Cellular and Molecular Life Sciences最新文献

{"title":"TRPV6 channel function is involved in endometrial epithelial cell Ca²⁺ signaling and female mouse fecundity.","authors":"Adela Sota, Andreas Beck, Philipp Wartenberg, Anna-Lena Gehl, Manuel Winter, Ulrich Wissenbach, Marc Freichel, Markus R Meyer, Ulrich Boehm, Veit Flockerzi, Claudia Fecher-Trost, Petra Weissgerber","doi":"10.1007/s00018-025-05857-9","DOIUrl":"10.1007/s00018-025-05857-9","url":null,"abstract":"<p><p>The Ca²⁺-selective transient receptor potential vanilloid 6 (TRPV6) channel plays a fundamental role in the female and male murine reproductive system. We have previously shown that TRPV6 is essential for male fertility, and necessary for a proper placental Ca²⁺ transport, embryonic bone development and calcification, as well as for extracellular matrix formation in the placental labyrinth. Here, we show that lack of functional TRPV6 results in impaired fecundity in female mice with increased latency to first pregnancy, longer interpregnancy intervals and fewer and smaller litters. In mouse endometrium the TRPV6 protein is expressed in epithelial cells (MEECs). Using patch clamp recording and Ca²⁺ imaging, we show TRPV6-dependent whole-cell currents and that TRPV6 contributes to cytoplasmic Ca²⁺ signaling in MEECs. MEECs lacking functional TRPV6 Ca²⁺ channels reveal a significantly reduced frequency of spontaneous cytosolic Ca²⁺ oscillations, shown in isolated cells and in situ in whole mount uterus preparations. Our results reveal a previously unknown physiological role for TRPV6 in the regulation of endometrial Ca²⁺ homeostasis and its impact on female fecundity in mice, providing a molecular and cellular framework for further investigation of reproductive disorders, such as those associated with defective Ca²⁺ regulation in women.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"346"},"PeriodicalIF":6.2,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12504177/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238347","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Splicing factor Sf3b1 facilitates maintenance of neuronal dendrites by modulating mitochondrial health.","authors":"Wei-Chia Tsao, Yi-Chun Huang, Hsin-Ho Sung, Chi-Hung Lin, Hwei-Jan Hsu, Hsiu-Fen Lin, Cheng-Ting Chien","doi":"10.1007/s00018-025-05860-0","DOIUrl":"10.1007/s00018-025-05860-0","url":null,"abstract":"<p><p>The intricate process of dendritic arborization is essential for forming functional neural circuits, and many of the underlying molecular and cellular mechanisms have been uncovered. However, how they are linked to regulate dendritic arborization in neurons remains further exploration. Through genetic screening, we identify the splicing factor Sf3b1 as functioning cell-autonomously in neuronal dendrite growth and maintenance. Our transcriptomic analysis links Sf3b1-regulated alternative splicing to modulation of metabolic pathways, and we assess altered splicing patterns for several mitochondria-related genes. Importantly, Sf3b1 knockdown in neurons results in dramatic mitochondrial fragmentation and specific reductions in mitochondrial counts and ATP levels in dendrites, revealing a pivotal role for Sf3b1 in modulating the energy supply necessary for dendritic arborization. Additionally, a genetic rescue experiment uncovered mitophagy-modulating molecules that effectively restored the mitochondrial health and dendritic arborization of Sf3b1-depeted neurons. Our study establishes a previously unrecognized connection between RNA splicing and mitochondrial demand in differentiating neurons, providing insights into bioenergetic requirements for dendritic growth and maintenance.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"347"},"PeriodicalIF":6.2,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12504175/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238413","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cerebellar α1_D- adrenergic receptors mediate stress-induced dystonia in tottering^tg/tg mice.","authors":"Pauline Bohne, Mareike Josten, Lina Rambuscheck, Jana Brüggemann, Xinran Zhu, Max O Rybarski, Melanie D Mark","doi":"10.1007/s00018-025-05843-1","DOIUrl":"10.1007/s00018-025-05843-1","url":null,"abstract":"<p><p>Episodic ataxia type 2 (EA2) is an inherited neurological disorder, where patients suffer from chronic ataxia and severe episodes of motor dysfunction exhibited as dystonia. Despite other factors, physical and emotional stress triggers those episodes reliably in both human and mice. We used the well-established EA2 mouse model tottering to explore the cerebellar adrenergic receptor (AR) involvement in stress-induced dystonic attacks. We found that α1-ARs in cerebellar Purkinje cells (PCs) are activated by norepinephrine (NE), differentially expressed and required for initiation of dystonia, while α2-ARs are not. Moreover, pharmacological blockade and shRNA-induced knock down of cerebellar α1_D-ARs was sufficient to effectively prevent stress-induced dystonia in homozygous tottering^tg/tg mice but had no impact on ataxia amelioration. In vivo recordings and live calcium (Ca²⁺) imaging of PCs demonstrated that α1_D-AR blockade successfully protects PCs from NE-mediated erratic firing patterns through decreased release of Ca²⁺ from intracellular stores, thus preventing stress-induced dystonia. Together, our data show the modulatory effects of NE on dystonia severity and suggest a predominant role of cerebellar α1_D-ARs in the formation of stress-induced dystonia in tottering^tg/tg mice.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"344"},"PeriodicalIF":6.2,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12500514/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145231483","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"USP4-Mediated deubiquitination of A2AR suppresses autophagy-dependent ferroptosis in gastric cancer.","authors":"Xuan Zhao, Sheng Lu, Zhaoyu Xiang, Min Yan, Zheng-Gang Zhu, Feng Dong, Chao Yan","doi":"10.1007/s00018-025-05826-2","DOIUrl":"10.1007/s00018-025-05826-2","url":null,"abstract":"<p><p>Deubiquitinating enzymes (DUBs) are crucial for regulating the degradation of specific proteins and represent a novel therapeutic direction in cancer. In gastric cancer, USP4 levels are significantly elevated, though its therapeutic potential remains underexplored. Our study demonstrates that USP4 plays a pivotal role in gastric cancer cells via the autophagy-dependent ferroptosis pathway. Specifically, USP4 selectively removes Lys48-linked polyubiquitin chains through its deubiquitination activity at the C311 site, stabilizing the A2AR protein. This action precisely modulates autophagy and inhibits ferroptosis, thereby promoting gastric cancer progression. Additionally, our findings indicate that targeting USP4 or A2AR can activate autophagy and restore the ferroptosis process, which is essential for autophagy-dependent ferroptosis. Consequently, the USP4-A2AR signaling pathway is critically important for the survival of gastric cancer cells and represents a potential therapeutic target for gastric cancer.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"342"},"PeriodicalIF":6.2,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12501093/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145231539","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epigenetic regulation by DNA methylation, histone modifications and chromatin remodeling complexes in controlling spermatogenesis and their dysfunction with male infertility.","authors":"Yinghong Cui, Jiakun Deng, Yueling Zhang, Li Du, Fen Jiang, Chunyun Li, Wei Chen, Haibin Zhang, Zuping He","doi":"10.1007/s00018-025-05831-5","DOIUrl":"10.1007/s00018-025-05831-5","url":null,"abstract":"<p><p>As key factors of cellular development, epigenetic regulation can accurately control gene expression through multiple manners, e.g., DNA methylation, histone modification, and chromatin remodeling complexes (CRCs). Epigenetic factors play pivotal roles in various kinds of cell processes, including cell proliferation, differentiation, and apoptosis, and diseases may be resulted from their dysfunction. Spermatogenesis refers to the complex process by which spermatogonial stem cells (SSCs) self-renew and differentiate into the differentiating spermatogonia that further develop to spermatocytes and mature spermatids. Significantly, epigenetic regulation has recently been shown to mediate fate determinations of SSCs to ensure normal spermatogenesis. Interestingly, much progress has recently been made in epigenetic regulation and their dysfunction in controlling spermatogenesis and male infertility, respectively. In this review, we address the dynamic expression patterns, functions and mechanisms of DNA methylation, histone modification, and CRCs in mediating the development of SSCs and spermatogenesis, and we also discuss the association between epigenetic dysfunction and male infertility. We further point out the perspectives in epigenetic regulation on human spermatogenesis. Our review on the in-depth analysis of epigenetic regulatory mechanisms in normal and abnormal spermatogenesis not only helps us better understand the etiology of male infertility but also provides novel targets for treating this disease.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"343"},"PeriodicalIF":6.2,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12500515/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145231499","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Adenine base editing of CFTR using receptor targeted nanoparticles restores function to G542X cystic fibrosis airway epithelial cells.","authors":"Isabelle Rose, Miriam Greenwood, Matthew Biggart, Natalie Baumlin, Robert Tarran, Stephen L Hart, Deborah L Baines","doi":"10.1007/s00018-025-05907-2","DOIUrl":"10.1007/s00018-025-05907-2","url":null,"abstract":"","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"341"},"PeriodicalIF":6.2,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12476327/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145173991","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Temporal characterisation and electrophysiological implications of TBI-induced serine/threonine kinase activity in mouse cortex.","authors":"Celine Gallagher, Thomas Mittmann","doi":"10.1007/s00018-025-05888-2","DOIUrl":"10.1007/s00018-025-05888-2","url":null,"abstract":"","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"340"},"PeriodicalIF":6.2,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12460198/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145130143","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bending the boundaries: the many facets of endophilin-As from membrane dynamics to disease.","authors":"Shiqiang Xu, Emilie Rigaux, Dorian Hène, Henri-François Renard, Louise Thines","doi":"10.1007/s00018-025-05856-w","DOIUrl":"10.1007/s00018-025-05856-w","url":null,"abstract":"<p><p>The endophilin-A proteins (EndoAs) are Bin/Amphiphysin/Rvs (BAR) domain proteins with key roles in both clathrin-mediated (CME) and clathrin-independent endocytosis (CIE). Humans have three differentially expressed EndoAs, EndoA1, -A2, and -A3, encoded by the SH3GL2/1/3 genes, respectively. Their functions primarily arise from their N-terminal BAR domain, which senses and induces local membrane curvature, and C-terminal SH3 domain, which mediates interactions with various proline-rich domain-containing partners. Among others, EndoA-mediated endocytosis coordinates synaptic vesicle recycling, as well as internalization of cell adhesion molecules, ligand-stimulated receptors, and pathogens. Consequently, EndoAs influence key cellular processes like neurotransmission, signaling, cell adhesion, and infection. Importantly, EndoA dysregulation has been observed in several pathologies, notably neurodegeneration, cardiovascular diseases, and cancer. This review provides an overview of the function and regulation of the EndoA proteins in CME and CIE, and explores their lesser-characterized involvement in other processes such as autophagy. It further addresses how these functions contribute to physiological processes and the development of pathologies, with a particular focus on cancer pathophysiology. Together, it emphasizes non-redundant roles of EndoA proteins in various cellular processes and highlights the complex relationship between membrane trafficking and diseases.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"339"},"PeriodicalIF":6.2,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12457278/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145124264","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Linc01271 promotes lipid synthesis and MASLD/MASH progression via miR-149-3p/RAB35 axis.","authors":"Zhaoqing Yin, Caibin Yue, Zhipeng Li, Xiuwen Guo, Guohao Wang, Hao Zhang, Wei Wang, Lan Liu","doi":"10.1007/s00018-025-05847-x","DOIUrl":"10.1007/s00018-025-05847-x","url":null,"abstract":"<p><p>Metabolic associated steatohepatitis (MASH) is a severe form of metabolic dysfunction-associated steatotic liver disease (MASLD) characterized by hepatocellular injury, inflammation, and fibrosis. Despite advances in understanding its pathophysiology, the molecular mechanisms driving MASH progression remain unclear. This study investigates the role of long non-coding RNA Linc01271 in MASLD/MASH pathogenesis, ant its involvement in the miR-149-3p/RAB35 axis and PI3K/AKT/mTOR signaling pathway. Transcriptome sequencing and RT-qPCR revealed significant upregulation of Linc01271 in MASH tissues, which correlated with lipid accumulation and inflammatory responses. Knockdown of Linc01271 in THLE-2 cells reduced lipid droplet formation, triglyceride and cholesterol levels, and the expression of lipid metabolism-related genes (CD36, ACC1, FASN) and pro-inflammatory cytokines (IL-6, IL-8, TGF-β1). Conversely, Linc01271 overexpression had the opposite effect. Dual-luciferase reporter assays confirmed Linc01271's interaction with miR-149-3p, which regulates RAB35, a downstream target of miR-149-3p. Knockdown of Linc01271 in mice attenuated MASH progression, reducing body weight, liver weight, blood glucose levels, and liver injury markers. These findings demonstrate that Linc01271 promotes lipid synthesis and inflammatory responses through the miR-149-3p/RAB35 axis and PI3K/AKT/mTOR pathway, highlighting its potential as a therapeutic target for MASLD/MASH. Further research is warranted to develop therapeutic agents targeting Linc01271 for clinical applications.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"338"},"PeriodicalIF":6.2,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12417349/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145013948","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rhapontigenin attenuates neurodegeneration in a parkinson's disease model by downregulating mtDNA-cGAS-STING-NF-κB-mediated neuroinflammation via PINK1/DRP1-dependent microglial mitophagy.","authors":"Zhongqiang Su, Hui Shu, Xingting Huang, Liuyan Ding, Fengchu Liang, Zongtang Xu, Ziting Zhu, Minshan Chen, Xiaobei Wang, Guihua Li, Huan Xia, Qiannan Cao, Wenlong Zhang, Pingyi Xu, Xinling Yang","doi":"10.1007/s00018-025-05873-9","DOIUrl":"10.1007/s00018-025-05873-9","url":null,"abstract":"<p><p>Microglial activation-induced neuroinflammation and impaired neuronal mitophagy are recognized as pivotal pathogeneses in Parkinson's disease (PD). However, the role of microglial mitophagy in microglial activation during PD development remains unclear, and therapeutic interventions targeting this interaction are lacking. Rhapontigenin (Rhap), a stilbenoid enriched in Vitis vinifera, exhibits dual anti-neuroinflammatory and mitophagy-enhancing properties, but its therapeutic potential and mechanisms in PD are unexplored. This study aimed to investigate the therapeutic efficacy of Rhap on neurodegeneration in a PD model and explore its underlying mechanism. Here, we showed that Rhap administration significantly ameliorated motor deficits, dopaminergic neuron loss, and neuroinflammation in MPTP-induced PD mice. Mechanistically, Rhap suppressed neuroinflammation by inhibiting the cGAS-STING-NF-κB signaling axis in both PD model mice and MPP⁺-induced BV2 microglia. Crucially, its anti-inflammatory effects depend on the PINK1-mediated enhancement of microglial mitophagy to control cytosolic mtDNA leakage. Specifically, Rhap bound to PINK1 strengthened the PINK1-DRP1 interaction, promoted mitochondrial fission in damaged organelles, and enhanced mitophagy clearance. This mitophagy activation prevents cytosolic leakage of mitochondrial DNA (mtDNA), thereby attenuating mtDNA-cGAS-STING-NF-κB-derived neuroinflammation and subsequent neurodegeneration in PD. PINK1 deficiency in BV2 microglia abolished Rhap's ability to suppress mtDNA-cGAS-STING-NF-κB activation and enhance mitophagy. Overall, our study reveals a previously unrecognized mechanism by which Rhap ameliorates PD-associated neurodegeneration through dual modulation of PINK1/DRP1-dependent microglial mitophagy and the mtDNA-cGAS-STING-NF-κB neuroinflammatory axis, suggesting a potential therapeutic strategy for PD and related neurodegenerative disorders.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"337"},"PeriodicalIF":6.2,"publicationDate":"2025-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12414094/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145005932","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}