The aftermath of the interplay between the endoplasmic reticulum stress response and redox signaling

Abstract

The endoplasmic reticulum (ER) is an essential organelle of eukaryotic cells. Its main functions include protein synthesis, proper protein folding, protein modification, and the transportation of synthesized proteins. Any perturbations in ER function, such as increased demand for protein folding or the accumulation of unfolded or misfolded proteins in the ER lumen, lead to a stress response called the unfolded protein response (UPR). The primary aim of the UPR is to restore cellular homeostasis; however, it triggers apoptotic signaling during prolonged stress. The core mechanisms of the ER stress response, the failure to respond to cellular stress, and the final fate of the cell are not yet clear. Here, we discuss cellular fate during ER stress, cross talk between the ER and mitochondria and its significance, and conditions that can trigger ER stress response failure. We also describe how the redox environment affects the ER stress response, and vice versa, and the aftermath of the ER stress response, integrating a discussion on redox imbalance-induced ER stress response failure progressing to cell death and dynamic pathophysiological changes.

TMBIM6 regulates redox-associated posttranslational modifications of IRE1α and ER stress response failure in aging mice and humans

“…S5D ). A defective nuclear translocation of sXBP1 has been observed in several pathological conditions such as obesity, insulin resistance, and diabetic nephropathy [ [51] , [52] , [53] ], in which the interaction between sXBP1 and regulatory subunits of PI3K (p85α and p85β) was impaired, aggravating the pathogenesis of diseases [ 4 , 51 ]. Previous studies identified TMBIM6 as a regulator of the pharmacologically-induced ER stress response (particularly p-IRE1α -mediated XBP1 splicing) [ 37 , 38 ].…”

“…Importantly, transmembrane ER-resident proteins including inositol requiring enzyme 1α (IRE1α), PKR-like ER kinase (PERK), and activating transcription factor 6α (ATF6α) are activated during UPR activation. UPR is primarily activated to increase adaptive response and restore protein folding, but prolonged ER stress causes adaptive response failure and activates terminal UPR signals promoting cellular apoptosis [ [2] , [3] , [4] ].…”

“…ER stress is extensively studied, but ER stress response failure and its cellular fate linked studied are limited. Previously, we proposed that the failure of the ER stress response could be associated with several metabolic diseases including aging [ 4 , 5 ]. Aging is a very complex process and cannot be explained by a single mechanism.…”

Antioxidant Role of Kaempferol in Prevention of Hepatocellular Carcinoma

“…UPR is the complex cellular response that is associated with the various membrane biosensors; protein kinase RNA (PKR)-like ER kinase (PERK), inositol requiring enzyme 1α (IRE1α), and activating transcription factor 6 (ATF6) [ 97 ]. Other studies have also indicated that oxidative stress is strongly connected with ER stress [ 108 , 109 ]. Both of them trigger various inflammatory molecules and apoptosis cascades which are involved in the pathogenesis of many diseases, specifically liver injuries.…”

Vitamin K2 Modulates Organelle Damage and Tauopathy Induced by Streptozotocin and Menadione in SH-SY5Y Cells

“…Heightened ER stress response also results in increased oxidative stress along with autophagy dysfunction [10]. On the other hand, studies also reveal that oxidative stress is considered the major etiology in AD, which contributes to impairment of mitochondrial function [12], ER stress [13], autophagy dysfunction [14], dysfunctional glucose metabolism [15], and an increase in tauopathy and Aβ secretion [12]. Increasing evidence also shows that elevated levels of glycogen synthase kinase 3 (GSK3), a serine/threonine protein kinase, are found in human and mouse models of AD.…”