Endoplasmic Reticulum Stress and Associated ROS

Abstract

The endoplasmic reticulum (ER) is a fascinating network of tubules through which secretory and transmembrane proteins enter unfolded and exit as either folded or misfolded proteins, after which they are directed either toward other organelles or to degradation, respectively. The ER redox environment dictates the fate of entering proteins, and the level of redox signaling mediators modulates the level of reactive oxygen species (ROS). Accumulating evidence suggests the interrelation of ER stress and ROS with redox signaling mediators such as protein disulfide isomerase (PDI)-endoplasmic reticulum oxidoreductin (ERO)-1, glutathione (GSH)/glutathione disuphide (GSSG), NADPH oxidase 4 (Nox4), NADPH-P450 reductase (NPR), and calcium. Here, we reviewed persistent ER stress and protein misfolding-initiated ROS cascades and their significant roles in the pathogenesis of multiple human disorders, including neurodegenerative diseases, diabetes mellitus, atherosclerosis, inflammation, ischemia, and kidney and liver diseases.

Anti-inflammatory actions of (−)-epicatechin in the adipose tissue of obese mice

“…Here we observed increased levels of 4-HNE-protein derivatives, an indicator of oxidative stress, in the HFD mice visceral fat which was prevented by EC supplementation. ER and oxidative stresses are interrelated events (Zeeshan et al, 2016; Santos et al, 2009; Merksamer et al, 2008). Oxidative stress can under certain conditions cause ER stress.…”

“…Indeed, parameters of ER stress activation are found in the adipose tissue from obese and insulin resistant individuals (Boden et al, 2008), which improve after weight loss (Gregor et al, 2009). ER and oxidative stress are intertwined processes (Zeeshan et al, 2016) and both are intimately linked to the development and perpetuation of inflammation. In this regard, during protein folding, particularly in the formation of disulfide bonds, a significant amount of reactive oxygen species (ROS) are generated (Zeeshan et al, 2016).…”

“…ER and oxidative stress are intertwined processes (Zeeshan et al, 2016) and both are intimately linked to the development and perpetuation of inflammation. In this regard, during protein folding, particularly in the formation of disulfide bonds, a significant amount of reactive oxygen species (ROS) are generated (Zeeshan et al, 2016). ER stress also induces the expression of the NADPH oxidase NOX4 (Li et al, 2010), a major enzymatic cell source of the free radical superoxide anion.…”

EGFR inhibition attenuates diabetic nephropathy through decreasing ROS and endoplasmic reticulum stress

“…In addition, Endoplasmic reticulum (ER) stress, with misfolded and/or unfolded proteins in ER membranes, has been shown to mediate DN development and progression [10]. The crosstalk between ER stress and ROS production is well established in cancer biology, in which increasing ROS induces ER stress to trigger cancer cell apoptosis [11–13]. Interestingly, ERGR signaling plays a key role regulating ER stress and ROS accumulation [14, 15].…”

Extracellular superoxide dismutase and its role in cancer

“…These diffusibility limitations impart compartmentalization of ROS signaling, which is influenced by the redox state native within individual organelles. For example, disulfide bond formation in the ER is particularly sensitive to ROS stress [13]. Disruptions in redox homeostasis, tending towards a more oxidizing state, termed oxidative stress, constitute an imbalance between the production of ROS and the available systemic mechanisms of detoxification, whereby oxidants adversely modify DNA, lipids and proteins, generating toxic adducts deleterious to organismal health and contributing to genomic instability.…”