Cell calciumPub Date : 2024-10-05DOI: 10.1016/j.ceca.2024.102958
Cristina Mammucari
{"title":"The intricacies of mitochondrial calcium and enzyme regulation in liver metabolism","authors":"Cristina Mammucari","doi":"10.1016/j.ceca.2024.102958","DOIUrl":"10.1016/j.ceca.2024.102958","url":null,"abstract":"<div><div>Mitochondrial Ca<sup>2+</sup> plays a positive role in regulating pyruvate dehydrogenase, as well as the TCA cycle enzymes isocitrate dehydrogenase and α-ketoglutarate dehydrogenase. This regulation boosts the production of reducing equivalents that fuel the electron transport chain, ultimately driving ATP production. The Mitochondrial Calcium Uniporter (MCU) is the highly selective channel responsible for mitochondrial Ca<sup>2+</sup> uptake when local Ca<sup>2+</sup> levels reach the threshold for channel activation. In a recent study, LaMoia et al. used an innovative [<sup>13</sup>C<sub>5</sub>]glutamine-based metabolic flux analysis method (Q-flux) to measure in vivo hepatic metabolic fluxes in liver-specific MCU<sup>-/-</sup> mice. Surprisingly, they observed increased flux through isocitrate dehydrogenase and α-ketoglutarate dehydrogenase. Metabolic pathways are continuously reorganized in response to intrinsic cellular signals, as well as hormonal and nutritional inputs. Integrating metabolic flux analysis into complex systems can provide deeper insights into how metabolic adaptations occur under different conditions.</div></div>","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"124 ","pages":"Article 102958"},"PeriodicalIF":4.3,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142406164","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell calciumPub Date : 2024-09-25DOI: 10.1016/j.ceca.2024.102957
Tal Brandwine-Shemmer , Baruch Minke , Irena Levitan
{"title":"Inhibition of TRPV1 by an antagonist in clinical trials is dependent on cholesterol binding","authors":"Tal Brandwine-Shemmer , Baruch Minke , Irena Levitan","doi":"10.1016/j.ceca.2024.102957","DOIUrl":"10.1016/j.ceca.2024.102957","url":null,"abstract":"<div><div>TRP Vanilloid 1 (TRPV1) channel, one of the major members of the TRP family was discovered to play a critical role in pain sensation, particularly inflammatory pain, and is associated with hyperalgesia, an enhanced sensitivity to pain. A new study by <em><u>Fan</u></em> <u>et al.</u> <em><u>“</u><u>Structural basis of TRPV1 inhibition by SAF312 and cholesterol</u></em>” sheds new light on the mechanistic structural basis of TRPV1 inhibition by SAF312 (Libvatrep), a TRPV1 antagonist, currently in phase II clinical trials. They discover that the binding site of SAF312 in TRPV1 is in close vicinity and partially overlaps with the binding site of cholesterol and that removal of cholesterol interferes with the ability of SAF312 to suppress TRPV1 current.</div></div>","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"124 ","pages":"Article 102957"},"PeriodicalIF":4.3,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142364555","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell calciumPub Date : 2024-09-23DOI: 10.1016/j.ceca.2024.102956
Martin J. Kelly , Jian Qiu
{"title":"TRPC5 channels play a critical role in mediating multiple behaviors in mice and men","authors":"Martin J. Kelly , Jian Qiu","doi":"10.1016/j.ceca.2024.102956","DOIUrl":"10.1016/j.ceca.2024.102956","url":null,"abstract":"","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"124 ","pages":"Article 102956"},"PeriodicalIF":4.3,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142364556","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell calciumPub Date : 2024-09-12DOI: 10.1016/j.ceca.2024.102955
Riccardo Filadi , Paola Pizzo
{"title":"Endoplasmic reticulum-mitochondria lockdown in Wolfram syndrome","authors":"Riccardo Filadi , Paola Pizzo","doi":"10.1016/j.ceca.2024.102955","DOIUrl":"10.1016/j.ceca.2024.102955","url":null,"abstract":"<div><p>Wolfram syndrome (WS) is an incurable autosomal recessive disorder originally described as a mitochondriopathy. In a recent work, Liiv and colleagues found that an impaired endoplasmic reticulum (ER)-to-mitochondria calcium shuttling underlies mitochondrial dysfunction in WS models.</p></div>","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"124 ","pages":"Article 102955"},"PeriodicalIF":4.3,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142232160","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell calciumPub Date : 2024-08-23DOI: 10.1016/j.ceca.2024.102947
Megan L. Perry , Kristen M. Varney , Pratyush Tiwary , David J. Weber , Erick O. Hernández-Ochoa
{"title":"Unveiling the intricate role of S100A1 in regulating RyR1 activity: A commentary on “Structural insights into the regulation of RyR1 by S100A1”","authors":"Megan L. Perry , Kristen M. Varney , Pratyush Tiwary , David J. Weber , Erick O. Hernández-Ochoa","doi":"10.1016/j.ceca.2024.102947","DOIUrl":"10.1016/j.ceca.2024.102947","url":null,"abstract":"<div><p>S100A1, a calcium-binding protein, plays a crucial role in regulating Ca<sup>2+</sup> signaling pathways in skeletal and cardiac myocytes via interactions with the ryanodine receptor (RyR) to affect Ca<sup>2+</sup> release and contractile performance. Biophysical studies strongly suggest that S100A1 interacts with RyRs but have been inconclusive about both the nature of this interaction and its competition with another important calcium-binding protein, calmodulin (CaM). Thus, high-resolution cryo-EM studies of RyRs in the presence of S100A1, with or without additional CaM, were needed. The elegant work by Weninger <em>et al</em>. demonstrates the interaction between S100A1 and RyR1 through various experiments and confirms that S100A1 activates RyR1 at sub-micromolar Ca<sup>2+</sup> concentrations, increasing the open probability of RyR1 channels.</p></div>","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"123 ","pages":"Article 102947"},"PeriodicalIF":4.3,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142122458","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell calciumPub Date : 2024-08-23DOI: 10.1016/j.ceca.2024.102946
Patrick G Hogan
{"title":"The quest to map STIM1 activation in granular detail","authors":"Patrick G Hogan","doi":"10.1016/j.ceca.2024.102946","DOIUrl":"10.1016/j.ceca.2024.102946","url":null,"abstract":"<div><p>The conformational change in STIM1 that communicates sensing of ER calcium-store depletion from the STIM ER-luminal domain to the STIM cytoplasmic region and ultimately to ORAI channels in the plasma membrane is broadly understood. However, the structural basis for the STIM luminal-domain dimerization that drives the conformational change has proven elusive. A recently published study has approached this question via molecular dynamics simulations. The report pinpoints STIM residues that may be part of a luminal-domain dimerization interface, and provides unexpected insight into how torsional movements of the STIM luminal domains might trigger release of the cytoplasmic SOAR/CAD domain from its resting tethers to the STIM CC1 segments.</p></div>","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"123 ","pages":"Article 102946"},"PeriodicalIF":4.3,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142122459","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell calciumPub Date : 2024-08-14DOI: 10.1016/j.ceca.2024.102945
Alexandra S. Goriounova , M. Flori Sassano , Joe A. Wrennall , Robert Tarran
{"title":"ELD607 specifically traffics Orai1 to the lysosome leading to inhibition of store operated calcium entry","authors":"Alexandra S. Goriounova , M. Flori Sassano , Joe A. Wrennall , Robert Tarran","doi":"10.1016/j.ceca.2024.102945","DOIUrl":"10.1016/j.ceca.2024.102945","url":null,"abstract":"<div><p>Orai1 is a plasma membrane Ca<sup>2+</sup> channel involved in store operated calcium entry (SOCE). SOCE can regulate cell growth, exocytosis, gene expression and inflammation. We previously found that short palate lung and nasal epithelial clone 1′s (SPLUNC1) sixth α-helix (α6) bound Orai1 to inhibit SOCE. SPLUNC1 was not proteolytically stable, so we developed ELD607, an 11 amino acid peptide based on SPLUNC1’s α6 region which was more stable and more potent than SPLUNC1/α6. Here, we studied ELD607’s mechanism of action. We overexpressed either Orai1-HA or Orai1-YFP in HEK293T cells to probe ELD607-Orai1 interactions by confocal microscopy. We also measured changes in Fluo-4 fluorescence in a multiplate reader as a marker of cytoplasmic Ca<sup>2+</sup> levels. ELD607 internalized Orai1 independently of STIM1. Both 15 min and 3 h exposure to ELD607 similarly depleted Orai1 in the plasma membrane. However, 3 h exposure to ELD607 yielded greater inhibition of SOCE. ELD607 continued to colocalize with Orai1 after internalization and this process was dependent on the presence of the ubiquitin ligase NEDD4.2. Similarly, ELD607 increased the colocalization between Orai1 and ubiquitin. ELD607 also increased the colocalization between Orai1 and Rab5 and 7, but not Rab11, suggesting that Orai1 trafficked through early and late but not recycling endosomes. Finally, ELD607 caused Orai1, but not Orai2, Orai3, or STIM1 to traffic to lysosomes. We conclude that ELD607 rapidly binds to Orai1 and works in an identical fashion as full length SPLUNC1 by internalizing Orai1 and sending it to lysosomes, leading to a decrease in SOCE.</p></div>","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"123 ","pages":"Article 102945"},"PeriodicalIF":4.3,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0143416024001039/pdfft?md5=fb9b28cebc700529d56816f0ae473c7a&pid=1-s2.0-S0143416024001039-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142075753","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Duchenne muscular dystrophy skeletal muscle cells derived from human induced pluripotent stem cells recapitulate various calcium dysregulation pathways","authors":"Arnaud Delafenêtre , Charles-Albert Chapotte-Baldacci , Léa Dorémus , Emmanuelle Massouridès , Marianne Bernard , Matthieu Régnacq , Jérôme Piquereau , Aurélien Chatelier , Christian Cognard , Christian Pinset , Stéphane Sebille","doi":"10.1016/j.ceca.2024.102943","DOIUrl":"10.1016/j.ceca.2024.102943","url":null,"abstract":"<div><p>Duchenne muscular dystrophy (DMD) is an X-linked progressive muscle degenerative disease, caused by mutations in the dystrophin gene and resulting in premature death. As a major secondary event, an abnormal elevation of the intracellular calcium concentration in the dystrophin-deficient muscle contributes to disease progression in DMD. In this study, we investigated the specific functional features of induced pluripotent stem cell-derived muscle cells (hiPSC-skMCs) generated from DMD patients to regulate intracellular calcium concentration. As compared to healthy hiPSC-skMCs, DMD hiPSC-skMCs displayed specific spontaneous calcium signatures with high levels of intracellular calcium concentration. Furthermore, stimulations with electrical field or with acetylcholine perfusion induced higher calcium response in DMD hiPSC-skMCs as compared to healthy cells. Finally, Mn2+ quenching experiments demonstrated high levels of constitutive calcium entries in DMD hiPSC-skMCs as compared to healthy cells. Our findings converge on the fact that DMD hiPSC-skMCs display intracellular calcium dysregulation as demonstrated in several other models. Observed calcium disorders associated with RNAseq analysis on these DMD cells highlighted some mechanisms, such as spontaneous and activated sarcoplasmic reticulum (SR) releases or constitutive calcium entries, known to be disturbed in other dystrophin-deficient models. However, store operated calcium entries (SOCEs) were not found to be dysregulated in our DMD hiPSC-skMCs model. These results suggest that all the mechanisms of calcium impairment observed in other animal models may not be as pronounced in humans and could point to a preference for certain mechanisms that could correspond to major molecular targets for DMD therapies.</p></div>","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"123 ","pages":"Article 102943"},"PeriodicalIF":4.3,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0143416024001015/pdfft?md5=8264d1db13ed561425b5160803383264&pid=1-s2.0-S0143416024001015-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141998326","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell calciumPub Date : 2024-08-12DOI: 10.1016/j.ceca.2024.102944
Oishika Chatterjee , Jagannath Jana , Suman Panda , Anindya Dutta , Akshay Sharma , Suman Saurav , Rajender K. Motiani , Klaus Weisz , Subhrangsu Chatterjee
{"title":"Remodeling Ca2+ dynamics by targeting a promising E-box containing G-quadruplex at ORAI1 promoter in triple-negative breast cancer","authors":"Oishika Chatterjee , Jagannath Jana , Suman Panda , Anindya Dutta , Akshay Sharma , Suman Saurav , Rajender K. Motiani , Klaus Weisz , Subhrangsu Chatterjee","doi":"10.1016/j.ceca.2024.102944","DOIUrl":"10.1016/j.ceca.2024.102944","url":null,"abstract":"<div><p>ORAI1 is an intrinsic component of store-operated calcium entry (SOCE) that strictly regulates Ca<sup>2+</sup> influx in most non-excitable cells. ORAI1 is overexpressed in a wide variety of cancers, and its signal transduction has been associated with chemotherapy resistance. There is extensive proteomic interaction of ORAI1 with other channels and effectors, resulting in various altered phenotypes. However, the transcription regulation of ORAI1 is not well understood. We have found a putative G-quadruplex (G4) motif, <em>ORAI1-Pu</em>, in the upstream promoter region of the gene, having regulatory functions. High-resolution 3-D NMR structure elucidation suggests that <em>ORAI1-Pu</em> is a stable parallel-stranded G4, having a long 8-nt loop imparting dynamics without affecting the structural stability. The protruded loop further houses an E-box motif that provides a docking site for transcription factors like Zeb1. The G4 structure was also endogenously observed using Chromatin Immunoprecipitation (ChIP) with anti-G4 antibody (BG4) in the MDA-MB-231 cell line overexpressing ORAI1. Ligand-mediated stabilization suggested that the stabilized G4 represses transcription in cancer cell line MDA-MB-231. Downregulation of transcription further led to decreased Ca<sup>2+</sup> entry by the SOCE pathway, as observed by live-cell Fura-2 Ca<sup>2+</sup> imaging.</p></div>","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"123 ","pages":"Article 102944"},"PeriodicalIF":4.3,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142075790","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}