Transient receptor potential vanilloid subtype 1 (TRPV1) is a non-selective cation channel that is mainly sensitive to stimuli such as high temperature, acidic environment, and capsaicin. Studies have reported that TRPV1 is expressed in skeletal muscle tissues and is involved in the regulation of a variety of physiological and pathological processes in skeletal muscle, but its regulatory mechanisms have not been analyzed and discussed. For this reason, we summarized the role of TRPV1 in skeletal muscle function and the mechanism of its influence on skeletal muscle-related physiopathological changes, such as myotube formation, inflammation, autophagy, mitochondrial biogenesis, and energy metabolism, which provides a theoretical basis and therapeutic target for understanding TRPV1 regulation of skeletal muscle-related diseases.
{"title":"TRPV1 signaling in skeletal muscle: A mini review of physiological and pathological roles.","authors":"Xiaoqing Ding, Chenyu Zhu, Qi Lu, Yuhao Zhang, Binghong Gao","doi":"10.1016/j.ceca.2025.103057","DOIUrl":"10.1016/j.ceca.2025.103057","url":null,"abstract":"<p><p>Transient receptor potential vanilloid subtype 1 (TRPV1) is a non-selective cation channel that is mainly sensitive to stimuli such as high temperature, acidic environment, and capsaicin. Studies have reported that TRPV1 is expressed in skeletal muscle tissues and is involved in the regulation of a variety of physiological and pathological processes in skeletal muscle, but its regulatory mechanisms have not been analyzed and discussed. For this reason, we summarized the role of TRPV1 in skeletal muscle function and the mechanism of its influence on skeletal muscle-related physiopathological changes, such as myotube formation, inflammation, autophagy, mitochondrial biogenesis, and energy metabolism, which provides a theoretical basis and therapeutic target for understanding TRPV1 regulation of skeletal muscle-related diseases.</p>","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"131 ","pages":"103057"},"PeriodicalIF":4.0,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144811842","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 : 2025-10-27DOI: 10.1016/j.ceca.2025.103089
Alvaro Macias-Diaz , Joel Nieto-Felipe , Sandra Alvarado , Francisco J. Martin-Romero , Gines M. Salido , Isaac Jardin , Tarik Smani , Jose J. Lopez , Juan A. Rosado
Orai family members are the pore-forming subunits of the Ca2+ release-activated Ca2+ (CRAC) channels that mediate store-operated Ca2+ entry (SOCE), a major mechanism for Ca2+ influx controlled by the filling state of the intracellular Ca2+ stores, that regulates a variety of cellular processes. While Orai1 plays a predominant role in SOCE, in luminal breast cancer cells, such as the MCF-7 cell line, SOCE is strongly dependent on Orai3. Using Orai1-knockout (KO) MCF-7 cells or silencing the expression of Orai1 by RNAi in wild-type MCF-7 or T47D cells we show that Orai1 plays a relevant functional role in the regulation of Orai3 expression, thus influencing SOCE. Transfection of Orai1-KO MCF-7 cells with Orai1α expression plasmid induces recovery of Orai1α that initially is not associated to changes in Orai3 protein levels or SOCE but after 7 days results in recovery of Orai3 protein content and SOCE. In Orai1-deficient MCF-7 cells, Orai3 protein synthesis was found to be attenuated, while Orai3 endo-lysosomal degradation was enhanced. Furthermore, Orai1 regulates the expression of estrogen receptor alpha (ERα), which has been associated to Orai3 expression in luminal breast cancer cells. Orai1 induces NFAT2 nuclear translocation in MCF-7 cells and NFAT2 overexpression attenuates ERα and Orai3 protein content in cells expressing Orai1. Our findings show that Orai1 is functionally associated with sustaining Orai3 synthesis and stability and ERα expression in luminal breast cancer cells, consequently modulating the ERα-Orai3 axis, rather than acting as a primary SOCE component.
{"title":"Orai1 plays a critical role in Orai3 synthesis and stability in luminal breast cancer cells","authors":"Alvaro Macias-Diaz , Joel Nieto-Felipe , Sandra Alvarado , Francisco J. Martin-Romero , Gines M. Salido , Isaac Jardin , Tarik Smani , Jose J. Lopez , Juan A. Rosado","doi":"10.1016/j.ceca.2025.103089","DOIUrl":"10.1016/j.ceca.2025.103089","url":null,"abstract":"<div><div>Orai family members are the pore-forming subunits of the Ca<sup>2+</sup> release-activated Ca<sup>2+</sup> (CRAC) channels that mediate store-operated Ca<sup>2+</sup> entry (SOCE), a major mechanism for Ca<sup>2+</sup> influx controlled by the filling state of the intracellular Ca<sup>2+</sup> stores, that regulates a variety of cellular processes. While Orai1 plays a predominant role in SOCE, in luminal breast cancer cells, such as the MCF-7 cell line, SOCE is strongly dependent on Orai3. Using Orai1-knockout (KO) MCF-7 cells or silencing the expression of Orai1 by RNAi in wild-type MCF-7 or T47D cells we show that Orai1 plays a relevant functional role in the regulation of Orai3 expression, thus influencing SOCE. Transfection of Orai1-KO MCF-7 cells with Orai1α expression plasmid induces recovery of Orai1α that initially is not associated to changes in Orai3 protein levels or SOCE but after 7 days results in recovery of Orai3 protein content and SOCE. In Orai1-deficient MCF-7 cells, Orai3 protein synthesis was found to be attenuated, while Orai3 endo-lysosomal degradation was enhanced. Furthermore, Orai1 regulates the expression of estrogen receptor alpha (ERα), which has been associated to Orai3 expression in luminal breast cancer cells. Orai1 induces NFAT2 nuclear translocation in MCF-7 cells and NFAT2 overexpression attenuates ERα and Orai3 protein content in cells expressing Orai1. Our findings show that Orai1 is functionally associated with sustaining Orai3 synthesis and stability and ERα expression in luminal breast cancer cells, consequently modulating the ERα-Orai3 axis, rather than acting as a primary SOCE component.</div></div>","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"132 ","pages":"Article 103089"},"PeriodicalIF":4.0,"publicationDate":"2025-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145412535","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 : 2025-10-22DOI: 10.1016/j.ceca.2025.103088
Jiaxiao Chen , Geyan Tian , Ming Hua , Min Gu , Wentao Sun , Jingyi Xu , Changjiao Luan , Juping Chen , Jiaxin Shi , Yinsong Chen , Xingjie Ma
Calcium and intracellular calcium signaling have emerged as critical mediators of cellular senescence. However, the mechanisms by which calcium signaling participates in the regulation of senescence remain only partially understood. In this study, we identified that Transglutaminase 2 (TGM2) is remarkably upregulated in response to senescence stimuli. Furthermore, TGM2 overexpression accelerated fibroblast senescence, as evidenced by the upregulation of p16, p21, increased senescence associated β-galactosidase (SA-β-Gal) activity, decreased cell proliferative capacity and induction of senescence-associated secretory phenotype (SASP), whereas the silencing of TGM2 staved off the senescent phenotype of fibroblasts induced by therapy. Mechanistically, TGM2 facilitates mitochondrial calcium accumulation, thereby contributing to mitochondrial dysfunction, activation of cGAS-STING signaling and ultimately leading to fibroblast cellular senescence. Furthermore, RNA-sequencing of senescent cells containing siRNA control or siRNA against TGM2 revealed that TGM2 triggers fibroblast senescence by repressing mechanosensitive ion channel PIEZO2. Interestingly, knockdown of PIEZO2 counteracted the effect of TGM2 repression on inhibiting cGAS-STING signaling and delaying cellular senescence. Taken together, our findings demonstrate that TGM2 serves as a key regulator of fibroblast senescence by modulating calcium dependent mitochondrial dysfunction and provide potential therapeutical targets for combating aging process and age-associated disorders.
{"title":"Transglutaminase 2 controls calcium dependent mitochondrial dysfunction and fibroblast senescence by repressing PIEZO2","authors":"Jiaxiao Chen , Geyan Tian , Ming Hua , Min Gu , Wentao Sun , Jingyi Xu , Changjiao Luan , Juping Chen , Jiaxin Shi , Yinsong Chen , Xingjie Ma","doi":"10.1016/j.ceca.2025.103088","DOIUrl":"10.1016/j.ceca.2025.103088","url":null,"abstract":"<div><div>Calcium and intracellular calcium signaling have emerged as critical mediators of cellular senescence. However, the mechanisms by which calcium signaling participates in the regulation of senescence remain only partially understood. In this study, we identified that Transglutaminase 2 (TGM2) is remarkably upregulated in response to senescence stimuli. Furthermore, TGM2 overexpression accelerated fibroblast senescence, as evidenced by the upregulation of p16, p21, increased senescence associated β-galactosidase (SA-β-Gal) activity, decreased cell proliferative capacity and induction of senescence-associated secretory phenotype (SASP), whereas the silencing of TGM2 staved off the senescent phenotype of fibroblasts induced by therapy. Mechanistically, TGM2 facilitates mitochondrial calcium accumulation, thereby contributing to mitochondrial dysfunction, activation of cGAS-STING signaling and ultimately leading to fibroblast cellular senescence. Furthermore, RNA-sequencing of senescent cells containing siRNA control or siRNA against TGM2 revealed that TGM2 triggers fibroblast senescence by repressing mechanosensitive ion channel PIEZO2. Interestingly, knockdown of PIEZO2 counteracted the effect of TGM2 repression on inhibiting cGAS-STING signaling and delaying cellular senescence. Taken together, our findings demonstrate that TGM2 serves as a key regulator of fibroblast senescence by modulating calcium dependent mitochondrial dysfunction and provide potential therapeutical targets for combating aging process and age-associated disorders.</div></div>","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"132 ","pages":"Article 103088"},"PeriodicalIF":4.0,"publicationDate":"2025-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145358126","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 : 2025-10-22DOI: 10.1016/j.ceca.2025.103087
Ewelina Jurewicz , Joanna Moraczewska , Anna Filipek
The actin cytoskeleton is a dynamic network present in all eukaryotic cells. It plays a central role in various cellular processes, including cell shape maintenance, motility, intracellular transport, and cell division. The actin cytoskeleton consists of actin filaments and a diverse array of associated actin-binding proteins (ABPs), which regulate the assembly, organization, and functions of actin filaments. S100 proteins, a family of low-molecular-weight Ca²⁺-binding proteins, have emerged as important regulators of actin filaments. They exert their regulatory functions either directly, through interactions with actin and actin-binding proteins (ABPs), or indirectly, by modulating Ca2+ release and thereby influencing actin-dependent contractility. This review article provides a comprehensive overview of current literature on the S100-dependent regulation of actin cytoskeleton dynamics in diverse cellular contexts. Specifically, it highlights the role of S100 proteins in modulating striated muscle contractility, actin–myosin interactions in smooth muscle, mechanotransduction, stress fiber assembly, lamellipodia formation, actin cortex organization, and structural organization of the actin cytoskeleton within synapses.
{"title":"Regulation of actin cytoskeleton by Ca2+-binding S100 proteins","authors":"Ewelina Jurewicz , Joanna Moraczewska , Anna Filipek","doi":"10.1016/j.ceca.2025.103087","DOIUrl":"10.1016/j.ceca.2025.103087","url":null,"abstract":"<div><div>The actin cytoskeleton is a dynamic network present in all eukaryotic cells. It plays a central role in various cellular processes, including cell shape maintenance, motility, intracellular transport, and cell division. The actin cytoskeleton consists of actin filaments and a diverse array of associated actin-binding proteins (ABPs), which regulate the assembly, organization, and functions of actin filaments. S100 proteins, a family of low-molecular-weight Ca²⁺-binding proteins, have emerged as important regulators of actin filaments. They exert their regulatory functions either directly, through interactions with actin and actin-binding proteins (ABPs), or indirectly, by modulating Ca<sup>2+</sup> release and thereby influencing actin-dependent contractility. This review article provides a comprehensive overview of current literature on the S100-dependent regulation of actin cytoskeleton dynamics in diverse cellular contexts. Specifically, it highlights the role of S100 proteins in modulating striated muscle contractility, actin–myosin interactions in smooth muscle, mechanotransduction, stress fiber assembly, lamellipodia formation, actin cortex organization, and structural organization of the actin cytoskeleton within synapses.</div></div>","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"132 ","pages":"Article 103087"},"PeriodicalIF":4.0,"publicationDate":"2025-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145399957","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 : 2025-10-22DOI: 10.1016/j.ceca.2025.103086
Natália Caroline Costa Coelho , Angela Maria Arenas Velásquez , Jhonatan Santos de Lima , Ana Laura Dias Ramos , Eduardo Maffud Cilli , Marcia A.S. Graminha
Calcium ion (Ca²⁺) signaling plays a pivotal role in the survival, differentiation, and virulence of trypanosomatids, including Leishmania spp., Trypanosoma brucei, and Trypanosoma cruzi, making it an attractive therapeutic target. This review integrates current knowledge on Ca²⁺ homeostasis in these parasites, addressing the plasma membrane, endoplasmic reticulum (ER), acidocalcisomes, mitochondria, lysosomes, and other organelles, with particular emphasis on key transporters and signaling pathways. In addition, we summarize genetic and pharmacological strategies used to validate Ca²⁺-related targets and highlight recent advances in both repurposed and novel compounds that disrupt Ca²⁺ homeostasis in trypanosomatids.
{"title":"Calcium homeostasis in trypanosomatids: A review of molecular targets and inhibitors","authors":"Natália Caroline Costa Coelho , Angela Maria Arenas Velásquez , Jhonatan Santos de Lima , Ana Laura Dias Ramos , Eduardo Maffud Cilli , Marcia A.S. Graminha","doi":"10.1016/j.ceca.2025.103086","DOIUrl":"10.1016/j.ceca.2025.103086","url":null,"abstract":"<div><div>Calcium ion (Ca²⁺) signaling plays a pivotal role in the survival, differentiation, and virulence of trypanosomatids, including <em>Leishmania</em> spp., <em>Trypanosoma brucei</em>, and <em>Trypanosoma cruzi</em>, making it an attractive therapeutic target. This review integrates current knowledge on Ca²⁺ homeostasis in these parasites, addressing the plasma membrane, endoplasmic reticulum (ER), acidocalcisomes, mitochondria, lysosomes, and other organelles, with particular emphasis on key transporters and signaling pathways. In addition, we summarize genetic and pharmacological strategies used to validate Ca²⁺-related targets and highlight recent advances in both repurposed and novel compounds that disrupt Ca²⁺ homeostasis in trypanosomatids.</div></div>","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"132 ","pages":"Article 103086"},"PeriodicalIF":4.0,"publicationDate":"2025-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145400018","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 : 2025-10-17DOI: 10.1016/j.ceca.2025.103085
Guilherme Rodrigo RM dos Santos , Maiara Ingrid Cavalcante Queiroz , Ana Catarina Rezende Leite
Calcium is a pivotal ion in cellular signaling, orchestrating pathways that support both cell survival and cell death. The mitochondria and endoplasmic reticulum are the principal organelles responsible for Ca²⁺ storage and play fundamental roles in maintaining intracellular Ca²⁺ homeostasis. The mitochondrial outer membrane (MOM) acts as a selective barrier that regulates the exchange of metabolites and other essential molecules necessary for mitochondrial function. This tightly regulated exchange depends on specific proteins, such as the voltage-dependent anion channel (VDAC), which serves as a key mediator of metabolite flux across the MOM. The mitochondrial Ca²⁺ uniporter (MCU) and the electrogenic Na⁺/Li⁺/Ca²⁺ exchanger (NCLX) represents the best-characterized mechanisms governing mitochondrial Ca²⁺ uptake and efflux, respectively. The leucine zipper EF-hand–containing transmembrane protein 1 (LETM1), localized to the inner mitochondrial membrane (IMM), has also been implicated in the regulation of mitochondrial Ca²⁺ homeostasis. This IMM protein was initially identified in association with Wolf–Hirschhorn Syndrome (WHS), a rare chromosomal disorder characterized by microcephaly, growth retardation, intellectual disability, and early-onset epileptic seizures. Approximately sixteen years ago, LETM1 was proposed to mediate K⁺/H⁺ exchange across the IMM. However, subsequent studies suggested an alternative function as a Ca²⁺/H⁺ exchanger, leading to an ongoing debate regarding its exact physiological role. Despite this controversy, the crucial contribution of LETM1 to mitochondrial physiology is widely acknowledged. LETM1 is considered an essential gene, and its dysfunction has been associated with a spectrum of pathological conditions, including Parkinson’s disease, obesity, and cancer.
{"title":"LETM1 and mitochondrial calcium homeostasis: A controversial but critical role in cellular function and disease","authors":"Guilherme Rodrigo RM dos Santos , Maiara Ingrid Cavalcante Queiroz , Ana Catarina Rezende Leite","doi":"10.1016/j.ceca.2025.103085","DOIUrl":"10.1016/j.ceca.2025.103085","url":null,"abstract":"<div><div>Calcium is a pivotal ion in cellular signaling, orchestrating pathways that support both cell survival and cell death. The mitochondria and endoplasmic reticulum are the principal organelles responsible for Ca²⁺ storage and play fundamental roles in maintaining intracellular Ca²⁺ homeostasis. The mitochondrial outer membrane (MOM) acts as a selective barrier that regulates the exchange of metabolites and other essential molecules necessary for mitochondrial function. This tightly regulated exchange depends on specific proteins, such as the voltage-dependent anion channel (VDAC), which serves as a key mediator of metabolite flux across the MOM. The mitochondrial Ca²⁺ uniporter (MCU) and the electrogenic Na⁺/Li⁺/Ca²⁺ exchanger (NCLX) represents the best-characterized mechanisms governing mitochondrial Ca²⁺ uptake and efflux, respectively. The leucine zipper EF-hand–containing transmembrane protein 1 (LETM1), localized to the inner mitochondrial membrane (IMM), has also been implicated in the regulation of mitochondrial Ca²⁺ homeostasis. This IMM protein was initially identified in association with Wolf–Hirschhorn Syndrome (WHS), a rare chromosomal disorder characterized by microcephaly, growth retardation, intellectual disability, and early-onset epileptic seizures. Approximately sixteen years ago, LETM1 was proposed to mediate K⁺/H⁺ exchange across the IMM. However, subsequent studies suggested an alternative function as a Ca²⁺/H⁺ exchanger, leading to an ongoing debate regarding its exact physiological role. Despite this controversy, the crucial contribution of LETM1 to mitochondrial physiology is widely acknowledged. LETM1 is considered an essential gene, and its dysfunction has been associated with a spectrum of pathological conditions, including Parkinson’s disease, obesity, and cancer.</div></div>","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"132 ","pages":"Article 103085"},"PeriodicalIF":4.0,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145358128","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 : 2025-10-14DOI: 10.1016/j.ceca.2025.103084
Haoran Zhang , Bowen Wang , Jing He , Shengyi Zhou , Juan Song , Ziwen Liu , Xiangyu Zeng , Ying Xing , Feng Guo , Jianyu Liu
Aim
To investigate the effects and underlying mechanisms of systemic PIEZO1 activation on the bone vasculature and osteogenesis.
Methods
Three-week-old C57BL/6J male mice were intraperitoneally injected with Yoda1, and changes in bone microstructure and vasculature were assessed via micro-CT and immunofluorescence. MC3T3-E1 osteoprogenitors and endothelial cells (human umbilical vein endothelial cells, HUVECs and human bone marrow microvascular endothelial cells, hBMECs) were treated with Yoda1 in vitro. Gene expression analysis, alkaline phosphatase (ALP) assays, and RNA sequencing were performed to assess osteogenic activity and endothelial identity, respectively. Alterations in the osteogenic-promoting function of endothelial cells upon PIEZO1 activation were evaluated by treating MC3T3-E1 cells with endothelial-conditioned media.
Results
Systemic Yoda1 administration reduced the abundance of CD31hiEMCNhi-type H vessels and disrupted trabecular bone microarchitecture. Yoda1 suppressed osteogenic gene expression and ALP activity in MC3T3-E1 cells, even at low concentrations. RNA-seq of Yoda1-treated hBMECs revealed a transcriptional shift toward an l-type endothelial phenotype and upregulation of the expression of BMP antagonists, including GREM1. Functional rescue assays confirmed that endothelial-derived GREM1 inhibits BMP4-induced osteogenic differentiation via paracrine signaling.
Conclusion
Our study reveals a dual role of PIEZO1 in bone biology, demonstrating that its activation disrupts vascular–osteogenic coupling and suppresses osteoblast differentiation through the PIEZO1–GREM1–BMP4 axis. These findings suggest that caution should be taken when targeting PIEZO1 for bone regeneration and highlight the importance of dose and duration in therapeutic applications.
{"title":"Endothelial PIEZO1 activation impairs osteogenesis via GREM1-mediated inhibition of BMP signaling","authors":"Haoran Zhang , Bowen Wang , Jing He , Shengyi Zhou , Juan Song , Ziwen Liu , Xiangyu Zeng , Ying Xing , Feng Guo , Jianyu Liu","doi":"10.1016/j.ceca.2025.103084","DOIUrl":"10.1016/j.ceca.2025.103084","url":null,"abstract":"<div><h3>Aim</h3><div>To investigate the effects and underlying mechanisms of systemic PIEZO1 activation on the bone vasculature and osteogenesis.</div></div><div><h3>Methods</h3><div>Three-week-old C57BL/6J male mice were intraperitoneally injected with Yoda1, and changes in bone microstructure and vasculature were assessed via micro-CT and immunofluorescence. MC3T3-E1 osteoprogenitors and endothelial cells (human umbilical vein endothelial cells, HUVECs and human bone marrow microvascular endothelial cells, hBMECs) were treated with Yoda1 in vitro. Gene expression analysis, alkaline phosphatase (ALP) assays, and RNA sequencing were performed to assess osteogenic activity and endothelial identity, respectively. Alterations in the osteogenic-promoting function of endothelial cells upon PIEZO1 activation were evaluated by treating MC3T3-E1 cells with endothelial-conditioned media.</div></div><div><h3>Results</h3><div>Systemic Yoda1 administration reduced the abundance of CD31<sup>hi</sup>EMCN<sup>hi</sup>-type H vessels and disrupted trabecular bone microarchitecture. Yoda1 suppressed osteogenic gene expression and ALP activity in MC3T3-E1 cells, even at low concentrations. RNA-seq of Yoda1-treated hBMECs revealed a transcriptional shift toward an <span>l</span>-type endothelial phenotype and upregulation of the expression of BMP antagonists, including GREM1. Functional rescue assays confirmed that endothelial-derived GREM1 inhibits BMP4-induced osteogenic differentiation via paracrine signaling.</div></div><div><h3>Conclusion</h3><div>Our study reveals a dual role of PIEZO1 in bone biology, demonstrating that its activation disrupts vascular–osteogenic coupling and suppresses osteoblast differentiation through the PIEZO1–GREM1–BMP4 axis. These findings suggest that caution should be taken when targeting PIEZO1 for bone regeneration and highlight the importance of dose and duration in therapeutic applications.</div></div>","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"132 ","pages":"Article 103084"},"PeriodicalIF":4.0,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145358127","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 : 2025-09-30DOI: 10.1016/j.ceca.2025.103083
Temitope Adeoye, Ghanim Ullah
Alzheimer's disease (AD) is characterized by profound disruption of synaptic function, with mounting evidence suggesting that amyloid-β (Aβ) oligomers disrupt calcium (Ca2+) homeostasis through membrane pore formation. While these pores are known to alter intracellular Ca2+ dynamics, their immediate impact on synaptic transmission and potential interaction with Familial AD (FAD)-associated endoplasmic reticulum (ER) dysfunction remains unclear. Here, we extend our previously developed model of presynaptic Ca2+ dynamics to examine how Aβ pores alter exocytosis and how such disruptions may manifest in the presence of FAD-associated ER dysfunction. Our model reveals that Aβ pores fundamentally alter both the timing and strength of neurotransmitter release. Unexpectedly, the impact of pores on synaptic function depends critically on their pattern of activity, where continuous pore activity leads to synaptic hyperactivation, while brief periods of intense pore activity trigger lasting hypoactivation at short timescales. These effects manifest most strongly in synapses with low and intermediate release probabilities, highlighting the established selective vulnerability of such synaptic configurations. We find that Aβ pores and FAD-driven ER Ca²⁺ dysregulation form an integrated pathological unit through bidirectional coupling of their respective Ca²⁺ microdomains to create complex patterns of disruptions. This coupling creates a feedback loop that produces an additive effect on neurotransmitter release during brief stimulations, but non-additive effects during sustained activity that promotes a shift towards asynchronous release. Surprisingly, our simulations predict that extended pore activity does not worsen indefinitely but only produces a modest additional disruption beyond initial pore formation that is likely determined by the intrinsic properties of the synapse. These findings indicate that early synaptic dysfunction in AD may arise from subtle perturbations in the temporal coordination of release rather than gross Ca2+ dysregulation, providing new mechanistic insights into the progressive nature of Aβ-driven synaptic failure in AD.
阿尔茨海默病（AD）的特点是突触功能严重破坏，越来越多的证据表明淀粉样蛋白-β (Aβ)寡聚物通过膜孔形成破坏钙（Ca2+）稳态。虽然已知这些孔可以改变细胞内Ca2+动力学，但它们对突触传递的直接影响以及与家族性AD （FAD）相关的内质网（ER）功能障碍的潜在相互作用仍不清楚。在这里，我们扩展了我们之前开发的突触前Ca2+动力学模型，以研究Aβ孔如何改变胞外分泌，以及这种破坏如何在fad相关的ER功能障碍中表现出来。我们的模型显示，Aβ孔从根本上改变了神经递质释放的时间和强度。出乎意料的是，孔对突触功能的影响主要取决于它们的活动模式，连续的孔活动导致突触过度激活，而短暂的强烈孔活动会在短时间尺度上引发持续的低激活。这些效应在低释放概率和中等释放概率的突触中表现得最强烈，突出了这种突触结构的既定选择性脆弱性。我们发现Aβ孔隙和fad驱动的ER Ca 2 +失调通过各自Ca 2 +微域的双向耦合形成了一个完整的病理单元，形成了复杂的破坏模式。这种耦合创造了一个反馈回路，在短暂刺激期间对神经递质释放产生加性效应，但在持续活动期间产生非加性效应，促进向异步释放转变。令人惊讶的是，我们的模拟预测，扩展的孔隙活动不会无限期地恶化，而只会在初始孔隙形成之外产生适度的额外破坏，这可能是由突触的内在特性决定的。这些发现表明，阿尔茨海默病的早期突触功能障碍可能源于释放时间协调的细微扰动，而不是总的Ca2+失调，这为阿尔茨海默病中a β驱动的突触衰竭的进行性本质提供了新的机制见解。
{"title":"Pathological calcium influx through amyloid beta pores disrupts synaptic function","authors":"Temitope Adeoye, Ghanim Ullah","doi":"10.1016/j.ceca.2025.103083","DOIUrl":"10.1016/j.ceca.2025.103083","url":null,"abstract":"<div><div>Alzheimer's disease (AD) is characterized by profound disruption of synaptic function, with mounting evidence suggesting that amyloid-β (Aβ) oligomers disrupt calcium (Ca<sup>2+</sup>) homeostasis through membrane pore formation. While these pores are known to alter intracellular Ca<sup>2+</sup> dynamics, their immediate impact on synaptic transmission and potential interaction with Familial AD (FAD)-associated endoplasmic reticulum (ER) dysfunction remains unclear. Here, we extend our previously developed model of presynaptic Ca<sup>2+</sup> dynamics to examine how Aβ pores alter exocytosis and how such disruptions may manifest in the presence of FAD-associated ER dysfunction. Our model reveals that Aβ pores fundamentally alter both the timing and strength of neurotransmitter release. Unexpectedly, the impact of pores on synaptic function depends critically on their pattern of activity, where continuous pore activity leads to synaptic hyperactivation, while brief periods of intense pore activity trigger lasting hypoactivation at short timescales. These effects manifest most strongly in synapses with low and intermediate release probabilities, highlighting the established selective vulnerability of such synaptic configurations. We find that Aβ pores and FAD-driven ER Ca²⁺ dysregulation form an integrated pathological unit through bidirectional coupling of their respective Ca²⁺ microdomains to create complex patterns of disruptions. This coupling creates a feedback loop that produces an additive effect on neurotransmitter release during brief stimulations, but non-additive effects during sustained activity that promotes a shift towards asynchronous release. Surprisingly, our simulations predict that extended pore activity does not worsen indefinitely but only produces a modest additional disruption beyond initial pore formation that is likely determined by the intrinsic properties of the synapse. These findings indicate that early synaptic dysfunction in AD may arise from subtle perturbations in the temporal coordination of release rather than gross Ca<sup>2+</sup> dysregulation, providing new mechanistic insights into the progressive nature of Aβ-driven synaptic failure in AD.</div></div>","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"132 ","pages":"Article 103083"},"PeriodicalIF":4.0,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145217036","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 : 2025-09-17DOI: 10.1016/j.ceca.2025.103082
Salah A. Baker , Bernard T. Drumm , Manushri Karwa , Katy M. Thompson , Benjamin Smith , Kenton M. Sanders
Interstitial cells of Cajal (ICC) generate contractile patterns of colonic motility. We investigated innervation of ICC within the plane of the myenteric plexus (ICC-MY) in proximal colon using mice expressing GCaMP6f in ICC. ICC-MY generated localized Ca2+ transients that couple to activation of ANO1 channels, a Ca2+-activated Cl- conductance. ICC are electrically coupled to SMCs, so activation or suppression of currents in ICC affects excitability of SMCs. ICC-MY displayed tonic inhibition, as the neurotoxin, TTX, increased the frequency of Ca2+ transients. Tonic inhibition was mimicked by a nitric oxide donor, NONOate, and by a guanylate cyclase agonist (Bay 58–2667). In contrast ODQ mimicked effects of TTX, increasing Ca2+ transients. Carbachol (CCh) increased Ca2+ transients in ICC-MY, and these effects were mediated by M3 muscarinic receptors. Neostigmine, also increased Ca2+ transients, suggesting there is tonic activation of enteric excitatory neurons in colonic muscles. Substance P and antagonists of NK1 and NK2 receptors had no effect on Ca2+ transients in ICC-MY. Electrical field stimulation (EFS), under conditions that emphasized excitatory neural responses, enhanced Ca2+ transients, and these effects were blocked by atropine or an M3 receptor antagonist (DAU 5884). EFS in the presence of atropine caused inhibition of Ca2+ via release of NO. Cessation of nitrergic stimulation resulted in a substantial increase in Ca2+ transients, known as post-stimulus excitation. In summary, ICC-MY, important for the generation of propulsive contractions in the colon, are innervated by excitatory (cholinergic) and inhibitory (nitrergic) motor neurons, and these inputs regulate the excitability of these cells.
{"title":"Neuronal regulation of myenteric interstitial cells of Cajal (ICC-MY) in the proximal colon","authors":"Salah A. Baker , Bernard T. Drumm , Manushri Karwa , Katy M. Thompson , Benjamin Smith , Kenton M. Sanders","doi":"10.1016/j.ceca.2025.103082","DOIUrl":"10.1016/j.ceca.2025.103082","url":null,"abstract":"<div><div>Interstitial cells of Cajal (ICC) generate contractile patterns of colonic motility. We investigated innervation of ICC within the plane of the myenteric plexus (ICC-MY) in proximal colon using mice expressing GCaMP6f in ICC. ICC-MY generated localized Ca<sup>2+</sup> transients that couple to activation of ANO1 channels, a Ca<sup>2+</sup>-activated Cl<sup>-</sup> conductance. ICC are electrically coupled to SMCs, so activation or suppression of currents in ICC affects excitability of SMCs. ICC-MY displayed tonic inhibition, as the neurotoxin, TTX, increased the frequency of Ca<sup>2+</sup> transients. Tonic inhibition was mimicked by a nitric oxide donor, NONOate, and by a guanylate cyclase agonist (Bay 58–2667). In contrast ODQ mimicked effects of TTX, increasing Ca<sup>2+</sup> transients. Carbachol (CCh) increased Ca<sup>2+</sup> transients in ICC-MY, and these effects were mediated by M3 muscarinic receptors. Neostigmine, also increased Ca<sup>2+</sup> transients, suggesting there is tonic activation of enteric excitatory neurons in colonic muscles. Substance P and antagonists of NK1 and NK2 receptors had no effect on Ca<sup>2+</sup> transients in ICC-MY. Electrical field stimulation (EFS), under conditions that emphasized excitatory neural responses, enhanced Ca<sup>2+</sup> transients, and these effects were blocked by atropine or an M3 receptor antagonist (DAU 5884). EFS in the presence of atropine caused inhibition of Ca<sup>2+</sup> via release of NO. Cessation of nitrergic stimulation resulted in a substantial increase in Ca<sup>2+</sup> transients, known as post-stimulus excitation. In summary, ICC-MY, important for the generation of propulsive contractions in the colon, are innervated by excitatory (cholinergic) and inhibitory (nitrergic) motor neurons, and these inputs regulate the excitability of these cells.</div></div>","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"132 ","pages":"Article 103082"},"PeriodicalIF":4.0,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145154986","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 : 2025-09-14DOI: 10.1016/j.ceca.2025.103080
Jie Wang , Yue Cui , Peng-Fei Ding , Jia-Tong Zhang , Xun-Zhi Liu , Sen Gao , Xiang-Xin Chen , Zheng Peng , Xiao-Jian Li , Ling-Yun Wu , Yong-Yue Gao , Chun-Hua Hang , Wei Li
Background
Subarachnoid hemorrhage (SAH) is a severe neurological emergency associated with substantial morbidity and mortality. Research into the mechanisms underlying neuronal injury following SAH has identified early brain injury (EBI) as a critical factor influencing clinical outcomes. Among the various pathological processes involved in EBI, calcium overload remains relatively understudied yet plays a pivotal role in neuronal damage. Excessive accumulation of calcium within mitochondria can initiate apoptotic and autophagic pathways, contributing to cell death. Mitochondrial calcium uptake 1 (MICU1), a regulatory protein located on the inner mitochondrial membrane, functions to modulate mitochondrial calcium ions by inhibiting calcium influx under conditions of low intracellular calcium concentration.
Methods
Mitochondria were extracted from the cerebrospinal fluid (CSF) of patients with SAH to evaluate the extent of mitochondrial damage. In vivo and in vitro SAH models were employed to assess mitochondrial damage and dynamic changes in both mitochondrial and cytosolic calcium levels. The interaction between MICU1 and mitochondria was further examined. To investigate the functional role of MICU1, lentivirus vectors were used to upregulate MICU1 expression, while siRNA was applied to knock down its expression in Neuron-2a (N2a) cells. Following hemoglobin (Hb) stimulation, mitochondrial damage and apoptosis were systematically evaluated.
Results
Analysis of CSF from SAH patients revealed decreased MICU1 expression and aggravated mitochondrial damage. Hb stimulation of primary neurons and N2a cells led to reduced MICU1 expression and mitochondrial calcium overload, which mediated mitochondrial damage and promoted the progression of neuronal apoptosis. Following upregulation of MICU1 expression in N2a cells, the cells exhibited enhanced tolerance to Hb-induced calcium overload, resulting in a significant reduction in mitochondrial damage. This protective effect was attenuated by MICU1 siRNA treatment. Moreover, MICU1 overexpression alleviated Hb-induced apoptosis in N2a cells, whereas siRNA-mediated knockdown of MICU1 exacerbated apoptotic responses.
Conclusion
Mitochondrial calcium overload in neurons following SAH contributes to the development of EBI and neuronal damage. MICU1 exerts a neuroprotective role by mitigating mitochondrial calcium overload, thereby reducing mitochondrial damage and neuronal apoptosis.
{"title":"MICU1 attenuates neuronal apoptosis after subarachnoid hemorrhage by inhibiting mitochondrial calcium overload and damage","authors":"Jie Wang , Yue Cui , Peng-Fei Ding , Jia-Tong Zhang , Xun-Zhi Liu , Sen Gao , Xiang-Xin Chen , Zheng Peng , Xiao-Jian Li , Ling-Yun Wu , Yong-Yue Gao , Chun-Hua Hang , Wei Li","doi":"10.1016/j.ceca.2025.103080","DOIUrl":"10.1016/j.ceca.2025.103080","url":null,"abstract":"<div><h3>Background</h3><div>Subarachnoid hemorrhage (SAH) is a severe neurological emergency associated with substantial morbidity and mortality. Research into the mechanisms underlying neuronal injury following SAH has identified early brain injury (EBI) as a critical factor influencing clinical outcomes. Among the various pathological processes involved in EBI, calcium overload remains relatively understudied yet plays a pivotal role in neuronal damage. Excessive accumulation of calcium within mitochondria can initiate apoptotic and autophagic pathways, contributing to cell death. Mitochondrial calcium uptake 1 (MICU1), a regulatory protein located on the inner mitochondrial membrane, functions to modulate mitochondrial calcium ions by inhibiting calcium influx under conditions of low intracellular calcium concentration.</div></div><div><h3>Methods</h3><div>Mitochondria were extracted from the cerebrospinal fluid (CSF) of patients with SAH to evaluate the extent of mitochondrial damage. In vivo and in vitro SAH models were employed to assess mitochondrial damage and dynamic changes in both mitochondrial and cytosolic calcium levels. The interaction between MICU1 and mitochondria was further examined. To investigate the functional role of MICU1, lentivirus vectors were used to upregulate MICU1 expression, while siRNA was applied to knock down its expression in Neuron-2a (N2a) cells. Following hemoglobin (Hb) stimulation, mitochondrial damage and apoptosis were systematically evaluated.</div></div><div><h3>Results</h3><div>Analysis of CSF from SAH patients revealed decreased MICU1 expression and aggravated mitochondrial damage. Hb stimulation of primary neurons and N2a cells led to reduced MICU1 expression and mitochondrial calcium overload, which mediated mitochondrial damage and promoted the progression of neuronal apoptosis. Following upregulation of MICU1 expression in N2a cells, the cells exhibited enhanced tolerance to Hb-induced calcium overload, resulting in a significant reduction in mitochondrial damage. This protective effect was attenuated by MICU1 siRNA treatment. Moreover, MICU1 overexpression alleviated Hb-induced apoptosis in N2a cells, whereas siRNA-mediated knockdown of MICU1 exacerbated apoptotic responses.</div></div><div><h3>Conclusion</h3><div>Mitochondrial calcium overload in neurons following SAH contributes to the development of EBI and neuronal damage. MICU1 exerts a neuroprotective role by mitigating mitochondrial calcium overload, thereby reducing mitochondrial damage and neuronal apoptosis.</div></div>","PeriodicalId":9678,"journal":{"name":"Cell calcium","volume":"132 ","pages":"Article 103080"},"PeriodicalIF":4.0,"publicationDate":"2025-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145102587","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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