Pub Date : 2025-03-04DOI: 10.1016/j.ceca.2025.103010
Gilnei Bruno da Silva , Geórgia de Carvalho Braga , Júlia Leão Batista Simões , Margarete Dulce Bagatini , Aniela Pinto Kempka
Mitochondria represent a fundamental structure for cellular homeostasis, controlling multiple conditions regarding energetic functions and cellular survival. To maintain these organelles functioning in ideal conditions, their membranes count with ion channels for different inorganic ions, which must be balanced to offer the proper function for both the organelle and the cell. However, studies have shown that other health conditions impair the activities of mitochondrial ion channels, including cancer. In this sense, the altered activities of potassium, calcium, and calcium-activated potassium channels are mainly linked with cancer development and cellular homeostasis alteration, demonstrating their role as pharmacological targets. With that in mind, scientists have found significant mitochondrial and cellular responses related to apoptosis and reduction of cellular survival from cells with modulated ion channels, indicating the potential of this possible therapy in carcinogenic contexts. Nonetheless, few studies still evaluate mitochondrial ion channel modulation as a treatment against cancer. Hence, more research must be conducted on this subject.
{"title":"Mitochondrial dysfunction and carcinogenesis: The engagement of ion channels in cancer development","authors":"Gilnei Bruno da Silva , Geórgia de Carvalho Braga , Júlia Leão Batista Simões , Margarete Dulce Bagatini , Aniela Pinto Kempka","doi":"10.1016/j.ceca.2025.103010","DOIUrl":"10.1016/j.ceca.2025.103010","url":null,"abstract":"<div><div>Mitochondria represent a fundamental structure for cellular homeostasis, controlling multiple conditions regarding energetic functions and cellular survival. To maintain these organelles functioning in ideal conditions, their membranes count with ion channels for different inorganic ions, which must be balanced to offer the proper function for both the organelle and the cell. However, studies have shown that other health conditions impair the activities of mitochondrial ion channels, including cancer. In this sense, the altered activities of potassium, calcium, and calcium-activated potassium channels are mainly linked with cancer development and cellular homeostasis alteration, demonstrating their role as pharmacological targets. With that in mind, scientists have found significant mitochondrial and cellular responses related to apoptosis and reduction of cellular survival from cells with modulated ion channels, indicating the potential of this possible therapy in carcinogenic contexts. Nonetheless, few studies still evaluate mitochondrial ion channel modulation as a treatment against cancer. Hence, more research must be conducted on this subject.</div></div>","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"128 ","pages":"Article 103010"},"PeriodicalIF":4.3,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143552733","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}
Pub Date : 2025-02-27DOI: 10.1016/j.ceca.2025.103013
Tam Nguyen , Zhihong Lin , Nirav Dhanesha , Rakesh B. Patel , Mallorie Lane , Grant C. Walters , Leonid P. Shutov , Stefan Strack , Anil K. Chauhan , Yuriy M. Usachev
Mitochondrial Ca2+ transport regulates many neuronal functions including synaptic transmission, ATP production, gene expression and neuronal survival. The mitochondrial Ca2+ uniporter (MCU) is the core molecular component of the mitochondrial Ca2+ uptake complex in the inner mitochondrial membrane. MCUb is a paralog of MCU that negatively regulates mitochondrial Ca2+ uptake in the heart and the cells of the immune system. However, the function of MCUb in the brain is largely unknown. Here, we report that MCUb knockout (KO) led to enhanced mitochondrial Ca2+ uptake in cortical neurons. By simultaneously monitoring changes in cytosolic and mitochondrial Ca2+ concentrations, [Ca2+]cyt and [Ca2+]mt, respectively, we also found that MCUb KO reduced the [Ca2+]cyt threshold required to induce mitochondrial uptake in cortical neurons during electrical stimulation. Exposure of cortical neurons to toxic concentrations of glutamate led to a collapse of mitochondrial membrane potential (ΔΨmt) and [Ca2+]cyt deregulation, and MCUb deletion accelerated the development of both events. Furthermore, using the middle cerebral artery occlusion (MCAO) as a model of transient ischemic stroke in mice, we found that MCUb KO significantly increased MCAO-induced brain damage in male, but not female mice. These results suggest that MCUb regulates neuronal Ca2+ dynamics and excitotoxicity and reveal a sex-dependent role of MCUb in controlling resistance to brain damage following ischemic stroke.
{"title":"Mitochondrial Ca2+ uniporter b (MCUb) regulates neuronal Ca2+ dynamics and resistance to ischemic stroke","authors":"Tam Nguyen , Zhihong Lin , Nirav Dhanesha , Rakesh B. Patel , Mallorie Lane , Grant C. Walters , Leonid P. Shutov , Stefan Strack , Anil K. Chauhan , Yuriy M. Usachev","doi":"10.1016/j.ceca.2025.103013","DOIUrl":"10.1016/j.ceca.2025.103013","url":null,"abstract":"<div><div>Mitochondrial Ca<sup>2+</sup> transport regulates many neuronal functions including synaptic transmission, ATP production, gene expression and neuronal survival. The mitochondrial Ca<sup>2+</sup> uniporter (MCU) is the core molecular component of the mitochondrial Ca<sup>2+</sup> uptake complex in the inner mitochondrial membrane. MCUb is a paralog of MCU that negatively regulates mitochondrial Ca<sup>2+</sup> uptake in the heart and the cells of the immune system. However, the function of MCUb in the brain is largely unknown. Here, we report that MCUb knockout (KO) led to enhanced mitochondrial Ca<sup>2+</sup> uptake in cortical neurons. By simultaneously monitoring changes in cytosolic and mitochondrial Ca<sup>2+</sup> concentrations, [Ca<sup>2+</sup>]<sub>cyt</sub> and [Ca<sup>2+</sup>]<sub>mt</sub>, respectively, we also found that MCUb KO reduced the [Ca<sup>2+</sup>]<sub>cyt</sub> threshold required to induce mitochondrial uptake in cortical neurons during electrical stimulation. Exposure of cortical neurons to toxic concentrations of glutamate led to a collapse of mitochondrial membrane potential (ΔΨ<sub>mt</sub>) and [Ca<sup>2+</sup>]<sub>cyt</sub> deregulation, and MCUb deletion accelerated the development of both events. Furthermore, using the middle cerebral artery occlusion (MCAO) as a model of transient ischemic stroke in mice, we found that MCUb KO significantly increased MCAO-induced brain damage in male, but not female mice. These results suggest that MCUb regulates neuronal Ca<sup>2+</sup> dynamics and excitotoxicity and reveal a sex-dependent role of MCUb in controlling resistance to brain damage following ischemic stroke.</div></div>","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"128 ","pages":"Article 103013"},"PeriodicalIF":4.3,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143578745","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}
Pub Date : 2025-02-15DOI: 10.1016/j.ceca.2025.103002
Barbara A. Niemeyer , David I. Yule
{"title":"Changing of the guards while steering a familiar course","authors":"Barbara A. Niemeyer , David I. Yule","doi":"10.1016/j.ceca.2025.103002","DOIUrl":"10.1016/j.ceca.2025.103002","url":null,"abstract":"","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"126 ","pages":"Article 103002"},"PeriodicalIF":4.3,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143436889","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}
Pub Date : 2025-02-07DOI: 10.1016/j.ceca.2025.103000
Jacob D. Cunningham, Taylor A. Phillips, Jaroslava Seflova, Ellen E. Cho, Seth L. Robia
To determine how regulation of the sarco(endo)plasmic reticulum calcium ATPase (SERCA) affects the Ca2+ content of the endoplasmic reticulum (ER), we developed a ratiometric ER-localized Ca2+ indicator to rapidly quantify Ca2+ stores and assess SERCA function in live cells. This assay enables screening of membrane micropeptides and small molecules that modulate SERCA and Na+/K+-ATPase activity and may facilitate development of therapies that target cellular Ca2+ handling. Of the micropeptides tested, phospholamban (PLB) had the greatest degree of inhibition of SERCA, as measured by a decrease in ER Ca2+ content compared to control. Sarcolipin (SLN), endoregulin (ELN), and another-regulin (ALN) also decreased ER Ca2+ content, though less potently than PLB. We also investigated micropeptides that have been shown to have a positive effect on ER Ca2+ uptake. Dwarf open reading frame (DWORF), a positive modulator of SERCA activity, and phospholemman (PLM), an inhibitor of the Na+/K+-ATPase, both increased ER Ca2+ content compared to control. A superinhibitory variant of PLM, R70C, further increased ER Ca2+ load compared to wild type PLM. Overall, our findings indicate that the inhibitory potency of micropeptides is governed by their relative binding affinities to SERCA. This allows for finely tuned modulation of Ca2+ handling in different tissues based on differential expressions of micropeptide species. Understanding the contribution of each micropeptide to SERCA regulation may reveal novel strategies for therapeutic intervention in conditions where calcium dysregulation plays a role, such as heart disease, vascular disease, or neurodegenerative disorders.
{"title":"Rapid quantification of intracellular calcium stores reveals effects of membrane micropeptides on SERCA function","authors":"Jacob D. Cunningham, Taylor A. Phillips, Jaroslava Seflova, Ellen E. Cho, Seth L. Robia","doi":"10.1016/j.ceca.2025.103000","DOIUrl":"10.1016/j.ceca.2025.103000","url":null,"abstract":"<div><div>To determine how regulation of the sarco(endo)plasmic reticulum calcium ATPase (SERCA) affects the Ca<sup>2+</sup> content of the endoplasmic reticulum (ER), we developed a ratiometric ER-localized Ca<sup>2+</sup> indicator to rapidly quantify Ca<sup>2+</sup> stores and assess SERCA function in live cells. This assay enables screening of membrane micropeptides and small molecules that modulate SERCA and Na<sup>+</sup>/K<sup>+</sup>-ATPase activity and may facilitate development of therapies that target cellular Ca<sup>2+</sup> handling. Of the micropeptides tested, phospholamban (PLB) had the greatest degree of inhibition of SERCA, as measured by a decrease in ER Ca<sup>2+</sup> content compared to control. Sarcolipin (SLN), endoregulin (ELN), and another-regulin (ALN) also decreased ER Ca<sup>2+</sup> content, though less potently than PLB. We also investigated micropeptides that have been shown to have a positive effect on ER Ca<sup>2+</sup> uptake. Dwarf open reading frame (DWORF), a positive modulator of SERCA activity, and phospholemman (PLM), an inhibitor of the Na<sup>+</sup>/K<sup>+</sup>-ATPase, both increased ER Ca<sup>2+</sup> content compared to control. A superinhibitory variant of PLM, R70C, further increased ER Ca<sup>2+</sup> load compared to wild type PLM. Overall, our findings indicate that the inhibitory potency of micropeptides is governed by their relative binding affinities to SERCA. This allows for finely tuned modulation of Ca<sup>2+</sup> handling in different tissues based on differential expressions of micropeptide species. Understanding the contribution of each micropeptide to SERCA regulation may reveal novel strategies for therapeutic intervention in conditions where calcium dysregulation plays a role, such as heart disease, vascular disease, or neurodegenerative disorders.</div></div>","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"126 ","pages":"Article 103000"},"PeriodicalIF":4.3,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143367809","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}
Pub Date : 2025-02-01DOI: 10.1016/j.ceca.2025.103001
Boris Lavanderos , Maria Paz Saldias , Scott Earley
Brain capillaries contribute to neurovascular coupling (NVC) by sensing neural activity and coordinating upstream arteriole dilation. However, the mechanisms underlying conducted vasodilation remain incompletely understood. Recent findings (PNAS, 2024) identify a novel process, “electrocalcium coupling,” in which hyperpolarizing signals from K+ channels drive long-range Ca²⁺ signaling in capillaries, revealing new insights into the integration of vasodilatory signals in the brain.
{"title":"Shocking insights for neurovascular coupling: Electrical signals ignite calcium dynamics in brain capillaries","authors":"Boris Lavanderos , Maria Paz Saldias , Scott Earley","doi":"10.1016/j.ceca.2025.103001","DOIUrl":"10.1016/j.ceca.2025.103001","url":null,"abstract":"<div><div>Brain capillaries contribute to neurovascular coupling (NVC) by sensing neural activity and coordinating upstream arteriole dilation. However, the mechanisms underlying conducted vasodilation remain incompletely understood. Recent findings (<em>PNAS</em>, 2024) identify a novel process, “electrocalcium coupling,” in which hyperpolarizing signals from K<sup>+</sup> channels drive long-range Ca²⁺ signaling in capillaries, revealing new insights into the integration of vasodilatory signals in the brain.</div></div>","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"126 ","pages":"Article 103001"},"PeriodicalIF":4.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143363765","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}
Pub Date : 2025-01-22DOI: 10.1016/j.ceca.2025.102999
Tamas Balla, Gergo Gulyas
Membrane contact sites (MCS) are specialized compartments found in all eukaryotic cells that are formed between membranes of different organelles that are in close proximity. MCS have important functions as they are sites of efficient transfer of molecules between neighboring organelles. Two recent articles have used the splitFAST system to mark and follow the dynamics of membrane contact sites and used the method to highlight the importance of MCS between the endoplasmic reticulum (ER) and lipid droplets in metabolic adaptation and MCS between the ER and mitochondria in Ca2+ signal propagation.
{"title":"You better keep an eye on your contacts","authors":"Tamas Balla, Gergo Gulyas","doi":"10.1016/j.ceca.2025.102999","DOIUrl":"10.1016/j.ceca.2025.102999","url":null,"abstract":"<div><div>Membrane contact sites (MCS) are specialized compartments found in all eukaryotic cells that are formed between membranes of different organelles that are in close proximity. MCS have important functions as they are sites of efficient transfer of molecules between neighboring organelles. Two recent articles have used the splitFAST system to mark and follow the dynamics of membrane contact sites and used the method to highlight the importance of MCS between the endoplasmic reticulum (ER) and lipid droplets in metabolic adaptation and MCS between the ER and mitochondria in Ca<sup>2+</sup> signal propagation.</div></div>","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"126 ","pages":"Article 102999"},"PeriodicalIF":4.3,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143037305","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}
Pub Date : 2025-01-21DOI: 10.1016/j.ceca.2025.102998
Johann Böhm
{"title":"Commentary to An Orai1 gain-of-function tubular aggregate myopathy mouse model phenocopies key features of the human disease (Zhao et al., EMBO Journal 2024) and A gain-of-function mutation in the Ca2+ channel ORAI1 causes Stormorken syndrome with tubular aggregates in mice (Pérez-Guàrdia et al., Cells 2024)","authors":"Johann Böhm","doi":"10.1016/j.ceca.2025.102998","DOIUrl":"10.1016/j.ceca.2025.102998","url":null,"abstract":"","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"126 ","pages":"Article 102998"},"PeriodicalIF":4.3,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143058318","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}
Pub Date : 2025-01-01DOI: 10.1016/j.ceca.2024.102984
Verena Untiet , Chritsine R. Rose , Maiken Nedergaard , Alexei Verkhratsky
{"title":"Ionic signalling (beyond calcium) in the nervous system: Physiology and pathophysiology","authors":"Verena Untiet , Chritsine R. Rose , Maiken Nedergaard , Alexei Verkhratsky","doi":"10.1016/j.ceca.2024.102984","DOIUrl":"10.1016/j.ceca.2024.102984","url":null,"abstract":"","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"125 ","pages":"Article 102984"},"PeriodicalIF":4.3,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142821956","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}
Pub Date : 2025-01-01DOI: 10.1016/j.ceca.2024.102980
Maria Livia Sassano , Robbe Van Gorp , Geert Bultynck , Patrizia Agostinis
The endoplasmic reticulum (ER) controls intracellular Ca2+ dynamics. Depletion of ER Ca2+ stores results in short-term activation of store-operated Ca2+ entry (SOCE) via STIM1/Orai1 at ER-plasma membrane (ER-PM) contact sites (MCSs) and the long-term activation of the unfolded protein response (UPR), securing ER proteostasis. Recent work by Carreras-Sureda and colleagues describes a bidirectional control between IRE1 and STIM1 within the ER lumen that regulates ER-PM contact assembly and SOCE to sustain T-cell activation and myoblast differentiation.
{"title":"STIMulating IRE1: How store-operated Ca2+ entry intersects with ER proteostasis","authors":"Maria Livia Sassano , Robbe Van Gorp , Geert Bultynck , Patrizia Agostinis","doi":"10.1016/j.ceca.2024.102980","DOIUrl":"10.1016/j.ceca.2024.102980","url":null,"abstract":"<div><div>The endoplasmic reticulum (ER) controls intracellular Ca<sup>2+</sup> dynamics. Depletion of ER Ca<sup>2+</sup> stores results in short-term activation of store-operated Ca<sup>2+</sup> entry (SOCE) via STIM1/Orai1 at ER-plasma membrane (ER-PM) contact sites (MCSs) and the long-term activation of the unfolded protein response (UPR), securing ER proteostasis. Recent work by Carreras-Sureda and colleagues describes a bidirectional control between IRE1 and STIM1 within the ER lumen that regulates ER-PM contact assembly and SOCE to sustain T-cell activation and myoblast differentiation.</div></div>","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"125 ","pages":"Article 102980"},"PeriodicalIF":4.3,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142791115","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}
Pub Date : 2025-01-01DOI: 10.1016/j.ceca.2024.102986
Leandro C. Clementino , Andrew P. Thomas , Emily M. Rocha , Sabine Hilfiker
Elevated free fatty acids and oxidative stress may function as pathogenic factors in endothelial dysfunction that is associated with various cardiovascular complications. In recent work, Feng and colleagues report that activation of a lysosomal Ca2+ channel may be a viable option to alleviate oxidative damage by boosting lysosome biogenesis and mitophagy.
{"title":"A role for lysosomal calcium channels in mitigating mitochondrial damage and oxidative stress","authors":"Leandro C. Clementino , Andrew P. Thomas , Emily M. Rocha , Sabine Hilfiker","doi":"10.1016/j.ceca.2024.102986","DOIUrl":"10.1016/j.ceca.2024.102986","url":null,"abstract":"<div><div>Elevated free fatty acids and oxidative stress may function as pathogenic factors in endothelial dysfunction that is associated with various cardiovascular complications. In recent work, Feng and colleagues report that activation of a lysosomal Ca<sup>2+</sup> channel may be a viable option to alleviate oxidative damage by boosting lysosome biogenesis and mitophagy.</div></div>","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"125 ","pages":"Article 102986"},"PeriodicalIF":4.3,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142853110","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}
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