homeostasis likely involve their integration with other stresses. Endoplasmic reticulum (ER) stress triggers complex adaptive or proapoptotic signaling defined as the unfolded protein response (UPR), involved in several pathophysiological processes. Since protein folding is highly redox-dependent, convergence between ER stress and oxidative stress has attracted interest. Evidence suggests that ROS production and oxidative stress are not only coincidental to ER stress, but are integral UPR components, being triggered by distinct types of ER stressors and contributing to support proapoptotic, as well as proadaptive UPR signaling. Thus, ROS generation can be upstream or downstream UPR targets and may display a UPR-specific plus a nonspecific component. Enzymatic mechanisms of ROS generation during UPR include: (a) Multiple thiol–disulfide exchanges involving ER oxidoreductases including flavooxidase Ero1 and protein disulfide isomerase (PDI); (b) Mitochondrial ele...