scholarly journals The unfolded protein response in relation to mitochondrial biogenesis in skeletal muscle cells

2017 ◽  
Vol 312 (5) ◽  
pp. C583-C594 ◽  
Author(s):  
Zahra S. Mesbah Moosavi ◽  
David A. Hood
Keyword(s):  
Er Stress ◽  
Mitochondrial Biogenesis ◽  
Contractile Activity ◽  
Muscle Cells ◽  
Unfolded Proteins ◽  
Protein Levels ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Mitochondrial Adaptations

Mitochondria comprise both nuclear and mitochondrially encoded proteins requiring precise stoichiometry for their integration into functional complexes. The augmented protein synthesis associated with mitochondrial biogenesis results in the accumulation of unfolded proteins, thus triggering cellular stress. As such, the unfolded protein responses emanating from the endoplasmic reticulum (UPRER) or the mitochondrion (UPRMT) are triggered to ensure correct protein handling. Whether this response is necessary for mitochondrial adaptations is unknown. Two models of mitochondrial biogenesis were used: muscle differentiation and chronic contractile activity (CCA) in murine muscle cells. After 4 days of differentiation, our findings depict selective activation of the UPRMTin which chaperones decreased; however, Sirt3 and UPRERmarkers were elevated. To delineate the role of ER stress in mitochondrial adaptations, the ER stress inhibitor TUDCA was administered. Surprisingly, mitochondrial markers COX-I, COX-IV, and PGC-1α protein levels were augmented up to 1.5-fold above that of vehicle-treated cells. Similar results were obtained in myotubes undergoing CCA, in which biogenesis was enhanced by ~2–3-fold, along with elevated UPRMTmarkers Sirt3 and CPN10. To verify whether the findings were attributable to the terminal UPRERbranch directed by the transcription factor CHOP, cells were transfected with CHOP siRNA. Basally, COX-I levels increased (~20%) and COX-IV decreased (~30%), suggesting that CHOP influences mitochondrial composition. This effect was fully restored by CCA. Therefore, our results suggest that mitochondrial biogenesis is independent of the terminal UPRER. Under basal conditions, CHOP is required for the maintenance of mitochondrial composition, but not for differentiation- or CCA-induced mitochondrial biogenesis.

scholarly journals The Role of the ER-Induced UPR Pathway and the Efficacy of Its Inhibitors and Inducers in the Inhibition of Tumor Progression

2019 ◽  
Vol 2019 ◽  
pp. 1-15 ◽  
Author(s):  
Anna Walczak ◽  
Kinga Gradzik ◽  
Jacek Kabzinski ◽  
Karolina Przybylowska-Sygut ◽  
Ireneusz Majsterek
Keyword(s):  
Er Stress ◽  
Molecular Mechanisms ◽  
Unfolded Proteins ◽  
Cell Protection ◽  
Protection Mechanism ◽  
Unfolded Protein ◽  
Er Stress Response ◽  
A Cell ◽  
The Unfolded Protein Response ◽  
Protein Response

Cancer is the second most frequent cause of death worldwide. It is considered to be one of the most dangerous diseases, and there is still no effective treatment for many types of cancer. Since cancerous cells have a high proliferation rate, it is pivotal for their proper functioning to have the well-functioning protein machinery. Correct protein processing and folding are crucial to maintain tumor homeostasis. Endoplasmic reticulum (ER) stress is one of the leading factors that cause disturbances in these processes. It is induced by impaired function of the ER and accumulation of unfolded proteins. Induction of ER stress affects many molecular pathways that cause the unfolded protein response (UPR). This is the way in which cells can adapt to the new conditions, but when ER stress cannot be resolved, the UPR induces cell death. The molecular mechanisms of this double-edged sword process are involved in the transition of the UPR either in a cell protection mechanism or in apoptosis. However, this process remains poorly understood but seems to be crucial in the treatment of many diseases that are related to ER stress. Hence, understanding the ER stress response, especially in the aspect of pathological consequences of UPR, has the potential to allow us to develop novel therapies and new diagnostic and prognostic markers for cancer.

scholarly journals Possible involvement of endoplasmic reticulum stress in the pathogenesis of Alzheimer’s disease

2015 ◽  
Vol 2 (1) ◽  
Author(s):  
Toru Hosoi ◽  
Jun Nomura ◽  
Koichiro Ozawa ◽  
Akinori Nishi ◽  
Yasuyuki Nomura
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Protein Quality ◽  
Unfolded Proteins ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

AbstractThe endoplasmic reticulum (ER) is an organelle that plays a crucial role in protein quality control such as protein folding. Evidence to indicate the involvement of ER in maintaining cellular homeostasis is increasing. However, when cells are exposed to stressful conditions, which perturb ER function, unfolded proteins accumulate leading to ER stress. Cells then activate the unfolded protein response (UPR) to cope with this stressful condition. In the present review, we will discuss and summarize recent advances in research on the basic mechanisms of the UPR. We also discuss the possible involvement of ER stress in the pathogenesis of Alzheimer’s disease (AD). Potential therapeutic opportunities for diseases targeting ER stress is also described.

scholarly journals Endoplasmic reticulum stress as target for treatment of hearing loss

STEMedicine ◽  
2020 ◽  
Vol 1 (3) ◽  
pp. e21
Author(s):  
Yanfei Wang ◽  
Zhigang Xu
Keyword(s):  
Endoplasmic Reticulum ◽  
Hearing Loss ◽  
Er Stress ◽  
Protein Biosynthesis ◽  
Unfolded Proteins ◽  
Unfolded Protein ◽  
Global Protein Synthesis ◽  
Acquired Hearing Loss ◽  
The Unfolded Protein Response ◽  
Protein Response

The endoplasmic reticulum (ER) plays pivotal roles in coordinating protein biosynthesis and processing. Under ER stress, when excessive misfolded or unfolded proteins are accumulated in the ER, the unfolded protein response (UPR) is activated. The UPR blocks global protein synthesis while activates chaperone expression, eventually leading to the alleviation of ER stress. However, prolonged UPR induces cell death. ER stress has been associated with various types of diseases. Recently, increasing evidences suggest that ER stress and UPR are also involved in hearing loss. In the present review, we will discuss the role of ER stress in hereditary hearing loss as well as acquired hearing loss. Moreover, we will discuss the emerging ER stress-based treatment of hearing loss. Further investigations are warranted to understand the mechanisms in detail how ER stress contributes to hearing loss, which will help us develop better ER stress-related treatments.

Endoplasmic reticulum stress in biological processing and disease

2021 ◽  
Vol 69 (2) ◽  
pp. 309-315
Author(s):  
Ali Riza Koksal ◽  
George Nicholas Verne ◽  
QiQi Zhou
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Chronic Diseases ◽  
Unfolded Proteins ◽  
Unfolded Protein ◽  
Inflammatory Bowel ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Er Homeostasis ◽  
Multiple Signaling

The ability of translated cellular proteins to perform their functions requires their proper folding after synthesis. The endoplasmic reticulum (ER) is responsible for coordinating protein folding and maturation. Infections, genetic mutations, environmental factors and many other conditions can lead to challenges to the ER known as ER stress. Altering ER homeostasis results in accumulation of misfolded or unfolded proteins. To eliminate this problem, a response is initiated by the cell called the unfolded protein response (UPR), which involves multiple signaling pathways. Prolonged ER stress or a dysregulated UPR can lead to premature apoptosis and an exaggerated inflammatory response. Following these discoveries, ER stress was shown to be related to several chronic diseases, such as diabetes mellitus, neurodegenerative disorders, fatty liver disease and inflammatory bowel disease that have not yet been clearly demonstrated pathophysiologically. Here, we review the field and present up-to-date information on the relationship between biological processing, ER stress, UPR, and several chronic diseases.

scholarly journals Loss of Dicer1 in mouse embryonic fibroblasts impairs ER stress-induced apoptosis

2015 ◽  
Author(s):  
Ananya Gupta ◽  
Danielle Read ◽  
Deepu Oommen ◽  
Afshin Samali ◽  
SANJEEV GUPTA
Keyword(s):  
Er Stress ◽  
Mirna Biogenesis ◽  
Unfolded Proteins ◽  
Embryonic Fibroblasts ◽  
Unfolded Protein ◽  
Critical Components ◽  
Induced Apoptosis ◽  
The Unfolded Protein Response ◽  
Protein Response

The endoplasmic reticulum (ER) is the site of folding for membrane and secreted proteins. Accumulation of unfolded or misfolded proteins in the ER triggers the unfolded protein response (UPR). The UPR can promote survival by reducing the load of unfolded proteins through upregulation of chaperones and global attenuation of protein synthesis. However, when ER stress is acute or prolonged cells undergo apoptosis. In this study we sought to determine the effect of globally compromised microRNA biogenesis on the UPR and ER stress-induced apoptosis. Here we report the role of Dicer-dependent miRNA biogenesis during the UPR and ER stress-induced apoptosis. We show that ER stress-induced caspase activation and apoptosis is attenuated in Dicer deficient fibroblasts. ER stress-mediated induction of GRP78, the key ER resident chaperone, and also HERP, an important component of ER-associated degradation, are significantly increased in Dicer deficient cells. Expression of the BCL-2 family members BIM and MCL1 were significantly higher in Dicer-null fibroblasts. However, ER stress-mediated induction of pro-apoptotic BH3 only protein BIM was compromised in Dicer mutant cells.These observations demonstrate key roles for Dicer in the UPR and implicate miRNAs as critical components of UPR.

scholarly journals Methods for Monitoring Endoplasmic Reticulum Stress and the Unfolded Protein Response

2010 ◽  
Vol 2010 ◽  
pp. 1-11 ◽  
Author(s):  
Afshin Samali ◽  
Una FitzGerald ◽  
Shane Deegan ◽  
Sanjeev Gupta
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Model Systems ◽  
Unfolded Proteins ◽  
Unfolded Protein ◽  
Cellular Repair ◽  
Standard Set ◽  
The Unfolded Protein Response ◽  
Protein Response

The endoplasmic reticulum (ER) is the site of folding of membrane and secreted proteins in the cell. Physiological or pathological processes that disturb protein folding in the endoplasmic reticulum cause ER stress and activate a set of signaling pathways termed the Unfolded Protein Response (UPR). The UPR can promote cellular repair and sustained survival by reducing the load of unfolded proteins through upregulation of chaperones and global attenuation of protein synthesis. Research into ER stress and the UPR continues to grow at a rapid rate as many new investigators are entering the field. There are also many researchers not working directly on ER stress, but who wish to determine whether this response is activated in the system they are studying: thus, it is important to list a standard set of criteria for monitoring UPR in different model systems. Here, we discuss approaches that can be used by researchers to plan and interpret experiments aimed at evaluating whether the UPR and related processes are activated. We would like to emphasize that no individual assay is guaranteed to be the most appropriate one in every situation and strongly recommend the use of multiple assays to verify UPR activation.

Stressed to death – mechanisms of ER stress-induced cell death

2014 ◽  
Vol 395 (1) ◽  
pp. 1-13 ◽  
Author(s):  
Natalia Sovolyova ◽  
Sandra Healy ◽  
Afshin Samali ◽  
Susan E. Logue
Keyword(s):  
Cell Death ◽  
Er Stress ◽  
Post Translational Modification ◽  
Unfolded Proteins ◽  
Unfolded Protein ◽  
Cell Death Pathway ◽  
The Unfolded Protein Response ◽  
And Function ◽  
Protein Response ◽  
Er Homeostasis

Abstract The endoplasmic reticulum (ER) is a highly dynamic organelle of fundamental importance present in all eukaryotic cells. The majority of synthesized structural and secreted proteins undergo post-translational modification, folding and oligomerization in the ER lumen, enabling proteins to carry out their physiological functions. Therefore, maintenance of ER homeostasis and function is imperative for proper cellular function. Physiological and pathological conditions can disturb ER homeostasis and thus negatively impact upon protein folding, resulting in an accumulation of unfolded proteins. Examples include hypoxia, hypo- and hyperglycemia, acidosis, and fluxes in calcium levels. Increased levels of unfolded/misfolded proteins within the ER lumen triggers a condition commonly referred to as ‘ER stress’. To combat ER stress, cells have evolved a highly conserved adaptive stress response referred to as the unfolded protein response (UPR). UPR signaling affords the cell a ‘window of opportunity’ for stress resolution however, if prolonged or excessive the UPR is insufficient and ER stress-induced cell death ensues. This review discusses the role of ER stress sensors IRE1, PERK and ATF6, describing their role in ER stress-induced death signaling with specific emphasis placed upon the importance of the intrinsic cell death pathway and Bcl-2 family regulation.

scholarly journals Calnexin Is Involved in Apoptosis Induced by Endoplasmic Reticulum Stress in the Fission Yeast

2008 ◽  
Vol 19 (10) ◽  
pp. 4404-4420 ◽  
Author(s):  
Renée Guérin ◽  
Geneviève Arseneault ◽  
Stéphane Dumont ◽  
Luis A. Rokeach
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Er Stress ◽  
Transmembrane Domain ◽  
Unfolded Proteins ◽  
Unfolded Protein ◽  
Apoptotic Death ◽  
Apoptosis Markers ◽  
The Unfolded Protein Response ◽  
Protein Response

Stress conditions affecting the functions of the endoplasmic reticulum (ER) cause the accumulation of unfolded proteins. ER stress is counteracted by the unfolded-protein response (UPR). However, under prolonged stress the UPR initiates a proapoptotic response. Mounting evidence indicate that the ER chaperone calnexin is involved in apoptosis caused by ER stress. Here, we report that overexpression of calnexin in Schizosaccharomyces pombe induces cell death with apoptosis markers. Cell death was partially dependent on the Ire1p ER-stress transducer. Apoptotic death caused by calnexin overexpression required its transmembrane domain (TM), and involved sequences on either side of the ER membrane. Apoptotic death caused by tunicamycin was dramatically reduced in a strain expressing endogenous levels of calnexin lacking its TM and cytosolic tail. This demonstrates the involvement of calnexin in apoptosis triggered by ER stress. A genetic screen identified the S. pombe homologue of the human antiapoptotic protein HMGB1 as a suppressor of apoptotic death due to calnexin overexpression. Remarkably, overexpression of human calnexin in S. pombe also provoked apoptotic death. Our results argue for the conservation of the role of calnexin in apoptosis triggered by ER stress, and validate S. pombe as a model to elucidate the mechanisms of calnexin-mediated cell death.

Endoplasmic reticulum stress and unfolded protein response in renal pathophysiology: Janus faces

2008 ◽  
Vol 295 (2) ◽  
pp. F323-F334 ◽  
Author(s):  
Masanori Kitamura
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Current Knowledge ◽  
Renal Diseases ◽  
Unfolded Proteins ◽  
Diverse Range ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

A number of pathophysiological insults lead to accumulation of unfolded proteins in the endoplasmic reticulum (ER) and cause ER stress. In response to accumulation of unfolded/misfolded proteins, cells adapt themselves to the stress condition via the unfolded protein response (UPR). For the cells, UPR is a double-edged sword. It triggers both prosurvival and proapoptotic signals. ER stress and UPR may, therefore, be involved in a diverse range of pathological situations. However, currently, information is limited regarding roles of ER stress and UPR in the renal pathophysiology. This review describes current knowledge on the relationship between ER stress and diseases and summarizes evidence for the link between ER stress/UPR and renal diseases.

scholarly journals The interdomain helix between the kinase and RNase domains of IRE1α transmits the conformational change that underlies ER stress-induced activation

2020 ◽  
Author(s):  
Daniela Ricci ◽  
Stephen Tutton ◽  
Ilaria Marrocco ◽  
Mingjie Ying ◽  
Daniel Blumenthal ◽  
...  
Keyword(s):  
Er Stress ◽  
Conformational Changes ◽  
Kinase Activity ◽  
Rnase Activity ◽  
Unfolded Proteins ◽  
Unfolded Protein ◽  
Detection Of Stress ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Biochemical Signals

AbstractThe unfolded protein response (UPR) plays an evolutionarily conserved role in homeostasis, and its dysregulation often leads to human disease, including diabetes and cancer. IRE1α is a major transducer that conveys endoplasmic reticulum (ER) stress to biochemical signals, yet major gaps persist in our understanding of how the detection of stress is converted to one of several molecular outcomes. It is known that upon sensing unfolded proteins via its ER luminal domain, IRE1α dimerizes and oligomerizes (often visualized as clustering), and then trans-autophosphorylates. The IRE1α kinase activity is required for activation of its RNase effector domain and for clustering of IRE1α. It is not yet clear if IRE1α clustering is a platform for the RNase activity, or if the two represent distinct biological functions. Here, we uncover a previously unrecognized role for helix αK between IRE1α kinase and RNase domains in conveying critical conformational changes. Using mutants within this inter-domain helix, we show for the first time that: 1) distinct substitutions (specifically, of Leu827) selectively affect oligomerization, RNase activity, and, unexpectedly, the kinase activity of IRE1α; 2) RNase activation can be uncoupled from IRE1α oligomerization, and phosphorylation of S729 marks the former but not the latter; 3) The nature of residue 827 determines the conformation that the IRE1α protein adopts, leading to different patterns of biochemical activities. In summary, this work reveals a previously unappreciated role for the inter-domain helix as a pivotal conduit for attaining the stress-responsive conformation of IRE1α.

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