Pub Date : 2025-05-07DOI: 10.1016/j.ceca.2025.103039
Qinghua Yu, Wen Tian
SERCA, the sarco/endoplasmic reticulum Ca2+-ATPase, is a pivotal protein that transports calcium ions (Ca2+) from the cytoplasm into the sarcoplasmic/endoplasmic reticulum (SR/ER), thus sustaining cellular Ca2+ homeostasis. A growing body of evidence indicates that SERCA dysfunction correlates with disrupted cellular Ca2+ homeostasis and ER stress, precipitating a spectrum of chronic diseases. As a regulator of Ca2+ homeostasis, SERCA emerges as a potential therapeutic target for conditions associated with Ca2+ imbalance. This review delineates the association between SERCA and a variety of vascular diseases.
{"title":"The role of SERCA in vascular diseases, a potential therapeutic target","authors":"Qinghua Yu, Wen Tian","doi":"10.1016/j.ceca.2025.103039","DOIUrl":"10.1016/j.ceca.2025.103039","url":null,"abstract":"<div><div>SERCA, the sarco/endoplasmic reticulum Ca<sup>2+</sup>-ATPase, is a pivotal protein that transports calcium ions (Ca<sup>2+</sup>) from the cytoplasm into the sarcoplasmic/endoplasmic reticulum (SR/ER), thus sustaining cellular Ca<sup>2+</sup> homeostasis. A growing body of evidence indicates that SERCA dysfunction correlates with disrupted cellular Ca<sup>2+</sup> homeostasis and ER stress, precipitating a spectrum of chronic diseases. As a regulator of Ca<sup>2+</sup> homeostasis, SERCA emerges as a potential therapeutic target for conditions associated with Ca<sup>2+</sup> imbalance. This review delineates the association between SERCA and a variety of vascular diseases.</div></div>","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"129 ","pages":"Article 103039"},"PeriodicalIF":4.3,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143942638","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 : 2025-04-18DOI: 10.1016/j.ceca.2025.103032
Cesare Sala , Andrea Ninu , Valentina Balducci , Giada Allegro , Alberto Montalbano , Matteo Lulli , Martina Lucia Boccitto , Elena Guzzolino , Valentina Spinelli , Annarosa Arcangeli , Laura Sartiani , Elisabetta Cerbai
SARS-CoV-2 infection affects the respiratory system but also many tissues and organs that may be adversely compromised. Accordingly, recent evidence has assessed virus ability to infect different cell phenotypes, translate viral proteins and promote virus replication. Among them, Envelope (E) proteins sustain virus replication, promote inflammatory processes and remodelling of host cells. However, despite advances on structure and sequence, E-protein specific location and effects in human host cells are still controversial and poorly investigated.
Using lentiviral vectors, we established HEK293 and hiPS cell lines stably expressing E-protein. Immunocytochemistry showed E-protein mainly locates within the endoplasmic reticulum, the ERGIC and the Golgi compartments, while only HEK293 cells display some protein staining in cell periphery suggesting a possible insertion into the plasmalemma. Electrophysiological recordings in HEK293 cells revealed E-protein self-assembles in the plasma membrane to mediate a cation efflux pore that is sensitive to amantadine blockade. Calcium fluorescence imaging in HEK293 and hiPS cells demonstrated E-protein expression induces a marked depletion of thapsigargin-sensitive intracellular calcium stores. The altered calcium homeostasis associates to reduced cell metabolic activity, mitochondrial potential, proliferation rate and promotes ER stress. Finally, trilineage differentiation of hiPS cells indicated E-protein expression preserves cell pluripotency while selectively impairs mesodermal differentiation. These results unveil a critical role of stable E-viroporin expression that through alteration of ER Ca²⁺ homeostasis, metabolic activity and induction of ER stress affects important cellular functions, including the differentiative process from pluripotent to mesodermal progenitors, a critical cell population in self-repair and homeostasis of most human tissue and organs.
SARS-CoV-2感染会影响呼吸系统，但也会影响许多可能受到不利损害的组织和器官。因此，最近的证据评估了病毒感染不同细胞表型、翻译病毒蛋白和促进病毒复制的能力。其中，包膜(E)蛋白维持病毒复制，促进炎症过程和宿主细胞的重塑。然而，尽管在结构和序列方面取得了进展，但e蛋白在人宿主细胞中的特异性定位和作用仍然存在争议，研究也很少。利用慢病毒载体，建立了稳定表达e蛋白的HEK293和hiPS细胞系。免疫细胞化学显示e蛋白主要位于内质网、ERGIC和高尔基区室内，而HEK293细胞仅在细胞外周显示一些蛋白染色，提示可能插入质膜。HEK293细胞的电生理记录显示，e蛋白在质膜中自组装，介导对金刚烷胺阻断敏感的阳离子外排孔。HEK293和hiPS细胞的钙荧光成像显示，e蛋白的表达导致细胞内对thapsigargin敏感的钙储存明显减少。钙稳态的改变与细胞代谢活性、线粒体电位、增殖率降低有关，并促进内质网应激。最后，hiPS细胞的三龄分化表明，e蛋白的表达保留了细胞的多能性，但选择性地损害了中胚层分化。这些结果揭示了稳定的E-viroporin表达的关键作用，通过改变ER Ca 2 +的稳态、代谢活性和诱导ER应激影响重要的细胞功能，包括从多能祖细胞到中胚层祖细胞的分化过程，这是大多数人体组织和器官自我修复和稳态的关键细胞群。
{"title":"Stable expression of SARS-CoV-2 envelope viroporin promotes intracellular calcium depletion in human cells: relevance for endoplasmic reticulum stress, cell proliferation, pluripotency and lineage differentiation","authors":"Cesare Sala , Andrea Ninu , Valentina Balducci , Giada Allegro , Alberto Montalbano , Matteo Lulli , Martina Lucia Boccitto , Elena Guzzolino , Valentina Spinelli , Annarosa Arcangeli , Laura Sartiani , Elisabetta Cerbai","doi":"10.1016/j.ceca.2025.103032","DOIUrl":"10.1016/j.ceca.2025.103032","url":null,"abstract":"<div><div>SARS-CoV-2 infection affects the respiratory system but also many tissues and organs that may be adversely compromised. Accordingly, recent evidence has assessed virus ability to infect different cell phenotypes, translate viral proteins and promote virus replication. Among them, Envelope (E) proteins sustain virus replication, promote inflammatory processes and remodelling of host cells. However, despite advances on structure and sequence, E-protein specific location and effects in human host cells are still controversial and poorly investigated.</div><div>Using lentiviral vectors, we established HEK293 and hiPS cell lines stably expressing E-protein. Immunocytochemistry showed E-protein mainly locates within the endoplasmic reticulum, the ERGIC and the Golgi compartments, while only HEK293 cells display some protein staining in cell periphery suggesting a possible insertion into the plasmalemma. Electrophysiological recordings in HEK293 cells revealed E-protein self-assembles in the plasma membrane to mediate a cation efflux pore that is sensitive to amantadine blockade. Calcium fluorescence imaging in HEK293 and hiPS cells demonstrated E-protein expression induces a marked depletion of thapsigargin-sensitive intracellular calcium stores. The altered calcium homeostasis associates to reduced cell metabolic activity, mitochondrial potential, proliferation rate and promotes ER stress. Finally, trilineage differentiation of hiPS cells indicated E-protein expression preserves cell pluripotency while selectively impairs mesodermal differentiation. These results unveil a critical role of stable E-viroporin expression that through alteration of ER Ca²⁺ homeostasis, metabolic activity and induction of ER stress affects important cellular functions, including the differentiative process from pluripotent to mesodermal progenitors, a critical cell population in self-repair and homeostasis of most human tissue and organs.</div></div>","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"128 ","pages":"Article 103032"},"PeriodicalIF":4.3,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143869415","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 : 2025-04-16DOI: 10.1016/j.ceca.2025.103031
Shi-Li Zhou , Lan-Lan Zhong , Yi-Lan Wu , Si-Wen Ji , Yong Li , Na Niu
Ion channels, membrane proteins that facilitate the transport of various inorganic ions across hydrophobic cellular lipid membranes, are ubiquitous in a wide variety of cell and tissue types. They are involved in establishing the cell membrane potential and play a role in various physiological activities by regulating ion concentrations within the cell. Dendritic cells (DCs) are specialised antigen-presenting cells found mainly on the surface of the body (skin and mucous membranes), in the mesenchyme of most organs, in the T-cell compartment of the spleen and in lymph nodes. DCs exert an important influence on the regulation of inflammation by activating T cells and producing cytokines. Studies have shown that ion channels expressed in DCs contribute to the regulation of the immune response, making them a key component of the immune system. This review summarises the major scientific advances in understanding the functional impact of ion channels (calcium channels, sodium channels and aquaporin) in DCs, including the regulation of inflammatory responses, antigen presentation, maturation, migration and cytokine production, to inform ongoing studies of ion channel function in DCs.
{"title":"The role of ion channels in the regulation of dendritic cell function","authors":"Shi-Li Zhou , Lan-Lan Zhong , Yi-Lan Wu , Si-Wen Ji , Yong Li , Na Niu","doi":"10.1016/j.ceca.2025.103031","DOIUrl":"10.1016/j.ceca.2025.103031","url":null,"abstract":"<div><div>Ion channels, membrane proteins that facilitate the transport of various inorganic ions across hydrophobic cellular lipid membranes, are ubiquitous in a wide variety of cell and tissue types. They are involved in establishing the cell membrane potential and play a role in various physiological activities by regulating ion concentrations within the cell. Dendritic cells (DCs) are specialised antigen-presenting cells found mainly on the surface of the body (skin and mucous membranes), in the mesenchyme of most organs, in the T-cell compartment of the spleen and in lymph nodes. DCs exert an important influence on the regulation of inflammation by activating T cells and producing cytokines. Studies have shown that ion channels expressed in DCs contribute to the regulation of the immune response, making them a key component of the immune system. This review summarises the major scientific advances in understanding the functional impact of ion channels (calcium channels, sodium channels and aquaporin) in DCs, including the regulation of inflammatory responses, antigen presentation, maturation, migration and cytokine production, to inform ongoing studies of ion channel function in DCs.</div></div>","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"128 ","pages":"Article 103031"},"PeriodicalIF":4.3,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143848346","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 : 2025-04-08DOI: 10.1016/j.ceca.2025.103017
Kriti Ahuja, Rajender K. Motiani
Mitochondria are robust signaling organelle that regulate a variety of cellular functions. One of the key mechanisms that drive mitochondrial signaling is inter-organelle crosstalk. Mitochondria communicates with other organelles primarily via exchange of calcium (Ca2+), reactive oxygen species (ROS) and lipids across organelle membranes. Mitochondria has its own genome but a majority of mitochondrial proteins are encoded by nuclear genome. Therefore, several mitochondrial functions are controlled by nucleus via anterograde signaling. However, the role of mitochondria in driving expression of genes encoded by nuclear genome has recently gained attention. Recent studies from independent groups have demonstrated a critical role for mitochondrial Ca2+signaling in stimulating nuclear gene expression. These studies report that inhibition of mitochondrial Ca2+uptake through silencing of Mitochondrial Ca2+Uniporter (MCU) leads to Ca2+oscillations in the cytosol. The rise in cytosolic Ca2+ results in activation of Ca2+ sensitive transcription factors such as NFATs and NF-B. These transcription factors consequently induce expression of their target genes in the nuclear genome. It is important to highlight that these groups used different cell types and elegantly presented a phenomenon that is conserved across various systems. Notably, mitochondrial Ca2+ signaling mediated transcriptional regulation controls diverse cellular functions ranging from B-cell activation, melanogenesis and aging associated inflammation. Future studies on this signaling module would result in better understanding of this axis in human pathophysiology and could lead to development of novel therapeutic strategies.
{"title":"Calcium acts as a critical determinant of mitochondria-nuclear networking driven retrograde signaling","authors":"Kriti Ahuja, Rajender K. Motiani","doi":"10.1016/j.ceca.2025.103017","DOIUrl":"10.1016/j.ceca.2025.103017","url":null,"abstract":"<div><div>Mitochondria are robust signaling organelle that regulate a variety of cellular functions. One of the key mechanisms that drive mitochondrial signaling is inter-organelle crosstalk. Mitochondria communicates with other organelles primarily via exchange of calcium (Ca<sup>2+</sup>), reactive oxygen species (ROS) and lipids across organelle membranes. Mitochondria has its own genome but a majority of mitochondrial proteins are encoded by nuclear genome. Therefore, several mitochondrial functions are controlled by nucleus via anterograde signaling. However, the role of mitochondria in driving expression of genes encoded by nuclear genome has recently gained attention. Recent studies from independent groups have demonstrated a critical role for mitochondrial Ca<sup>2+</sup>signaling in stimulating nuclear gene expression. These studies report that inhibition of mitochondrial Ca<sup>2+</sup>uptake through silencing of Mitochondrial Ca<sup>2+</sup>Uniporter (MCU) leads to Ca<sup>2+</sup>oscillations in the cytosol. The rise in cytosolic Ca<sup>2+</sup> results in activation of Ca<sup>2+</sup> sensitive transcription factors such as NFATs and NF-<span><math><mi>κ</mi></math></span>B. These transcription factors consequently induce expression of their target genes in the nuclear genome. It is important to highlight that these groups used different cell types and elegantly presented a phenomenon that is conserved across various systems. Notably, mitochondrial Ca<sup>2+</sup> signaling mediated transcriptional regulation controls diverse cellular functions ranging from B-cell activation, melanogenesis and aging associated inflammation. Future studies on this signaling module would result in better understanding of this axis in human pathophysiology and could lead to development of novel therapeutic strategies.</div></div>","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"127 ","pages":"Article 103017"},"PeriodicalIF":4.3,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143839191","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 : 2025-04-01DOI: 10.1016/j.ceca.2025.103016
Khaled Machaca
Dendritic Ca2+ signaling is critical for neural transmission and signal processing, however the detailed molecular mechanisms have not been elucidated. Using elegant and complementary imaging approaches Benedetti et al. discover a distinctive ER ladder architecture in dendrites and show that precise localization of Ca2+ signaling proteins at endoplasmic reticulum (ER)-plasma membrane (PM) junctions supports integration of Ca2+ signaling along the dendrite.
{"title":"Scaling up neuronal Ca2+, signaling on ER ladders","authors":"Khaled Machaca","doi":"10.1016/j.ceca.2025.103016","DOIUrl":"10.1016/j.ceca.2025.103016","url":null,"abstract":"<div><div>Dendritic Ca<sup>2+</sup> signaling is critical for neural transmission and signal processing, however the detailed molecular mechanisms have not been elucidated. Using elegant and complementary imaging approaches Benedetti et al. discover a distinctive ER ladder architecture in dendrites and show that precise localization of Ca<sup>2+</sup> signaling proteins at endoplasmic reticulum (ER)-plasma membrane (PM) junctions supports integration of Ca<sup>2+</sup> signaling along the dendrite.</div></div>","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"127 ","pages":"Article 103016"},"PeriodicalIF":4.3,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143799197","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 : 2025-03-25DOI: 10.1016/j.ceca.2025.103015
Grecia J. Medina-Terol , Luis Chimal , Saúl Huerta de la Cruz , Guillermo Ávila , Alberto Aranda , David Cruz-Robles , David Centurión , Julio Altamirano , Rocio Rojo , Norma Leticia Gómez-Viquez
Hydrogen sulfide (H2S) has been proposed to play a cardioprotective role, particularly due to its ability to revert left ventricular hypertrophy (LVH) and mitigate cardiac dysfunction in various cardiomyopathies, including hypertensive heart disease. However, the extent to which cardioprotection by H2S involves improvement in Ca2+ handling remains unclear. Although H2S has been reported to influence the function of key Ca2+ handling proteins, most studies have focused on acute administration of H2S donors in isolated cardiomyocytes, rather than in a therapeutic context. In this study, we used a rat model of hypertension induced by abdominal aortic coarctation (AAC) to evaluate the therapeutic potential of NaHS, an H2S donor, on LVH and Ca2+ handling. After 8 weeks of AAC, hypertensive rats developed moderate LVH, which was accompanied by a reduction in both the amplitude and the rate of rise of systolic Ca2+ transients, as well as a decrease in sarcoplasmic reticulum (SR) Ca2+ load. Despite the reduced SR Ca2+ load, the frequency of diastolic Ca2+ sparks remained high, while the incidence and propagation rate of spontaneous Ca2+ waves significantly increased, suggesting enhanced diastolic SR Ca2+ leak, most likely due to hypersensitivity of ryanodine receptors (RyR2) to Ca2+. On the other hand, NaHS administration during the final 4 weeks of AAC reverted both LVH and hypertension, and increased SR Ca2+ reuptake mediated by the SR Ca2+ ATPase (SERCA2a). However, NaHS treatment failed to restore the amplitude and rate of rise of systolic Ca2+ transients or SR Ca2+ load. Furthermore, SR Ca2+ leak might have worsened, since spontaneous Ca2+ waves increased. In conclusion, NaHS treatment does not appear to normalize all Ca2+ handling properties during hypertensive LVH. On the contrary, NaHS may exert an arrhythmogenic effect, likely due to enhanced SERCA2a activity under conditions of unresolved RyR2 Ca2+ hypersensitivity.
{"title":"H2S treatment reverts cardiac hypertrophy and increases SERCA2a activity but does not fully restore cardiac Ca2+ handling in hypertensive rats","authors":"Grecia J. Medina-Terol , Luis Chimal , Saúl Huerta de la Cruz , Guillermo Ávila , Alberto Aranda , David Cruz-Robles , David Centurión , Julio Altamirano , Rocio Rojo , Norma Leticia Gómez-Viquez","doi":"10.1016/j.ceca.2025.103015","DOIUrl":"10.1016/j.ceca.2025.103015","url":null,"abstract":"<div><div>Hydrogen sulfide (H<sub>2</sub>S) has been proposed to play a cardioprotective role, particularly due to its ability to revert left ventricular hypertrophy (LVH) and mitigate cardiac dysfunction in various cardiomyopathies, including hypertensive heart disease. However, the extent to which cardioprotection by H<sub>2</sub>S involves improvement in Ca<sup>2+</sup> handling remains unclear. Although H<sub>2</sub>S has been reported to influence the function of key Ca<sup>2+</sup> handling proteins, most studies have focused on acute administration of H<sub>2</sub>S donors in isolated cardiomyocytes, rather than in a therapeutic context. In this study, we used a rat model of hypertension induced by abdominal aortic coarctation (AAC) to evaluate the therapeutic potential of NaHS, an H<sub>2</sub>S donor, on LVH and Ca<sup>2+</sup> handling. After 8 weeks of AAC, hypertensive rats developed moderate LVH, which was accompanied by a reduction in both the amplitude and the rate of rise of systolic Ca<sup>2+</sup> transients, as well as a decrease in sarcoplasmic reticulum (SR) Ca<sup>2+</sup> load. Despite the reduced SR Ca<sup>2+</sup> load, the frequency of diastolic Ca<sup>2+</sup> sparks remained high, while the incidence and propagation rate of spontaneous Ca<sup>2+</sup> waves significantly increased, suggesting enhanced diastolic SR Ca<sup>2+</sup> leak, most likely due to hypersensitivity of ryanodine receptors (RyR2) to Ca<sup>2+</sup>. On the other hand, NaHS administration during the final 4 weeks of AAC reverted both LVH and hypertension, and increased SR Ca<sup>2+</sup> reuptake mediated by the SR Ca<sup>2+</sup> ATPase (SERCA2a). However, NaHS treatment failed to restore the amplitude and rate of rise of systolic Ca<sup>2+</sup> transients or SR Ca<sup>2+</sup> load. Furthermore, SR Ca<sup>2+</sup> leak might have worsened, since spontaneous Ca<sup>2+</sup> waves increased. In conclusion, NaHS treatment does not appear to normalize all Ca<sup>2+</sup> handling properties during hypertensive LVH. On the contrary, NaHS may exert an arrhythmogenic effect, likely due to enhanced SERCA2a activity under conditions of unresolved RyR2 Ca<sup>2+</sup> hypersensitivity.</div></div>","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"128 ","pages":"Article 103015"},"PeriodicalIF":4.3,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143769152","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}
The homeostasis of cellular reactive oxygen species (ROS) and calcium (Ca2+) are intricately linked. ROS signaling and Ca2+ signaling are reciprocally regulated within cellular microdomains and are crucial for transcription, metabolism and cell function. Tumor cells often highjack ROS and Ca2+ signaling mechanisms to ensure optimal cell survival and tumor progression. Expression and regulation of Ca2+ channels and transporters at the plasma membrane, endoplasmic reticulum, mitochondria and other endomembranes are often altered in tumor cells, and this includes their regulation by ROS and reactive nitrogen species (RNS). Likewise, alterations in cellular Ca2+ levels influence the generation and scavenging of oxidants and thus can alter the redox homeostasis of the cell. This interplay can be either beneficial or detrimental to the cell depending on the localization, duration and levels of ROS and Ca2+ signals. At one end of the spectrum, Ca2+ and ROS/RNS can function as signaling modules while at the other end, lethal surges in these species are associated with cell death. Here, we highlight the interplay between Ca2+ and ROS in cancer progression, emphasize the impact of redox regulation on Ca2+ transport mechanisms, and describe how Ca2+ signaling pathways, in turn, can regulate the cellular redox environment.
{"title":"Crosstalk between calcium and reactive oxygen species signaling in cancer revisited","authors":"Trayambak Pathak , J.Cory Benson , Priscilla W. Tang , Mohamed Trebak , Nadine Hempel","doi":"10.1016/j.ceca.2025.103014","DOIUrl":"10.1016/j.ceca.2025.103014","url":null,"abstract":"<div><div>The homeostasis of cellular reactive oxygen species (ROS) and calcium (Ca<sup>2+</sup>) are intricately linked. ROS signaling and Ca<sup>2+</sup> signaling are reciprocally regulated within cellular microdomains and are crucial for transcription, metabolism and cell function. Tumor cells often highjack ROS and Ca<sup>2+</sup> signaling mechanisms to ensure optimal cell survival and tumor progression. Expression and regulation of Ca<sup>2+</sup> channels and transporters at the plasma membrane, endoplasmic reticulum, mitochondria and other endomembranes are often altered in tumor cells, and this includes their regulation by ROS and reactive nitrogen species (RNS). Likewise, alterations in cellular Ca<sup>2+</sup> levels influence the generation and scavenging of oxidants and thus can alter the redox homeostasis of the cell. This interplay can be either beneficial or detrimental to the cell depending on the localization, duration and levels of ROS and Ca<sup>2+</sup> signals. At one end of the spectrum, Ca<sup>2+</sup> and ROS/RNS can function as signaling modules while at the other end, lethal surges in these species are associated with cell death. Here, we highlight the interplay between Ca<sup>2+</sup> and ROS in cancer progression, emphasize the impact of redox regulation on Ca<sup>2+</sup> transport mechanisms, and describe how Ca<sup>2+</sup> signaling pathways, in turn, can regulate the cellular redox environment.</div></div>","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"127 ","pages":"Article 103014"},"PeriodicalIF":4.3,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143686353","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}
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}
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