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The International Journal of... Jan 2012Endoplasmic reticulum (ER) stress activates an adaptive unfolded protein response (UPR) that facilitates cellular repair, however, under prolonged ER stress, the UPR can... (Review)
Review
Endoplasmic reticulum (ER) stress activates an adaptive unfolded protein response (UPR) that facilitates cellular repair, however, under prolonged ER stress, the UPR can ultimately trigger apoptosis thereby terminating damaged cells. The molecular mechanisms responsible for execution of the cell death program are relatively well characterized, but the metabolic events taking place during the adaptive phase of ER stress remain largely undefined. Here we discuss emerging evidence regarding the metabolic changes that occur during the onset of ER stress and how ER influences mitochondrial function through mechanisms involving calcium transfer, thereby facilitating cellular adaptation. Finally, we highlight how dysregulation of ER-mitochondrial calcium homeostasis during prolonged ER stress is emerging as a novel mechanism implicated in the onset of metabolic disorders.
Topics: Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Energy Metabolism; Humans; Mitochondria
PubMed: 22064245
DOI: 10.1016/j.biocel.2011.10.012 -
Molecular Neurobiology 2015Endoplasmic reticulum (ER) stress plays an important role in a range of neurological disorders, such as neurodegenation diseases, cerebral ischemia, spinal cord injury,... (Review)
Review
Endoplasmic reticulum (ER) stress plays an important role in a range of neurological disorders, such as neurodegenation diseases, cerebral ischemia, spinal cord injury, sclerosis, and diabetic neuropathy. Protein misfolding and accumulation in the ER lumen initiate unfolded protein response in energy-starved neurons which are relevant to toxic effects. In neurological disorders, such as Alzheimer's disease, Parkinson's disease, and Huntington's disease, ER dysfunction is well recognized, but the mechanisms remain unclear. In stroke and ischemia, spinal cord injury, and amyotrophic lateral sclerosis, chronic activation of ER stress is considered as main pathogeny which causes neuronal disorders. By targeting components of these ER signaling responses, to explore clinical treatment strategies or new drugs in CNS neurological diseases might become possible and valuable in the future.
Topics: Animals; Central Nervous System Diseases; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Humans; Neurons; Signal Transduction; Unfolded Protein Response
PubMed: 25048984
DOI: 10.1007/s12035-014-8813-7 -
Annual Review of Pathology 2008The endoplasmic reticulum (ER) is the site of synthesis and folding of membrane and secretory proteins, which, collectively, represent a large fraction of the total... (Review)
Review
The endoplasmic reticulum (ER) is the site of synthesis and folding of membrane and secretory proteins, which, collectively, represent a large fraction of the total protein output of a mammalian cell. Therefore, the protein flux through the ER must be carefully monitored for abnormalities, including the buildup of misfolded proteins. Mammalian cells have evolved an intricate set of signaling pathways from the ER to the cytosol and nucleus, to allow the cell to respond to the presence of misfolded proteins within the ER. These pathways, known collectively as the unfolded protein response, are important for normal cellular homeostasis and organismal development and may also play key roles in the pathogenesis of many diseases. This review provides background information on the unfolded protein response and discusses a selection of diseases whose pathogenesis involves ER stress.
Topics: Animals; Endoplasmic Reticulum; Humans; Metabolism, Inborn Errors; Protein Folding; Signal Transduction; Stress, Physiological
PubMed: 18039139
DOI: 10.1146/annurev.pathmechdis.3.121806.151434 -
Current Opinion in Cell Biology Aug 2006The endoplasmic reticulum (ER) is a dynamic pleiomorphic organelle containing continuous but distinct subdomains. The diversity of ER structures parallels its many... (Review)
Review
The endoplasmic reticulum (ER) is a dynamic pleiomorphic organelle containing continuous but distinct subdomains. The diversity of ER structures parallels its many functions, including secretory protein biogenesis, lipid synthesis, drug metabolism and Ca2+ signaling. Recent studies are revealing how elaborate ER structures arise in response to subtle changes in protein levels, dynamics, and interactions as well as in response to alterations in cytosolic ion concentrations. Subdomain formation appears to be governed by principles of self-organization. Once formed, ER subdomains remain malleable and can be rapidly transformed into alternative structures in response to altered conditions. The mechanisms that modulate ER structure are likely to be important for the generation of the characteristic shapes of other organelles.
Topics: Animals; Endoplasmic Reticulum; Humans
PubMed: 16806883
DOI: 10.1016/j.ceb.2006.06.008 -
Trends in Cell Biology Jun 2009The concept of the presence of sarcoplasmic reticulum (SR) membrane in the heart is widely accepted and has been considered merely to be a different name for the... (Review)
Review
The concept of the presence of sarcoplasmic reticulum (SR) membrane in the heart is widely accepted and has been considered merely to be a different name for the endoplasmic reticulum (ER) in muscle tissues. Cardiac SR membranes are specialized in the regulation of Ca(2+) transport and control of excitation-contraction coupling. By contrast, the ER is responsible for protein synthesis, modification, secretion, lipid and steroid synthesis, and modulation of Ca(2+) signaling. Recent developments have indicated that functional changes in proteins or pathways normally associated with ER and not SR membrane impact cardiac development and pathology. Here, we propose that the SR and ER might be functionally distinct internal membrane compartments in cardiomyocytes.
Topics: Animals; Endoplasmic Reticulum; Heart; Humans; Sarcoplasmic Reticulum
PubMed: 19409791
DOI: 10.1016/j.tcb.2009.03.006 -
Circulation Research Nov 2007Over the last decade, it has become clear that the accumulation of misfolded proteins contributes to a number of neurodegenerative, immune, and endocrine pathologies, as... (Review)
Review
Over the last decade, it has become clear that the accumulation of misfolded proteins contributes to a number of neurodegenerative, immune, and endocrine pathologies, as well as other age-related illnesses. Recent interest has focused on the possibility that the accumulation of misfolded proteins can also contribute to vascular and cardiac diseases. In large part, the misfolding of proteins takes place during synthesis on free ribosomes in the cytoplasm or on endoplasmic reticulum ribosomes. In fact, even under optimal conditions, approximately 30% of all newly synthesized proteins are rapidly degraded, most likely because of improper folding. Accordingly, stresses that perturb the folding of proteins during or soon after synthesis can lead to the accumulation of misfolded proteins and to potential cellular dysfunction and pathological consequences. To avert such outcomes, cells have developed elaborate protein quality-control systems for detecting misfolded proteins and making appropriate adjustments to the machinery responsible for protein synthesis and/or degradation. Important contributors to protein quality control include cytosolic and organelle-targeted molecular chaperones, which help fold and stabilize proteins from unfolding, and the ubiquitin proteasome system, which degrades terminally misfolded proteins. Both of these systems play important roles in cardiovascular biology. The focus of this review is the endoplasmic reticulum stress response, a protein quality-control and signal-transduction system that has not been well studied in the context of cardiovascular biology but that could be important for vascular and cardiac health and disease.
Topics: Animals; Cardiovascular Diseases; Endoplasmic Reticulum; Humans; Myocardium; Protein Folding; Protein Transport
PubMed: 17991891
DOI: 10.1161/CIRCRESAHA.107.161273 -
Current Opinion in Cell Biology Apr 2011Upon endoplasmic reticulum (ER) stress, ER-located transmembrane stress sensors evoke diverse protective responses. Although ER stress-dependent activation of the sensor... (Review)
Review
Upon endoplasmic reticulum (ER) stress, ER-located transmembrane stress sensors evoke diverse protective responses. Although ER stress-dependent activation of the sensor proteins is partly explained through their negative regulation by the ER-located chaperone BiP under non-stress conditions, each of the sensors is also regulated by distinct mechanism(s). For instance, yeast Ire1 is fully activated via its direct interaction with unfolded proteins accumulated in the ER. This insight is consistent with a classical notion that unfolded proteins per se trigger ER-stress responses, while various stress stimuli also seem to activate individual sensors independently of unfolded proteins and in a stimuli-specific manner. These properties may account for the different responses observed under different conditions in mammalian cells, which carry multiple ER-stress sensors.
Topics: Animals; Endoplasmic Reticulum; Endoplasmic Reticulum Chaperone BiP; Heat-Shock Proteins; Humans; Mammals; Protein Unfolding; Stress, Physiological; Yeasts
PubMed: 21093243
DOI: 10.1016/j.ceb.2010.10.008 -
International Review of Cell and... 2013The endoplasmic reticulum (ER) is a dynamic intracellular organelle with multiple functions essential for cellular homeostasis, development, and stress responsiveness.... (Review)
Review
The endoplasmic reticulum (ER) is a dynamic intracellular organelle with multiple functions essential for cellular homeostasis, development, and stress responsiveness. In response to cellular stress, a well-established signaling cascade, the unfolded protein response (UPR), is activated. This intricate mechanism is an important means of re-establishing cellular homeostasis and alleviating the inciting stress. Now, emerging evidence has demonstrated that the UPR influences cellular metabolism through diverse mechanisms, including calcium and lipid transfer, raising the prospect of involvement of these processes in the pathogenesis of disease, including neurodegeneration, cancer, diabetes mellitus and cardiovascular disease. Here, we review the distinct functions of the ER and UPR from a metabolic point of view, highlighting their association with prevalent pathologies.
Topics: Animals; Disease; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Humans; Proteolysis; Unfolded Protein Response
PubMed: 23317820
DOI: 10.1016/B978-0-12-407704-1.00005-1 -
Zhonghua Yi Xue Yi Chuan Xue Za Zhi =... Jun 2023Epilepsies are a group of chronic neurological disorders characterized by spontaneous recurrent seizures caused by abnormal synchronous firing of neurons and transient... (Review)
Review
Epilepsies are a group of chronic neurological disorders characterized by spontaneous recurrent seizures caused by abnormal synchronous firing of neurons and transient brain dysfunction. The underlying mechanisms are complex and not yet fully understood. Endoplasmic reticulum (ER) stress, as a condition of excessive accumulation of unfolded and/or misfolded proteins in the ER lumen, has been considered as a pathophysiological mechanism of epilepsy in recent years. ER stress can enhance the protein processing capacity of the ER to restore protein homeostasis through unfolded protein response, which may inhibit protein translation and promote misfolded protein degradation through the ubiquitin-proteasome system. However, persistent ER stress can also cause neuronal apoptosis and loss, which may aggravate the brain damage and epilepsy. This review has summarized the role of ER stress in the pathogenesis of genetic epilepsy.
Topics: Humans; Endoplasmic Reticulum Stress; Unfolded Protein Response; Endoplasmic Reticulum; Apoptosis; Epilepsy
PubMed: 37212016
DOI: 10.3760/cma.j.cn511374-20221027-00724 -
Antioxidants & Redox Signaling Dec 2007Pancreatic beta-cells are specialized for the production and regulated secretion of insulin to control blood-glucose levels. Increasing evidence indicates that... (Review)
Review
Pancreatic beta-cells are specialized for the production and regulated secretion of insulin to control blood-glucose levels. Increasing evidence indicates that stress-signaling pathways emanating from the endoplasmic reticulum (ER) are important in the maintenance of beta-cell homeostasis. Under physiological conditions, ER stress signaling has beneficial effects on beta-cells. Timely and proper activation of ER stress signaling is crucial for generating the proper amount of insulin in proportion to the need for it. In contrast, chronic and strong activation of ER stress signaling has harmful effects, leading to beta-cell dysfunction and death. Therefore, to dissect the molecular mechanisms of beta-cell failure and death in diabetes, it is necessary to understand the complex network of ER stress-signaling pathways. This review focuses on the function of the ER stress-signaling network in pancreatic beta-cells.
Topics: Animals; Endoplasmic Reticulum; Humans; Insulin-Secreting Cells; Models, Biological; Pancreas; Signal Transduction; Stress, Physiological
PubMed: 17894546
DOI: 10.1089/ars.2007.1790