Endoplasmic reticulum stress: bridging inflammation and obesity-associated adipose tissue.

Obesity presents a significant global health challenge, increasing the susceptibility to chronic conditions such as diabetes, cardiovascular disease, and hypertension. Within the context of obesity, lipid metabolism, adipose tissue formation, and inflammation are intricately linked to endoplasmic reticulum stress (ERS). ERS modulates metabolism, insulin signaling, inflammation, as well as cell proliferation and death through the unfolded protein response (UPR) pathway. Serving as a crucial nexus, ERS bridges the functionality of adipose tissue and the inflammatory response. In this review, we comprehensively elucidate the mechanisms by which ERS impacts adipose tissue function and inflammation in obesity, aiming to offer insights into targeting ERS for ameliorating metabolic dysregulation in obesity-associated chronic diseases such as hyperlipidemia, hypertension, fatty liver, and type 2 diabetes.

IRE1 signaling increases PERK expression during chronic ER stress.

The Unfolded Protein Response (UPR) is an essential cellular process activated by the accumulation of unfolded proteins within the Endoplasmic Reticulum (ER), a condition referred to as ER stress. Three ER anchored receptors, IRE1, PERK and ATF6 act as ER stress sensors monitoring the health of the ER. Upon detection of ER stress, IRE1, PERK and ATF6 initiate downstream signaling pathways collectively referred to as the UPR. The overarching aim of the UPR is to restore ER homeostasis by reducing ER stress, however if that is not possible, the UPR transitions from a pro-survival to a pro-death response. While our understanding of the key signaling pathways central to the UPR is well defined, the same is not true of the subtle signaling events that help fine tune the UPR, supporting its ability to adapt to varying amplitudes or durations of ER stress. In this study, we demonstrate cross talk between the IRE1 and PERK branches of the UPR, wherein IRE1 via XBP1s signaling helps to sustain PERK expression during prolonged ER stress. Our findings suggest cross talk between UPR branches aids adaptiveness thereby helping to support the plasticity of UPR signaling responses.

Mitochondria-Associated Membranes as Key Regulators in Cellular Homeostasis and the Potential Impact of Exercise on Insulin Resistance.

The communication between mitochondria and the endoplasmic reticulum (ER) is facilitated by a dynamic membrane structure formed by protein complexes known as mitochondria-associated membranes (MAMs). The structural and functional integrity of MAMs is crucial for insulin signal transduction, relying heavily on their regulation of intracellular calcium homeostasis, lipid homeostasis, mitochondrial quality control, and endoplasmic reticulum stress (ERS). This article reviews recent research findings, suggesting that exercise may promote the remodeling of MAMs structure and function by modulating the expression of molecules associated with their structure and function. This, in turn, restores cellular homeostasis and ultimately contributes to the amelioration of insulin resistance (IR). These insights provide additional possibilities for the study and treatment of insulin resistance-related metabolic disorders such as obesity, diabetes, fatty liver, and atherosclerosis.

Endoplasmic reticulum stress-induced necroptosis promotes cochlear inflammation: Implications for age-related hearing loss.

Age-related hearing loss (ARHL) is the most common sensory disorder associated with human aging. Chronic inflammation is supposed to be an important contributor to ARHL. Yet, the underlying mechanisms of developing cochlear inflammation are still not well understood. In this study, we found that the inflammation, endoplasmic reticulum (ER) stress and necroptosis signalings are activated in the cochlea of aged C57BL/6 mice. ER stress activator tunicamycin (TM) induced necroptosis in cochlear HEI-OC1 cells and cochlear explants, while necroptosis inhibitors protected cochlear cells from ER stress-induced cell death. The antioxidants inhibited necroptosis and protected HEI-OC1 cells from TM insults. Necroptotic HEI-OC1 cells promoted the activation of the co-cultured macrophages via Myd88 signaling. Moreover, necroptosis inhibitor protected from TM-induced hearing loss, and inhibited inflammation in C57BL/6 mice. These findings suggest that ER stress-induced necroptosis promotes cochlear inflammation and hearing loss. Targeting necroptosis serves as a potential approach for the treatment of cochlear inflammation and ARHL.

The Ailing ß-Cell in Diabetes: Insights From a Trip to the ER: The 2023 Outstanding Scientific Achievement Award Lecture.

The synthesis, processing, and secretion of insulin by the pancreatic ß-cell is key for the maintenance of systemic metabolic homeostasis, and loss or dysfunction of ß-cells underlies the development of both type 1 diabetes (T1D) and type 2 diabetes (T2D). Work in the Evans-Molina laboratory over the past 15 years has pioneered the idea that regulation of calcium dynamics is critical to ß-cell biology and diabetes pathophysiology. In this article, I will share three vignettes from the laboratory that demonstrate our bench-to-bedside approach to determining mechanisms of ß-cell stress that could improve therapeutic options and outcomes for individuals living with diabetes. The first of these vignettes will illustrate a role for the sarcoendoplasmic reticulum calcium ATPase (SERCA) pump in the regulation of endoplasmic reticulum (ER) calcium, protein trafficking, and proinsulin processing within the ß-cell. The second vignette will highlight how alterations in ß-cell calcium signaling intersect with T1D pathogenesis. The final vignette will demonstrate how activation of ß-cell stress pathways may serve as an anchor to inform biomarker strategies in T1D. Lastly, I will share my vision for the future of diabetes care, where multiple biomarkers of ß-cell stress may be combined with additional immune and metabolic biomarkers to better predict disease risk and improve therapies to prevent or delay T1D development.

Progression of unfolded protein response and ferroptosis in angiogenesis.

Angiogenesis is the growth of new blood vessels on preexisting ones. It is the outcome of a multifactorial effect involving several cells, which can be brought on by different stress reactions.The accumulation of unfolded proteins in the endoplasmic reticulum occurs when cells are stressed due to environmental changes, where physical or chemical stimuli induce endoplasmic reticulum stress, thereby activating the unfolded protein response (UPR), a homeostasis response designed to re-establish protein balance. Ferroptosis is a planned death of lipid peroxidation and anomalies in metabolism that is dependent on iron. Large concentrations of iron ions accumulate there, along with high concentrations of lipid peroxides and reactive oxygen species, all of which can contribute to the development of several diseases. Through the production of growth factors, adhesion factors, and inflammatory factors that trigger the start of angiogenesis, both UPR and Ferroptosis can be implicated in angiogenesis.To set the stage for further research on angiogenesis, this work concentrated on the effects of Ferroptosis and UPR on angiogenesis, respectively.

Collective cell migration relies on PPP1R15-mediated regulation of the endoplasmic reticulum stress response.

Collective cell migration is integral to many developmental and disease processes. Previously, we discovered that protein phosphatase 1 (Pp1) promotes border cell collective migration in the Drosophila ovary. We now report that the Pp1 phosphatase regulatory subunit dPPP1R15 is a critical regulator of border cell migration. dPPP1R15 is an ortholog of mammalian PPP1R15 proteins that attenuate the endoplasmic reticulum (ER) stress response. We show that, in collectively migrating border cells, dPPP1R15 phosphatase restrains an active physiological protein kinase R-like ER kinase- (PERK)-eIF2α-activating transcription factor 4 (ATF4) stress pathway. RNAi knockdown of dPPP1R15 blocks border cell delamination from the epithelium and subsequent migration, increases eIF2α phosphorylation, reduces translation, and drives expression of the stress response transcription factor ATF4. We observe similar defects upon overexpression of ATF4 or the eIF2α kinase PERK. Furthermore, we show that normal border cells express markers of the PERK-dependent ER stress response and require PERK and ATF4 for efficient migration. In many other cell types, unresolved ER stress induces initiation of apoptosis. In contrast, border cells with chronic RNAi knockdown of dPPP1R15 survive. Together, our results demonstrate that the PERK-eIF2α-ATF4 pathway, regulated by dPPP1R15 activity, counteracts the physiological ER stress that occurs during collective border cell migration. We propose that in vivo collective cell migration is intrinsically "stressful," requiring tight homeostatic control of the ER stress response for collective cell cohesion, dynamics, and movement.

Endoplasmic reticulum stress: A possible connection between intestinal inflammation and neurodegenerative disorders.

BACKGROUND: Different studies have shown the key role of endoplasmic reticulum (ER) stress in autoimmune and chronic inflammatory disorders, as well as in neurodegenerative diseases. ER stress leads to the formation of misfolded proteins which affect the secretion of different cell types that are crucial for the intestinal homeostasis. PURPOSE: In this review, we discuss the role of ER stress and its involvement in the development of inflammatory bowel diseases, chronic conditions that can cause severe damage of the gastrointestinal tract, focusing on the alteration of Paneth cells and goblet cells (the principal secretory phenotypes of the intestinal epithelial cells). ER stress is also discussed in the context of neurodegenerative diseases, in which protein misfolding represents the signature mechanism. ER stress in the bowel and consequent accumulation of misfolded proteins might represent a bridge between bowel inflammation and neurodegeneration along the gut-to-brain axis, affecting intestinal epithelial homeostasis and the equilibrium of the commensal microbiota. Targeting intestinal ER stress could foster future studies for designing new biomarkers and new therapeutic approaches for neurodegenerative disorders.

MemPrep, a new technology for isolating organellar membranes provides fingerprints of lipid bilayer stress.

Biological membranes have a stunning ability to adapt their composition in response to physiological stress and metabolic challenges. Little is known how such perturbations affect individual organelles in eukaryotic cells. Pioneering work has provided insights into the subcellular distribution of lipids in the yeast Saccharomyces cerevisiae, but the composition of the endoplasmic reticulum (ER) membrane, which also crucially regulates lipid metabolism and the unfolded protein response, remains insufficiently characterized. Here, we describe a method for purifying organelle membranes from yeast, MemPrep. We demonstrate the purity of our ER membrane preparations by proteomics, and document the general utility of MemPrep by isolating vacuolar membranes. Quantitative lipidomics establishes the lipid composition of the ER and the vacuolar membrane. Our findings provide a baseline for studying membrane protein biogenesis and have important implications for understanding the role of lipids in regulating the unfolded protein response (UPR). The combined preparative and analytical MemPrep approach uncovers dynamic remodeling of ER membranes in stressed cells and establishes distinct molecular fingerprints of lipid bilayer stress.

ER stress and the unfolded protein response in gastrointestinal stem cells and carcinogenesis.

Endoplasmic reticulum (ER) stress and the adaptive response that follows, termed the unfolded protein response (UPR), are crucial molecular mechanisms to maintain cellular integrity by safeguarding proper protein synthesis. Next to being important in protein homeostasis, the UPR is intricate in cell fate decisions such as proliferation, differentiation, and stemness. In the intestine, stem cells are critical in governing epithelial homeostasis and they are the cell of origin of gastrointestinal malignancies. In this review, we will discuss the role of ER stress and the UPR in the gastrointestinal tract, focusing on stem cells and carcinogenesis. Insights in mechanisms that connect ER stress and UPR with stemness and carcinogenesis may broaden our understanding in the development of cancer throughout the gastrointestinal tract and how we can exploit these mechanisms to target these malignancies.

KCNH6 is essential for insulin secretion by regulating intracellular ER Ca2+ store.

Appropriate Ca2+ concentration in the endoplasmic reticulum (ER), modulating cytosolic Ca2+ signal, serves significant roles in physiological function of pancreatic ß cells. To maintaining ER homeostasis, Ca2+ movement across the ER membrane is always accompanied by a simultaneous K+ flux in the opposite direction. KCNH6 was proven to modulate insulin secretion by controlling plasma membrane action potential duration and intracellular Ca2+ influx. Meanwhile, the specific function of KCNH6 in pancreatic ß-cells remains unclear. In this study, we found that KCNH6 exhibited mainly ER localization and Kcnh6 ß-cell-specific knockout (ßKO) mice suffered from abnormal glucose tolerance and impaired insulin secretion in adulthood. ER Ca2+ store was overloaded in islets of ßKO mice, which contributed to ER stress and ER stress-induced apoptosis in ß cells. Next, we verified that ethanol treatment induced increases in ER Ca2+ store and apoptosis in pancreatic ß cells, whereas adenovirus-mediated KCNH6 overexpression in islets attenuated ethanol-induced ER stress and apoptosis. In addition, tail-vein injections of KCNH6 lentivirus rescued KCNH6 expression in ßKO mice, restored ER Ca2+ overload and attenuated ER stress in ß cells, which further confirms that KCNH6 protects islets from ER stress and apoptosis. These data suggest that KCNH6 on the ER membrane may help to stabilize intracellular ER Ca2+ stores and protect ß cells from ER stress and apoptosis. In conclusion, our study reveals the protective potential of KCNH6-targeting drugs in ER stress-induced diabetes.

ER stress and lipid imbalance drive diabetic embryonic cardiomyopathy in an organoid model of human heart development.

Congenital heart defects are the most prevalent human birth defects, and their incidence is exacerbated by maternal health conditions, such as diabetes during the first trimester (pregestational diabetes). Our understanding of the pathology of these disorders is hindered by a lack of human models and the inaccessibility of embryonic tissue. Using an advanced human heart organoid system, we simulated embryonic heart development under pregestational diabetes-like conditions. These organoids developed pathophysiological features observed in mouse and human studies before, including ROS-mediated stress and cardiomyocyte hypertrophy. scRNA-seq revealed cardiac cell-type-specific dysfunction affecting epicardial and cardiomyocyte populations and alterations in the endoplasmic reticulum and very-long-chain fatty acid lipid metabolism. Imaging and lipidomics confirmed these findings and showed that dyslipidemia was linked to fatty acid desaturase 2 mRNA decay dependent on IRE1-RIDD signaling. Targeting IRE1 or restoring lipid levels partially reversed the effects of pregestational diabetes, offering potential preventive and therapeutic strategies in humans.

HRD1-induced TMEM2 ubiquitination promotes ER stress-mediated apoptosis through a non-canonical pathway in intestinal ischemia/reperfusion.

Intestinal ischemia/reperfusion (I/R) injury is a typical pathological course in the clinic with a high morbidity rate. Recent research has pointed out the critical role of ubiquitination during the occurrence and development of intestinal I/R by precisely mediating protein quality control and function. Here, we conducted an integrated multiomic analysis to identify critical ubiquitination-associated molecules in intestinal I/R and identified endoplasmic reticulum-located HRD1 as a candidate molecule. During intestinal I/R, excessive ER stress plays a central role by causing apoptotic pathway activation. In particular, we found that ER stress-mediated apoptosis was mitigated by HRD1 knockdown in intestinal I/R mice. Mechanistically, TMEM2 was identified as a new substrate of HRD1 in intestinal I/R by mass spectrometry analysis, which has a crucial role in attenuating apoptosis and promoting non-canonical ER stress resistance. A strong negative correlation was found between the protein levels of HRD1 and TMEM2 in human intestinal ischemia samples. Specifically, HRD1 interacted with the lysine 42 residue of TMEM2 and reduced its stabilization by K48-linked polyubiquitination. Furthermore, KEGG pathway analysis revealed that TMEM2 regulated ER stress-mediated apoptosis in association with the PI3k/Akt signaling pathway rather than canonical ER stress pathways. In summary, HRD1 regulates ER stress-mediated apoptosis through a non-canonical pathway by ubiquitinating TMEM2 and inhibiting PI3k/Akt activation during intestinal I/R. The current study shows that HRD1 is an intestinal I/R critical regulator and that targeting the HRD1/TMEM2 axis may be a promising therapeutic approach.

The role of endoplasmic reticulum-mitochondria-associated membranes in diabetic kidney disease.

Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease worldwide. The pathomechanisms of DKD are multifactorial, yet haemodynamic and metabolic changes in the early stages of the disease appear to predispose towards irreversible functional loss and histopathological changes. Recent studies highlight the importance of endoplasmic reticulum-mitochondria-associated membranes (ER-MAMs), structures conveying important cellular homeostatic and metabolic effects, in the pathology of DKD. Disruption of ER-MAM integrity in diabetic kidneys is associated with DKD progression, but the regulation of ER-MAMs and their pathogenic contribution remain largely unknown. Exploring the cell-specific components and dynamic changes of ER-MAMs in diabetic kidneys may lead to the identification of new approaches to detect and stratify diabetic patients with DKD. In addition, these insights may lead to novel therapeutic approaches to target and/or reverse disease progression. In this review, we discuss the association of ER-MAMs with key pathomechanisms driving DKD such as insulin resistance, dyslipidaemia, ER stress, and inflammasome activation and the importance of further exploration of ER-MAMs as diagnostic and therapeutic targets in DKD.

Cholesterol-induced HRD1 reduction accelerates vascular smooth muscle cell senescence via stimulation of endoplasmic reticulum stress-induced reactive oxygen species.

Senescence of vascular smooth muscle cells (VSMCs) is a key contributor to plaque vulnerability in atherosclerosis (AS), which is affected by endoplasmic reticulum (ER) stress and reactive oxygen species (ROS) production. However, the crosstalk between ER stress and ROS production in the pathogenesis of VSMC senescence remains to be elucidated. ER-associated degradation (ERAD) is a complex process that clears unfolded or misfolded proteins to maintain ER homeostasis. HRD1 is the major E3 ligase in mammalian ERAD machineries that catalyzes ubiquitin conjugation to the unfolded or misfolded proteins for degradation. Our results showed that HRD1 protein levels were reduced in human AS plaques and aortic roots from ApoE-/- mice fed with high-fat diet (HFD), along with the increased ER stress response. Exposure to cholesterol in VSMCs activated inflammatory signaling and induced senescence, while reduced HRD1 protein expression. CRISPR Cas9-mediated HRD1 knockout (KO) exacerbated cholesterol- and thapsigargin-induced cell senescence. Inhibiting ER stress with 4-PBA (4-Phenylbutyric acid) partially reversed the ROS production and cell senescence induced by HRD1 deficiency in VSMCs, suggesting that ER stress alone could be sufficient to induce ROS production and senescence in VSMCs. Besides, HRD1 deficiency led to mitochondrial dysfunction, and reducing ROS production from impaired mitochondria partly reversed HRD1 deficiency-induced cell senescence. Finally, we showed that the overexpression of HDR1 reversed cholesterol-induced ER stress, ROS production, and cellular senescence in VSMCs. Our findings indicate that HRD1 protects against senescence by maintaining ER homeostasis and mitochondrial functionality. Thus, targeting HRD1 function may help to mitigate VSMC senescence and prevent vascular aging related diseases. TRIAL REGISTRATION: A real-world study based on the discussion of primary and secondary prevention strategies for coronary heart disease, URL:https://www.clinicaltrials.gov, the trial registration number is [2022]-02-121-01.

DDRGK1-mediated ER-phagy attenuates acute kidney injury through ER-stress and apoptosis.

Acute kidney injury (AKI) constitutes a prevalent clinical syndrome characterized by elevated morbidity and mortality rates, emerging as a significant public health issue. This study investigates the interplay between endoplasmic reticulum (ER) stress, unfolded protein response (UPR), and ER-associated degradation (ER-phagy) in the pathogenesis of AKI. We employed four distinct murine models of AKI-induced by contrast media, ischemia-reperfusion injury, cisplatin, and folic acid-to elucidate the relationship between ER-phagy, ER stress, and apoptosis. Our findings reveal a marked decrease in ER-phagy coinciding with an accumulation of damaged ER, elevated ER stress, and increased apoptosis across all AKI models. Importantly, overexpression of DDRGK1 in HK-2 cells enhanced ER-phagy levels, ameliorating contrast-induced ER stress and apoptosis. These findings unveil a novel protective mechanism in AKI, wherein DDRGK1-UFL1-mediated ER-phagy mitigates ER stress and apoptosis in renal tubular epithelial cells. Our results thereby contribute to understanding the molecular underpinnings of AKI and offer potential therapeutic targets for its treatment.

Adaptive changes in tumor cells in response to reductive stress.

Reductive stress is characterized by an excess of cellular electron donors and can be linked with various human pathologies including cancer. We developed melanoma cell lines resistant to reductive stress agents: rotenone (ROTR), n-acetyl-L-cysteine, (NACR), or dithiothreitol (DTTR). Resistant cells divided more rapidly and had intracellular homeostatic redox-couple ratios that were shifted towards the reduced state. Resistance caused alterations in general cell morphology, but only ROTR cells had significant changes in mitochondrial morphology with higher numbers that were more isolated, fragmented and swollen, with greater membrane depolarization and decreased numbers of networks. These changes were accompanied by lower basal oxygen consumption and maximal respiration rates. Whole cell flux analyses and mitochondrial function assays showed that NACR and DTTR preferentially utilized tricarboxylic acid (TCA) cycle intermediates, while ROTR used ketone body substrates such as D, L-ß-hydroxybutyric acid. NACR and DTTR cells had constitutively decreased levels of reactive oxygen species (ROS), although this was accompanied by activation of nuclear factor erythroid 2-related factor 2 (Nrf2), with concomitant increased expression of the downstream gene products such as glutathione S-transferase P (GSTP). Further adaptations included enhanced expression of endoplasmic reticulum proteins controlling the unfolded protein response (UPR). Although expression patterns of these UPR proteins were distinct between the resistant cells, a trend implied that resistance to reductive stress is accompanied by a constitutively increased UPR phenotype in each line. Overall, tumor cells, although tolerant of oxidative stress, can adapt their energy and survival mechanisms in lethal reductive stress conditions.

Unfolded Protein Response Signaling in Hepatic Stem Cell Activation in Liver Fibrosis.

Frequent exposure to various external and internal adverse forces (stresses) disrupts cell protein homeostasis through endoplasmic reticulum (ER) capacity saturation. This process leads to the unfolded protein response (UPR), which aims to re-establish/maintain optimal cellular equilibrium. This complex mechanism is involved in the pathogenesis of various disorders, such as metabolic syndrome, fibrotic diseases, neurodegeneration, and cancer, by altering cellular metabolic changes integral to activating the hepatic stellate cells (HSCs). The development of hepatic fibrosis is one of the consequences of UPR activation. Therefore, novel therapies that target the UPR pathway effectively and specifically are being studied. This article covers the involvement of the UPR signaling pathway in cellular damage in liver fibrosis. Investigating the pathogenic pathways related to the ER/UPR stress axis that contribute to liver fibrosis can help to guide future drug therapy approaches.

Induction mechanisms of autophagy and endoplasmic reticulum stress in intestinal ischemia-reperfusion injury, inflammatory bowel disease, and colorectal cancer.

In recent years, the incidence of intestinal ischemia-reperfusion injury (II/RI), inflammatory bowel disease (IBD), and colorectal cancer (CRC) has been gradually increasing, posing significant threats to human health. Autophagy and endoplasmic reticulum stress (ERS) play important roles in II/RI. Damage caused by ischemia and cellular stress can activate ERS, which in turn initiates autophagy to clear damaged organelles and abnormal proteins, thereby alleviating ERS and maintaining the intestinal environment. In IBD, chronic inflammation damages intestinal tissues and activates autophagy and ERS. Autophagy is initiated by upregulating ATG genes and downregulating factors that inhibit autophagy, thereby clearing abnormal proteins, damaged organelles, and bacteria. Simultaneously, persistent inflammatory stimulation can also trigger ERS, leading to protein imbalance and abnormal folding in the ER lumen. The activation of ERS can maintain cellular homeostasis by initiating the autophagy process, thereby reducing inflammatory responses and cell apoptosis in the intestine. In CRC, excessive cell proliferation and protein synthesis lead to increased ERS. The activation of ERS, regulated by signaling pathways such as IRE1α and PERK, can initiate autophagy to clear abnormal proteins and damaged organelles, thereby reducing the negative effects of ERS. It can be seen that autophagy and ERS play a crucial regulatory role in the development of intestinal diseases. Therefore, the progress in targeted therapy for intestinal diseases based on autophagy and ERS provides novel strategies for managing intestinal diseases. In this paper, we review the advances in regulation of autophagy and ERS in intestinal diseases, emphasizing the potential molecular mechanisms for therapeutic applications.

The endoplasmic reticulum: Homeostasis and crosstalk in retinal health and disease.

The endoplasmic reticulum (ER) is the largest intracellular organelle carrying out a broad range of important cellular functions including protein biosynthesis, folding, and trafficking, lipid and sterol biosynthesis, carbohydrate metabolism, and calcium storage and gated release. In addition, the ER makes close contact with multiple intracellular organelles such as mitochondria and the plasma membrane to actively regulate the biogenesis, remodeling, and function of these organelles. Therefore, maintaining a homeostatic and functional ER is critical for the survival and function of cells. This vital process is implemented through well-orchestrated signaling pathways of the unfolded protein response (UPR). The UPR is activated when misfolded or unfolded proteins accumulate in the ER, a condition known as ER stress, and functions to restore ER homeostasis thus promoting cell survival. However, prolonged activation or dysregulation of the UPR can lead to cell death and other detrimental events such as inflammation and oxidative stress; these processes are implicated in the pathogenesis of many human diseases including retinal disorders. In this review manuscript, we discuss the unique features of the ER and ER stress signaling in the retina and retinal neurons and describe recent advances in the research to uncover the role of ER stress signaling in neurodegenerative retinal diseases including age-related macular degeneration, inherited retinal degeneration, achromatopsia and cone diseases, and diabetic retinopathy. In some chapters, we highlight the complex interactions between the ER and other intracellular organelles focusing on mitochondria and illustrate how ER stress signaling regulates common cellular stress pathways such as autophagy. We also touch upon the integrated stress response in retinal degeneration and diabetic retinopathy. Finally, we provide an update on the current development of pharmacological agents targeting the UPR response and discuss some unresolved questions and knowledge gaps to be addressed by future research.