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 electron transport; (c) Nox4 NADPH oxidase complex, particularly Nox4. Understanding the roles of such mechanisms and how they interconnect with the UPR requires more investigation. Integration among such ROS sources may depend on Ca(2+) levels, ROS themselves, and PDI, which associates with NADPH oxidase and regulates its function. Oxidative stress may frequently integrate with a background of ER stress/UPR in several diseases; here we discuss a focus in the vascular system.

Endoplasmic reticulum calcium release potentiates the ER stress and cell death caused by an oxidative stress in MCF-7 cells

“…Furthermore, the relationship between oxidative stress and ER stress is a matter of debate, because activation of the UPR can also result in ROS generation [50][51][52]. In our study, we found that pro-oxidant Asc/Men treatment induced the translational control arm of the UPR (by enhancing eIF2 phosphorylation) and upregulation of ER folding capacity (by the increase in GRP94 protein, one of the major ER chaperones).…”

“…These are still speculations and need further study. It has been proposed that BAPTA-AM interferes with Fenton's reaction [41,42] or may protect against a poorly defined pro-oxidative calciumassociated process, such as calcium-induced iron release [49] or ER stress-generated ROS production [50][51][52].…”

“…Furthermore, the relationship between oxidative stress and ER stress is a matter of debate, because activation of the UPR can also result in ROS generation [50][51][52]. In our study, we found that pro-oxidant Asc/Men treatment induced the translational control arm of the UPR A c c e p t e d M a n u s c r i p t 18 represent one of the pathways leading to this event; this observation also underlines the capacity of TG to trigger DNA fragmentation, as shown by others [43][44][45]57].…”

Cell death and diseases related to oxidative stress:4-hydroxynonenal (HNE) in the balance

“…110 In support of this idea, it was shown that the folding of protein to allow optimal formation of disulfide bonds is highly redox-dependent in the ER. 111 Thus, the accumulation of misfolded proteins with HNE-adducts in ER could compromise cell survival. The UPR is an adaptive process but the non-re-establishment of cell homeostasis strongly compromises tissue integrity and can initiate or promote pathologies.…”

Reactive oxygen species and vascular biology: implications in human hypertension

“…Characterization of Noxes as they pertain to vascular biology and hypertension has recently been reviewed. 76,77 In vessels, in addition to vascular cells possessing functional Noxes, resident macrophages, neutrophils and platelets express NAD(P)H oxidase, particularly in pathological states. Accordingly these cells can also contribute to vascular oxidative stress in disease.…”