Biochimica et biophysica acta. Molecular cell research最新文献

{"title":"Role and regulatory mechanism of DLX5 in rhabdomyosarcoma tumorigenesis","authors":"Yanxue Zhao ,&nbsp;Xinpei Liu ,&nbsp;Zining Wu ,&nbsp;Guotao Ma ,&nbsp;Quanli Gao ,&nbsp;Jun Zheng ,&nbsp;Chaoji Zhang","doi":"10.1016/j.bbamcr.2025.119959","DOIUrl":"10.1016/j.bbamcr.2025.119959","url":null,"abstract":"<div><div>Rhabdomyosarcoma (RMS), a common malignant tumor in children, presents numerous challenges in clinical treatment. This study investigated the specific functions and regulatory mechanisms of distal-less homeobox 5 (<em>DLX5</em>) in RMS. Data from TCGA, GEO and GEPIA databases were downloaded and analyzed. The effect of <em>DLX5</em> and <em>PAX3-FOXO1</em> on RMS cells was examined through cellular experiments. Binding activity between DLX5 and H3K9me2 was assessed using pull-down and chromatin immunoprecipitation-qPCR assays. Additionally, RMS model mice were constructed via xenotransplantation to validate the in vivo effects of <em>DLX5</em> on RMS. The results revealed that DLX5 was upregulated in RMS tissues and increased in various RMS cell lines, particularly in alveolar RMS cell lines. <em>DLX5</em> knockdown inhibited malignant biological behaviors. Besides, DLX5 expression was associated with myogenic differentiation of RMS cells. While the overexpression or knockdown of <em>DLX5</em> did not affect <em>PAX-FOXO1</em> expression. <em>PAX3-FOXO1</em> knockdown reduced DLX5 expression, indicating that <em>DLX5</em> act as a downstream effector of <em>PAX3-FOXO1</em>. Mechanistically, <em>PAX3-FOXO1</em> regulated DLX5 expression through <em>KDM4B/H3K9me2</em> axis. In vitro experiments further demonstrated that knockout of <em>DLX5</em> or <em>KDM4B</em> inhibited tumor growth. In conclusion, DLX5 expression was increased in <em>PAX3-FOXO1</em>–driven RMS, and its knockdown inhibited malignant biological behaviors of RMS cells. Moreover, the aberrant expression of DLX5 in <em>PAX3-FOXO1</em>–driven RMS was regulated by <em>KDM4B/H3K9me2</em> axis. These findings provided potential therapeutic targets for RMS treatment.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 5","pages":"Article 119959"},"PeriodicalIF":4.6,"publicationDate":"2025-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143854694","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}

{"title":"New insights into Gremlin-1: A tumour microenvironment landscape re-engineer and potential therapeutic target","authors":"Chengpeng Sun ,&nbsp;Zijun Ding ,&nbsp;Benjie li ,&nbsp;Sihong Chen ,&nbsp;Enliang Li ,&nbsp;Qingping Yang","doi":"10.1016/j.bbamcr.2025.119962","DOIUrl":"10.1016/j.bbamcr.2025.119962","url":null,"abstract":"<div><div>Gremlin-1 (GREM1), a well-known bone morphogenetic protein (BMP) antagonist, is highly expressed in various malignant tumours. However, the specific role of GREM1 in tumours remains controversial and may be attributed to the heterogeneity and complexity of the tumour microenvironment (TME). It is currently believed that GREM1 regulates the complex landscape of the TME, primarily by antagonising BMP signalling or BMP-independent pathways. Both GREM1 and BMP play dual roles in tumour progression. Therefore, the mutual crosstalk between tumour cells and tumour-associated fibroblasts and the regulation of various secreted factors in the TME affect the secretion level of GREM1, which in turn regulates the amplitude balance between GREM1 and BMP, affecting tumour progression. The inhibition of GREM1 activity in the TME can disrupt this amplitude balance and prevent the formation of a tumour-supportive microenvironment, demonstrating that GREM1 is a potential therapeutic target. In this study, we reviewed the specific signalling pathways via which GREM1 in the TME regulates epithelial-mesenchymal transition, construction of the tumour immune microenvironment, and maintenance of tumour cell stemness via BMP-dependent and BMP-independent regulation, and also summarised the latest clinical progress of GREM1.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 5","pages":"Article 119962"},"PeriodicalIF":4.6,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143848577","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}

{"title":"POLR1F promotes proliferation and stemness of anaplastic thyroid cancer by activating F2R/p38 MAPK signaling","authors":"Yingying Gong ,&nbsp;Shanshan Wang ,&nbsp;Ziwen Fang ,&nbsp;Xiaoping Hu ,&nbsp;Ying Li ,&nbsp;Yulu Che ,&nbsp;Zhuo Tan ,&nbsp;Baochun Su ,&nbsp;Minghua Ge ,&nbsp;Zongfu Pan","doi":"10.1016/j.bbamcr.2025.119963","DOIUrl":"10.1016/j.bbamcr.2025.119963","url":null,"abstract":"<div><div>Anaplastic thyroid cancer (ATC) is one of the most aggressive cancers characterized by a rapid growth rate. Dysregulation of RNA polymerase (Pol) is critical for cancer development. However, little is known about its role and mechanism in ATC. In the present study, the expression of Pol family members is screened in a large-cohort proteome containing 113 ATCs and 20 normal thyroid samples. Combined with the mRNA levels and gene dependency scores, we find that RNA Polymerase I Subunit F (POLR1F) is significantly upregulated in ATC tissues with the strongest gene effect among the Pol family members. The results are confirmed in ATC tissues and cell lines, revealing that POLR1F mainly locates in the nucleus and expresses stronger than that in normal thyrocytes. Silencing POLR1F in ATC cell lines significantly inhibit cell proliferation, colony formation, and sphere sizes. POLR1F knockdown dramatically reduces ATC tumor growth in both zebrafish and nude mouse xenograft models. RNA sequencing reveals that the coagulation factor thrombin receptor (F2R) is a downstream target of POLR1F, which participates in the p38 MAPK pathway. POLR1F promotes the H3K4 methylation at the F2R promoter by reducing the binding of demethylase KDM5C to H3K4me3, thereby enhancing F2R transcription. These results demonstrate that POLR1F maintains ATC stemness and growth by activating F2R/p38 MAPK signaling, shedding light on the essential role of POLR1F in ATC progression.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 5","pages":"Article 119963"},"PeriodicalIF":4.6,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143848578","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}

{"title":"In vivo composition of the mitochondrial nucleoid in mice","authors":"Rodolfo García-Villegas ,&nbsp;Franka Odenthal ,&nbsp;Yvonne Giannoula ,&nbsp;Nina A. Bonekamp ,&nbsp;Inge Kühl ,&nbsp;Chan Bae Park ,&nbsp;Henrik Spåhr ,&nbsp;Elisa Motori ,&nbsp;Fredrik Levander ,&nbsp;Nils-Göran Larsson","doi":"10.1016/j.bbamcr.2025.119955","DOIUrl":"10.1016/j.bbamcr.2025.119955","url":null,"abstract":"<div><div>Mitochondrial DNA (mtDNA) is compacted into dynamic structures called mitochondrial nucleoids (mt-nucleoids), with the mitochondrial transcription factor A (TFAM) as the core packaging protein. We generated bacterial artificial chromosome (BAC) transgenic mice expressing FLAG-tagged TFAM protein (<em>Tfam-FLAG</em>^<em>BAC</em> mice) to investigate the mt-nucleoid composition <em>in vivo</em>. Importantly, we show that the TFAM-FLAG protein is functional and complements the absence of the wild-type TFAM protein in homozygous <em>Tfam</em> knockout mice. We performed immunoprecipitation experiments from different mouse tissues and identified 12 proteins as core mt-nucleoid components by proteomics analysis. Among these, eight proteins correspond to mtDNA replication and transcription factors, while the other four are involved in the mitoribosome assembly. In addition, we used the <em>Tfam-FLAG</em>^<em>BAC</em> mice to identify ten proteins that may stabilize TFAM-FLAG upon depletion of the mitochondrial RNA polymerase despite the absence of mtDNA and induction of the LONP1 protease. Finally, we evaluated the changes in mt-nucleoids caused by very high levels of TFAM unraveling nine interactors that could counteract the high TFAM levels to maintain active mtDNA transcription. Altogether, we demonstrate that the <em>Tfam-FLAG</em>^<em>BAC</em> mice are a valuable tool for investigating the mt-nucleoid composition <em>in vivo</em>.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 6","pages":"Article 119955"},"PeriodicalIF":4.6,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143883009","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}

{"title":"Inhibition of the Sp1/PI3K/AKT signaling pathway exacerbates doxorubicin-induced cardiomyopathy","authors":"Guojian Xiang ,&nbsp;Tingting Shi ,&nbsp;Cornelius Obinna Nwaele ,&nbsp;Huazhen Xiao ,&nbsp;Yucheng Liu ,&nbsp;Qingfeng Wang ,&nbsp;Jiancheng Zhang ,&nbsp;Yonghong Zheng","doi":"10.1016/j.bbamcr.2025.119960","DOIUrl":"10.1016/j.bbamcr.2025.119960","url":null,"abstract":"<div><h3>Objective</h3><div>This study aimed to investigate the interaction and underlying mechanisms between specificity protein 1 (Sp1) and the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) signaling pathway in the context of doxorubicin-induced cardiomyopathy (DIC).</div></div><div><h3>Methods</h3><div>A rat model of DIC was established by intraperitoneal injection of doxorubicin (1 mg/kg) twice a week for eight weeks. Cardiac function was evaluated using echocardiography, and myocardial histopathology was assessed by hematoxylin-eosin (HE) staining. In vitro, H9c2 cardiomyocytes were treated with doxorubicin (2 μmol/L) to induce cardiotoxicity, followed by co-treatment with the Sp1 inhibitor plicamycin or the PI3K/AKT inhibitor LY294002. Cell viability was measured by the CCK-8 assay. Oxidative stress markers, including reactive oxygen species (ROS) and lactate dehydrogenase (LDH), were quantified using flow cytometry and colorimetric assays. Apoptosis was detected via TUNEL staining, and protein expression of Sp1, PI3K, AKT, and Caspase-3 was analyzed by Western blotting.</div></div><div><h3>Results</h3><div>Doxorubicin treatment significantly impaired cardiac function in rats, as evidenced by an increase in both left ventricular internal diameters during diastole (LVIDd) and systole (LVIDs), along with decreased ejection fraction (EF) and fractional shortening (FS) (<em>p</em> &lt; 0.01). Myocardial HE staining in doxorubicin-treated rats revealed disorganized cardiomyocyte structures, edema, and cellular necrosis. In vitro, doxorubicin exposure led to reduced H9c2 cell viability, elevated ROS and LDH levels, and increased apoptosis rates (<em>p</em> &lt; 0.01). Western blotting demonstrated that doxorubicin significantly downregulated the expression of Sp1, PI3K, and AKT while upregulating Caspase-3. Inhibition of Sp1 or PI3K/AKT exacerbated these effects, resulting in further cardiac dysfunction, oxidative stress, and apoptosis. Moreover, Sp1 inhibition led to decreased PI3K/AKT pathway activation, while PI3K/AKT inhibition reciprocally suppressed Sp1 expression, indicating a bidirectional regulatory relationship.</div></div><div><h3>Conclusion</h3><div>Doxorubicin induces cardiotoxicity by promoting oxidative stress and apoptosis through the downregulation of the Sp1/PI3K/AKT signaling pathway. Inhibition of this pathway exacerbates cardiac injury, suggesting that targeting Sp1 and PI3K/AKT may offer novel therapeutic strategies for the prevention and treatment of DIC.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 5","pages":"Article 119960"},"PeriodicalIF":4.6,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143843877","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}

{"title":"Catalytic proteasome subunits are heterogeneously active in human platelets with β1i playing a role in signaling and granule release","authors":"Lara Smrdel ,&nbsp;Slavica Stanišić ,&nbsp;Živa Zajec ,&nbsp;Martina Gobec","doi":"10.1016/j.bbamcr.2025.119961","DOIUrl":"10.1016/j.bbamcr.2025.119961","url":null,"abstract":"<div><div><ul><li><span>•</span><span><div>Human platelets contain catalytically active subunits of both constitutive and immunoproteasomes, with predominant expression of β5i, β5c, β1i, and β1c subunits.</div></span></li><li><span>•</span><span><div>Analysis of 31 healthy donors revealed substantial interindividual variability in both the protein levels and active states of proteasome subunits in platelets.</div></span></li><li><span>•</span><span><div>The proteasome catalytic subunit β1i was found to play a significant role in regulating platelet signaling pathways, particularly influencing the p38 and NFкB pathway.</div></span></li><li><span>•</span><span><div>Inhibition of β1i enhanced α-granule release, notably increasing CCL5 secretion, upon ADP activation, highlighting its potential role in platelet activation and immune regulation.</div></span></li></ul></div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 5","pages":"Article 119961"},"PeriodicalIF":4.6,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143843790","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}

{"title":"POLR1D, a shared subunit of RNA polymerase I and III, modulates mTORC1 activity","authors":"Neuton Gorjão ,&nbsp;Lukasz S. Borowski ,&nbsp;Roman J. Szczesny ,&nbsp;Damian Graczyk","doi":"10.1016/j.bbamcr.2025.119957","DOIUrl":"10.1016/j.bbamcr.2025.119957","url":null,"abstract":"<div><div>The mechanistic target of rapamycin complex 1 (mTORC1) is a crucial nutrient sensor and a major regulator of cell growth and proliferation. While mTORC1 activity is frequently upregulated in cancer, the mechanisms regulating mTORC1 are not fully understood. POLR1D, a shared subunit of RNA polymerases I and III, is often upregulated in colorectal cancer (CRC) and mutated in Treacher-Collins syndrome. POLR1D, together with its binding partner POLR1C, forms a dimer that is believed to initiate the assembly of the multisubunit RNA polymerases I and III.</div><div>Our data reveal an unexpected link between POLR1D and mTORC1 signalling. We found that the overproduction of POLR1D in human cells stimulates mTORC1 activity. In contrast, the downregulation of POLR1D leads to the repression of the mTORC1 pathway. Additionally, we demonstrate that a pool of POLR1D localises to the cytoplasm and interacts with the mTORC1 regulator RAGA and RAPTOR. Furthermore, POLR1D enhances the interaction between RAPTOR and RAGA and sustains mTORC1 activity under starvation conditions.</div><div>We have identified a novel role for the RNA polymerase I/III subunit POLR1D in regulating mTORC1 signalling. Our findings suggest the existence of a new node in the already complex mTORC1 signalling network, where POLR1D functions to convey the cell's internal status, namely polymerase assembly, to this kinase.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 5","pages":"Article 119957"},"PeriodicalIF":4.6,"publicationDate":"2025-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143869500","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}

{"title":"5-HT promotes pancreatic α-to-β cell transdifferentiation","authors":"Na Liu ,&nbsp;Tengli Liu ,&nbsp;Nijat Alim ,&nbsp;Jiaqi Zou ,&nbsp;Xiaoyan Hu ,&nbsp;Boya Zhang ,&nbsp;Fei Liu ,&nbsp;Xuejie Ding ,&nbsp;Peng Sun ,&nbsp;Shusen Wang ,&nbsp;Lanqiu Zhang ,&nbsp;Rongxiu Zheng ,&nbsp;Rui Liang","doi":"10.1016/j.bbamcr.2025.119958","DOIUrl":"10.1016/j.bbamcr.2025.119958","url":null,"abstract":"<div><div>The role of 5-HT in maintaining glucose homeostasis during metabolic stress and inhibiting glucagon secretion is well documented, however, its effect on α cell identity remained unclear. In this study, we demonstrated that 5-HT suppressed the expression of α cell markers, such as Arx and Gcg, while enhancing the expression of β cell markers in mouse pancreatic α cell lines. We further found that treatment with 5-HT significantly increased the percentage of Gcg⁺Ins⁺ and Gcg⁺Nkx6.1⁺ cells in isolated human and mouse islets. Using pancreatic α cell lineage-tracing Gcg^cre+; tdTomato/tdTomato mice, we observed that 5-HT treatment significantly reduced random blood glucose levels and increased tdTomato⁺Ins⁺, Gcg⁺Ins⁺ and Gcg⁺Nkx6.1⁺ cells in a high fat diet and streptozotocin (HFD + STZ) induced diabetes model. Additionally, in situ detection of 5-HT production in the human pancreas revealed a reduction of 5-HT expression in β cells of human T2D patients. These findings suggest that 5-HT treatment induces the transdifferentiation of α to β cells, potentially contributing to the recovery of β cell mass in T2D.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 5","pages":"Article 119958"},"PeriodicalIF":4.6,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143828723","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}

{"title":"The versatile role of YidC in membrane protein biosynthesis and quality control","authors":"Mehmet Caliseki ,&nbsp;Christiane Schaffitzel ,&nbsp;Burak Veli Kabasakal","doi":"10.1016/j.bbamcr.2025.119956","DOIUrl":"10.1016/j.bbamcr.2025.119956","url":null,"abstract":"<div><div>Membrane proteins are essential for bacterial survival, facilitating vital processes such as energy production, nutrient transport, and cell wall synthesis. YidC is a key player in membrane protein biogenesis, acting as both an insertase and a chaperone to ensure proper protein folding and integration into the lipid bilayer. Its conserved structure and adaptability enable it to mediate co-translational and post-translational protein insertion into the membrane through both Sec-dependent and Sec-independent pathways. In addition to facilitating protein insertion, YidC collaborates with FtsH in protein quality control, preventing the accumulation of misfolded proteins that could impair cellular function. This important relationship between YidC and FtsH is poorly understood, and there is a need for further investigation into their collaboration. Understanding how YidC and FtsH coordinate their roles could provide valuable insights into the links between bacterial membrane protein biogenesis and quality control pathways. Moreover, given its central functions, YidC represents a potential target for antimicrobial development. Small molecules disrupting its function in protein folding and insertion, hold promise. However, achieving bacterial specificity without impacting eukaryotic homologs remains a challenge. Here, we review our current understanding of YidC's structure, molecular function in membrane protein biogenesis and quality control, known interactions and its therapeutic potential.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 5","pages":"Article 119956"},"PeriodicalIF":4.6,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143820480","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}

{"title":"Improving mitochondria-associated endoplasmic reticulum membranes integrity as converging therapeutic strategy for rare neurodegenerative diseases and cancer","authors":"Michal Cagalinec ,&nbsp;Adnan Mohd ,&nbsp;Silvia Borecka ,&nbsp;Geert Bultynck ,&nbsp;Vinay Choubey ,&nbsp;Shira Yanovsky-Dagan ,&nbsp;Shlomit Ezer ,&nbsp;Daniela Gasperikova ,&nbsp;Tamar Harel ,&nbsp;Dana Jurkovicova ,&nbsp;Allen Kaasik ,&nbsp;Jean-Charles Liévens ,&nbsp;Tangui Maurice ,&nbsp;Marco Peviani ,&nbsp;Elodie Marie Richard ,&nbsp;Jan Skoda ,&nbsp;Martina Skopkova ,&nbsp;Pauline Tarot ,&nbsp;Robbe Van Gorp ,&nbsp;Liga Zvejniece ,&nbsp;Benjamin Delprat","doi":"10.1016/j.bbamcr.2025.119954","DOIUrl":"10.1016/j.bbamcr.2025.119954","url":null,"abstract":"<div><div>Membrane contact sites harbor a distinct set of proteins with varying biological functions, thereby emerging as hubs for localized signaling nanodomains underlying adequate cell function. Here, we will focus on mitochondria-associated endoplasmic reticulum membranes (MAMs), which serve as hotspots for Ca²⁺ signaling, redox regulation, lipid exchange, mitochondrial quality and unfolded protein response pathway. A network of MAM-resident proteins contributes to the structural integrity and adequate function of MAMs. Beyond endoplasmic reticulum (ER)-mitochondrial tethering proteins, MAMs contain several multi-protein complexes that mediate the transfer of or are influenced by Ca²⁺, reactive oxygen species and lipids. Particularly, IP₃ receptors, intracellular Ca²⁺-release channels, and Sigma-1 receptors (S1Rs), ligand-operated chaperones, serve as important platforms that recruit different accessory proteins and intersect with these local signaling processes. Furthermore, many of these proteins are directly implicated in pathophysiological conditions, where their dysregulation or mutation is not only causing diseases such as cancer and neurodegeneration, but also rare genetic diseases, for example familial Parkinson's disease (PINK1, Parkin, DJ-1), familial Amyotrophic lateral sclerosis (TDP43), Wolfram syndrome1/2 (WFS1 and CISD2), Harel-Yoon syndrome (ATAD3A). In this review, we will discuss the current state-of-the-art regarding the molecular components, protein platforms and signaling networks underlying MAM integrity and function in cell function and how their dysregulation impacts MAMs, thereby driving pathogenesis and/or impacting disease burden. We will highlight how these insights can generate novel, potentially therapeutically relevant, strategies to tackle disease outcomes by improving the integrity of MAMs and the signaling processes occurring at these membrane contact sites.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 5","pages":"Article 119954"},"PeriodicalIF":4.6,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143863859","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}