An involvement of oxidative stress in endoplasmic reticulum stress and its associated diseases

Abstract

The endoplasmic reticulum (ER) is the major site of calcium storage and protein folding. It has a unique oxidizing-folding environment due to the predominant disulfide bond formation during the process of protein folding. Alterations in the oxidative environment of the ER and also intra-ER Ca2+ cause the production of ER stress-induced reactive oxygen species (ROS). Protein disulfide isomerases, endoplasmic reticulum oxidoreductin-1, reduced glutathione and mitochondrial electron transport chain proteins also play crucial roles in ER stress-induced production of ROS. In this article, we discuss ER stress-associated ROS and related diseases, and the current understanding of the signaling transduction involved in ER stress.

Figure 1

Endoplasmatic reticulum (ER) stress and unfolded protein response (UPR) induction. During the pathological conditions, proteins are aggregated causing accumulation of misfolded proteins in the ER lumen. This accumulation of misfolded proteins enhances UPR. During the initiation of UPR, BiP preferentially binds to the unfolded proteins, driving its equilibrium binding away from inositol requiring enzyme 1 (IRE-1), PKR-like endoplasmic reticulum kinase (PERK) and activating transcription factor 6 (ATF-6) proteins which are considered as initiators of the three main signaling cascades of UPR. IRE-1 protein dimerizes and activates its protein kinase activity (for autophosphorylation) and its endoribonuclease activity. It cleaves X-box-binding protein 1 (XBP1) mRNA to remove a small intron, converting unspliced (XBP1u) to spliced form (XBP1s), resulting in yielding a more potent transcriptional activator. Similarly, PERK also dimerizes and activates to phosphorylate eukaryotic initiation factor 2 (eIF2) on the α-subunit. This action selectively translates ATF-4 mRNA which further induces more transcriptional activator. Activation of ATF-6 allows it to translocate to the golgi apparatus, where it is cleaved by a protease, changing it to the active cytosolic ATF-6 fragment. This fragment migrates to the nucleus, activating the transcription of UPR target genes.

Figure 2

Pathway of oxidative protein folding. The formation of disulfide bonds in proteins in the ER is driven by protein disulfide isomerase (PDI) and endoplasmic reticulum oxidoreductin-1 (ERO-1). ERO-1 uses a (FAD)-dependent reaction to transfer electrons from PDI to molecular oxygen (O₂), resulting in ER protein folding-induced oxidative stress. When incorrect disulfide bonds are formed, GSH assists in reducing them, and this decreases the GSH/GSSG ratio. This condition alters the redox environment in the ER.

Figure 3

ER and mitochondrial associated reactive oxygen species (ROS) production under ER stress. ROS are generated in the ER as a part of an oxidative folding process during electron transfer between protein disulfide isomerase (PDI) and endoplasmic reticulum oxidoreductin-1 (ERO-1). ER-induced oxidative stress is further tuned for the generation of mitochondrial ROS. Ca²⁺ ions released from the ER augments the production of mitochondrial ROS which induces the Kreb’s cycle to further induce oxidative phosphorylation at the electron transport chain (ETC). Moreover, Ca²⁺ ions increase cytochrome c release impairing electron transfer, altering mitochondrial membrane potential and increasing the generation of ROS.