Cells最新文献

{"title":"Single-Cell Transcriptomic Landscape of the Gill in Hypoxia-Stressed <i>Tachysurus vachellii</i> (Richardson, 1846): Insights into Cell-Type-Specific Responses of Different Epithelial Cells and Erythrocytes.","authors":"Xiaoyun Wu, Yeyu Chen, Feiyang Li, Luyun Ni, Pengcheng Li, Quan Gong","doi":"10.3390/cells15191747","DOIUrl":"10.3390/cells15191747","url":null,"abstract":"<p><p>The study aims to construct a single-cell atlas of the gill of yellow catfish <i>Tachysurus vachellii</i> (Richardson, 1846) and to explore the response patterns of gill cells under acute hypoxia stress. In this study, we performed single-cell sequencing and histological observations of <i>T. vachellii,</i> gills. A total of 37,090 cells and 33 cell clusters were collected, and 18 cell types were identified. We found that three clusters of NECs have different functions, and in the gene enrichment results of MC differential expression during hypoxia and reoxygenation, we observed that MC may be regulated by non-neuronal neurotransmitter signals during hypoxia stress. There are also differences in cellular communication and transcription factors between different NECs and MCs. After acute hypoxia, the expression of <i>tjp2</i> and <i>lima1</i> in PVC was significantly upregulated, and there was no significant change in the number of erythrocytes. Observation of the organizational structure revealed that muscle, skin, and gill tissues were affected after hypoxia, resulting in changes in the flattened epithelial cells and MRC ultrastructure of the gill. This study provides single-cell atlas and data support for the acute hypoxia and reoxygenation model of fish gill tissue.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"15 19","pages":""},"PeriodicalIF":6.0,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13664461/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149191531","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":"High Sensitivity of the <i>rpiAB Escherichia coli</i> Mutants to Antibiotics Is Associated with the Participation of the <i>deo</i>-Operon in a Hypothetical Ribose-5-Phosphate Futile Cycle.","authors":"Tatyana A Seregina, Rustem S Shakulov, Svetlana A Sklyarova, Alexander S Mironov","doi":"10.3390/cells15191740","DOIUrl":"10.3390/cells15191740","url":null,"abstract":"<p><p>Previously, we demonstrated that disruption of ribose-5-phosphate biosynthesis in the pentose phosphate pathway increases the sensitivity of <i>E. coli</i> bacteria to a broad spectrum of antibiotics, and this sensitivity can be suppressed by deletion of the <i>deoB</i> gene. In this study, we showed that antibiotic sensitivity can also be suppressed by the deletion of the <i>apt</i> gene, which, along with the <i>deoBD</i> genes, constitutes the salvage pathway for purine base uptake. We propose that in the <i>rpiAB</i> mutant, these genes, together with the <i>prs</i> gene responsible for phosphoribosyl pyrophosphate (PRPP) synthesis, participate in a futile cycle, converting ATP to AMP and pyrophosphate (PPi). The data obtained on the genetic complementation of deletions of the <i>apt</i> and <i>deoBD</i> genes, combined with restored ATP levels in the <i>rpiAB</i> mutant cells, support the model of the hypothetical futile cycle of ribose-5-phosphate.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"15 19","pages":""},"PeriodicalIF":6.0,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13664218/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149191141","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":"Heat-Inactivated <i>Lactiplantibacillus plantarum</i> (RSB11) as a Multifunctional Postbiotic: Anti-Inflammatory Effects Compared with Live RSB11 Across Multiple Human Cell Models.","authors":"Teodora Nicola, Tanmaya Madhvacharyula, Ajay Ashok, Aryan Mandot, Iman Abdelgawad, Ryaan Singh, Kara Siedman, Youfeng Yang, Namasivayam Ambalavanan, Charitharth Vivek Lal","doi":"10.3390/cells15191736","DOIUrl":"10.3390/cells15191736","url":null,"abstract":"<p><p>The clinical potential of probiotics is increasingly recognized; however, dependence on microbial viability, formulation and storage constraints, and safety considerations in vulnerable populations can limit their broader application. Postbiotics offer an alternative by providing inanimate microbial preparations with retained biological activity, yet whether heat inactivation preserves the functional effects of probiotic-derived candidates remains an important question. Here, we compare <i>Lactiplantibacillus plantarum</i> RSB11 in its live (RSB11 life) and heat-inactivated (RSB11-HI) forms across human cell models representing the gut, lung, ovary, bone, kidney, and liver. Following inflammatory challenge with lipopolysaccharide or <i>Escherichia coli</i>, we assessed MMP-9 expression and the pro-inflammatory cytokines TNF-α, IL-6, and IL-1β. Both RSB11 life and RSB11-HI broadly suppressed inflammatory responses, with RSB11-HI maintaining effects comparable to the live preparation across the MMP-9 and cytokine endpoints, where the two forms were tested side by side, and demonstrating greater suppression in selected experimental contexts. Additionally, RSB11-HI increased β-glucuronidase and estradiol levels relative to untreated controls in a gut-ovarian conditioned-medium model, suggesting effects extending beyond inflammatory modulation; a live comparator was not included in the β-glucuronidase measurements, so this effect is not established as specific to the inactivated form. Collectively, these findings demonstrate that heat inactivation preserves key biological functions of RSB11 and support RSB11-HI as a multifunctional candidate postbiotic with potential for expanded formulation and application.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"15 19","pages":""},"PeriodicalIF":6.0,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13664586/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149191178","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":"Cellular Crosstalk at the Gut-Liver Interface in Liver Cirrhosis: Epithelial Barrier Failure, Bacterial Translocation and Immune Activation as a Bidirectional Network.","authors":"Thomas N Nitsotolis, Stelios F Assimakopoulos, Eleftheria Mastoridou, Nikolaos-Gavriel Kolios, Dimitrios Biros, Eleni-Dimitra Oikonomidi, Maria Lagadinou, Alexia Papalexandrou, Haralampos Milionis, Eirini Christaki, Georgios Kalambokis","doi":"10.3390/cells15191739","DOIUrl":"10.3390/cells15191739","url":null,"abstract":"<p><p>The gut-liver axis is central to the systemic complications of liver cirrhosis, but it is usually described as a linear cascade in which barrier failure releases microbial products that activate a downstream immune response. This review proposes instead a four-compartment framework, in which the epithelial/barrier, innate immune, adaptive effector, and stromal-endothelial compartments-the last including the gut-vascular barrier-are treated as reciprocally interacting nodes, and pathological bacterial translocation is treated as both an input to and an output of the network rather than as its endpoint. Applying this framework across the stages of cirrhosis, we examine how tight-junction disassembly, mucus-layer thinning, Paneth-cell dysfunction and reduced secretory IgA, together with dysbiosis and small-intestinal bacterial overgrowth, permit translocation; how translocated bacteria and pathogen-associated molecular patterns activate all four compartments; and how the resulting cytokine circuits further degrade the barrier, generating feed-forward loops that underlie cirrhosis-associated immune dysfunction and chronic systemic inflammation. We relate these circuits to spontaneous bacterial peritonitis, hepatic encephalopathy, aggravated portal hypertension, and acute-on-chronic liver failure, distinguishing throughout between mechanisms demonstrated in humans and those inferred from animal or in vitro models. We identified evidence through structured searches of PubMed/MEDLINE, Embase, and Web of Science, and report it according to the SANRA checklist. Framed as a network, biomarkers become compartment-specific reporters, and barrier-, microbiome-, and immune-directed therapies become interventions at defined nodes and edges-a view that clarifies both their rationale and the current limits of the evidence.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"15 19","pages":""},"PeriodicalIF":6.0,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13664048/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149191559","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":"Fast-Dissociating High-Supply Peptides as Contributors to MHC-I Antigen Presentation.","authors":"Om H Gandhi, Michael E Bryan, Malcolm J W Sim, Tim Elliott","doi":"10.3390/cells15191735","DOIUrl":"10.3390/cells15191735","url":null,"abstract":"<p><p>The major histocompatibility complex class I (MHC-I) immunopeptidome is dynamic and determined by numerous biochemical and cellular features. Computational tools to predict peptide-MHC-I binding focus on the affinity of a specific peptide-MHC interaction; separate tools predict complex stability or presentation. Methods used to define the immunopeptidome may preferentially recover stable complexes, and presentation predictors trained on those data may inherit that bias. However, peptides that dissociate rapidly but are generated at high rates could reach surface densities sufficient for CD8⁺ T cell recognition. Here, we examine evidence relevant to these fast-dissociating high-supply (FDHS) peptides and develop a two-axis model, whereby peptide supply is considered alongside stability. We examine how defective ribosomal products and ribosome-associated quality control supply peptides for MHC-I loading. We set out the limits of tapasin-mediated editing and compare the model with the binding, stability and presentation predictors now in use. Experiments have linked peptide abundance and complex stability to relative presentation, but the extent of compensation for endogenous FDHS peptides remains to be quantified. We present experimental systems to test the magnitude and limits of this compensation, specifying the key measurements. We also propose that FDHS ligands generated under tumour-specific translational stress could be less constrained by central tolerance if their presentation is insufficient during thymic selection. We believe this model has implications for understanding the broader immunopeptidome, how it contributes to innate and adaptive immunity, and designing better immunotherapies.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"15 19","pages":""},"PeriodicalIF":6.0,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13664392/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149191657","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":"Skull Bone Marrow as a Cranial Neuroimmune Reservoir in Alzheimer's Disease: Amyloid, Osteoimmune Remodeling, and Translational Imaging Evidence.","authors":"James Chmiel, Jerzy Leszek","doi":"10.3390/cells15191738","DOIUrl":"10.3390/cells15191738","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Alzheimer's disease (AD) has traditionally been conceptualized as a disorder driven primarily by cerebral amyloid-β accumulation, tau pathology, synaptic failure, vascular dysfunction, and chronic neuroinflammation. However, emerging evidence suggests that AD pathobiology may also involve extracerebral cranial compartments positioned at the interface between the brain, meninges, cerebrospinal fluid, and skull bone marrow. Recent anatomical and experimental studies have identified direct vascular and osseous channels connecting skull bone marrow with the dura mater, allowing bidirectional exchange of immune cells, soluble mediators, and cerebrospinal fluid-derived signals. These findings support the concept that skull bone marrow functions as a specialized cranial immune reservoir capable of sensing central nervous system-derived molecular cues and supplying myeloid and lymphoid cells to meningeal and brain-border compartments. In AD models and human imaging studies, amyloid-β-related signals have been detected in skull marrow, where they may promote IL-6-dependent B lymphopoiesis, expansion of age-associated B cells, microglial activation, and amplification of cerebral amyloid pathology. In parallel, AD-related amyloid precursor protein and amyloid-β signaling may remodel the skull marrow niche through osteoblast dysfunction, altered osteoclast activity, vascular channel expansion, marrow adiposity, and inflammatory reprogramming. Human PET and MRI studies indicate that skull marrow-associated inflammatory, amyloid-related, and cerebrospinal-fluid drainage signals can be detected in vivo; however, these observations remain indirect, method-dependent, and insufficiently validated for diagnostic or prognostic use. Importantly, much of the anatomical foundation for skull marrow-meninges-brain communication derives from non-AD studies of CNS-border physiology, stroke, meningitis, spinal cord injury, and infection, whereas the strongest AD-specific mechanistic evidence is currently derived from transgenic mouse models. Accordingly, we frame the skull marrow-meninges-brain axis as a testable conceptual model rather than an established causal pathway in human AD. This review integrates anatomical, immunological, osteoimmune, and imaging evidence while explicitly distinguishing AD-specific findings from evidence extrapolated from other neurological or inflammatory contexts. Determining whether skull marrow alterations represent a cause, consequence, compensatory response, or amplifier of AD pathology will require longitudinal, biomarker-defined human studies and further mechanistic validation. The review also compares the principal in vivo strategies used to distinguish skull-marrow-derived immune cells from circulating leukocytes and examines ischemic stroke and brain tumors as comparator CNS conditions. These disease models demonstrate that cranial marrow responses can be rapid, spatially organized, and either protective or pathogenic depending o","PeriodicalId":9743,"journal":{"name":"Cells","volume":"15 19","pages":""},"PeriodicalIF":6.0,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13664314/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149191488","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":"Cilastatin Protects Against Chemotherapy-Induced Neuropathy via the FKBP51/DPEP1 Axis: Confocal Insights into Protein Dynamics.","authors":"Rita Martín-Ramírez, Karen Álvarez-Tosco, María Ángeles González-Nicolás, Elena Vázquez-Ogando, Alberto Lázaro, Felipe-Manuel Rosa-González, Julio Ávila, Manuel Morales, Pablo Martín-Vasallo","doi":"10.3390/cells15191737","DOIUrl":"10.3390/cells15191737","url":null,"abstract":"<p><p>Dorsal root ganglion (DRG) neuroinflammation is a hallmark feature of oxaliplatin-induced peripheral neuropathy (OIPN), a dose-limiting side effect with poorly understood molecular mechanisms. In this study, we investigated the protective potential of cilastatin (CIL), a dipeptidase 1 (DPEP1) inhibitor, while elucidating the regulatory roles of FK506-binding protein 51 (FKBP51) and DPEP1 in OIPN pathogenesis. Behavioral allodynia was evaluated using the acetone test in an oxaliplatin (OxPt) rat model. Lumbar DRGs were imaged via advanced confocal microscopy (Zeiss LSM980 Airyscan 2, Zeiss, Oberkochen, Germany) and analyzed using Fiji 1.54t software to determine fluorescence intensity, subcellular distribution, and co-localization metrics (Pearson's and Manders' coefficients). OxPt administration induced marked downregulation and cytoplasmic-to-nuclear translocation of FKBP51 within DRG neuronal and glial compartments. Notably, FKBP51 frequently co-localized with DPEP1 and the pro-inflammatory cytokines TNF-α and IL-6. DPEP1 was strongly expressed in DRG neurons, where it exhibited enhanced perinuclear localization. Concomitant CIL treatment significantly reversed these alterations by attenuating the OxPt-induced cell-type- and compartment-specific changes in FKBP51 and DPEP1 distribution, suppressing TNF-α and IL-6 expression, and preventing GFAP overexpression. These findings identify a novel interplay between FKBP51 and DPEP1 within the DRG during OIPN-elicited neuroinflammation, potentially linking stress protein signaling to pro-inflammatory cytokine activation. Consequently, CIL represents a promising therapeutic candidate to prevent chemotherapy-induced neurotoxicity.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"15 19","pages":""},"PeriodicalIF":6.0,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13663939/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149191530","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":"B-Cell Immune Responses in Myocarditis: Mechanisms, B-Cell Receptor Repertoire, and Clinical Translation.","authors":"Xixiong Lin, Xinsheng Yao, Jun Li","doi":"10.3390/cells15191734","DOIUrl":"10.3390/cells15191734","url":null,"abstract":"<p><p>Myocarditis is an inflammatory myocardial disease induced by infection, autoimmunity, or immune checkpoint inhibitor (ICI) therapy. Its immunopathogenesis has long been attributed primarily to T-cell-mediated cellular immunity. Increasing evidence now indicates that B cells contribute to the initiation, persistence, and myocardial remodeling of myocarditis not only as a source of autoantibodies, but also through antigen presentation, cytokine secretion, and immunoregulatory crosstalk. The emergence of single-cell sequencing and B-cell receptor (BCR) repertoire sequencing has begun to reveal B-cell clonal expansion, immunoglobulin class switching, and dynamic shifts in functional subsets, offering a new window into humoral immune responses in myocarditis. This review synthesizes current evidence on BCR repertoire remodeling, autoantibody-mediated myocardial injury, functional heterogeneity among B-cell subsets, and the clinical translation of these findings. B cells can mediate myocardial damage through autoantibodies against adenine nucleotide translocator (ANT), cardiac myosin, and acetylcholine receptor (AChR), and their pathogenic effects depend on immunoregulatory networks such as Th17/IL-17 signaling and autophagy. Notably, B cells are functionally heterogeneous, TNF-α⁺ B cells promote persistent inflammation and myocardial fibrosis, whereas IL-10⁺ regulatory B cells (Bregs) confer immune protection by suppressing Th17 responses and maintaining Treg homeostasis. Studies of ICI-associated myocarditis suggest that BCR repertoire features and autoantibody profiles may provide insights into disease-associated immune remodeling. However, the clinical utility of these features as biomarkers remains uncertain, given the lack of standardized assays and sufficiently validated sensitivity, specificity, and reproducibility. In the future, integrating BCR repertoire, multi-omics, and functional subset analyses may improve characterization of disease-associated humoral immune responses and help identify candidate biomarkers for further clinical investigation.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"15 19","pages":""},"PeriodicalIF":6.0,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13664030/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149191103","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":"Not All Extracellular Vesicles Are Equal: A Narrative Comparative Review of Source-Dependent Function and Therapeutic Potential.","authors":"Yasaman Zandi Mehran, Michael Weber, Fateme Hoseinzade","doi":"10.3390/cells15191731","DOIUrl":"10.3390/cells15191731","url":null,"abstract":"<p><p>Extracellular vesicles (EVs) are increasingly investigated as cell-free therapeutic platforms, yet EVs from different cellular sources are often considered functionally interchangeable despite substantial biological heterogeneity. This narrative comparative review evaluated how EV source influences molecular cargo, phenotype, biological function, therapeutic suitability, safety, and translational potential. PubMed/MEDLINE, Europe PMC, and OpenAlex were searched from inception through 14 August 2026, supplemented by targeted Google Scholar and backward and forward citation searching. Of the 9779 database records identified, 3799 duplicates were removed and 5980 unique records were screened. Sixty-seven database studies and three additional studies identified through supplementary searching met the criteria for direct within-study comparison of EVs from distinct parental cell or tissue sources. Across the 70 direct comparisons, source-associated differences in cargo, phenotype, target-cell responses, and therapeutic performance were frequently reported; however, the depth and consistency of supporting evidence varied substantially across source families and indications, with activity further influenced by cellular state, engineering, vesicle fraction, isolation method, and dose. Based on these findings, we propose EV-FIT+-Function, Indication, Trade-off, and Contra-Function-as an author-developed qualitative framework for rational EV source selection. No EV source is universally superior; therapeutic suitability depends on matching source- and product-specific biological characteristics and risks to the intended clinical objective.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"15 19","pages":""},"PeriodicalIF":6.0,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13664309/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149191514","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":"Mitochondria-Endoplasmic Reticulum Crosstalk in Pancreatic β-Cell Stress: A Driver of Diabetes.","authors":"Sara Anjum Niinuma, Ashleigh Suzu-Nishio Takemoto, William Junior Khalil, Alexandra E Butler, Abu Saleh Md Moin","doi":"10.3390/cells15191733","DOIUrl":"10.3390/cells15191733","url":null,"abstract":"<p><p>Pancreatic β-cell failure is central to the pathogenesis of type 2 diabetes (T2D), developing when chronic metabolic stress overwhelms the adaptive capacity of these cells. Because insulin biosynthesis and glucose-stimulated secretion depend on tightly coordinated organelle function, crosstalk between the endoplasmic reticulum (ER) and mitochondria strongly influences β-cell fate. The two organelles are physically coupled at mitochondria-associated membranes (MAMs), contact sites that synchronize ER Ca²⁺ release with mitochondrial Ca²⁺ uptake and adenosine triphosphate (ATP) production, and that help regulate redox balance, autophagy, mitophagy and the unfolded protein response. This review draws together evidence on three questions. First, which stresses converge on the β-cell: ER stress, oxidative stress and dysregulated autophagy and mitophagy. Second, how ER-mitochondria crosstalk sustains β-cell health through Ca²⁺ handling and the proteins that maintain MAM integrity, including inositol 1,4,5-trisphosphate (IP₃) receptors, voltage-dependent anion channel 1 (VDAC1), mitofusin 2 (Mfn2) and the ER stress sensors IRE1α and PERK. Third, how glucolipotoxic and inflammatory stress remodels these contacts and pushes communication towards a maladaptive state marked by mitochondrial Ca²⁺ overload, ROS accumulation, defective organelle quality control, cellular senescence and apoptosis. We contrast rodent and human data, where MAM composition and glucotoxic responses diverge, and consider therapeutic strategies, such as incretin-based agents and the mitochondrial-derived peptide MOTS-c, that target this interface to preserve β-cell function in diabetes.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"15 19","pages":""},"PeriodicalIF":6.0,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13664441/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149191580","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}