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Zinc finger homeobox-3 (ZFHX3) orchestrates genome-wide daily gene expression in the suprachiasmatic nucleus. 锌指同源盒-3 (ZFHX3)协调视交叉上核全基因组日常基因表达。
IF 6.4 1区 生物学
eLife Pub Date : 2025-03-21 DOI: 10.7554/eLife.102019
Akanksha Bafna, Gareth Banks, Vadim Vasilyev, Robert Dallmann, Michael H Hastings, Patrick M Nolan
{"title":"Zinc finger homeobox-3 (ZFHX3) orchestrates genome-wide daily gene expression in the suprachiasmatic nucleus.","authors":"Akanksha Bafna, Gareth Banks, Vadim Vasilyev, Robert Dallmann, Michael H Hastings, Patrick M Nolan","doi":"10.7554/eLife.102019","DOIUrl":"10.7554/eLife.102019","url":null,"abstract":"<p><p>The mammalian suprachiasmatic nucleus (SCN), situated in the ventral hypothalamus, directs daily cellular and physiological rhythms across the body. The SCN clockwork is a self-sustaining transcriptional-translational feedback loop (TTFL) that in turn coordinates the expression of clock-controlled genes (CCGs) directing circadian programmes of SCN cellular activity. In the mouse, the transcription factor, ZFHX3 (zinc finger homeobox-3), is necessary for the development of the SCN and influences circadian behaviour in the adult. The molecular mechanisms by which ZFHX3 affects the SCN at transcriptomic and genomic levels are, however, poorly defined. Here, we used chromatin immunoprecipitation sequencing to map the genomic localization of ZFHX3-binding sites in SCN chromatin. To test for function, we then conducted comprehensive RNA sequencing at six distinct times-of-day to compare the SCN transcriptional profiles of control and ZFHX3-conditional null mutants. We show that the genome-wide occupancy of ZFHX3 occurs predominantly around gene transcription start sites, co-localizing with known histone modifications, and preferentially partnering with clock transcription factors (CLOCK, BMAL1) to regulate clock gene(s) transcription. Correspondingly, we show that the conditional loss of ZFHX3 in the adult has a dramatic effect on the SCN transcriptome, including changes in the levels of transcripts encoding elements of numerous neuropeptide neurotransmitter systems while attenuating the daily oscillation of the clock TF <i>Bmal1</i>. Furthermore, various TTFL genes and CCGs exhibited altered circadian expression profiles, consistent with an advanced in daily behavioural rhythms under 12 h light-12 h dark conditions. Together, these findings reveal the extensive genome-wide regulation mediated by ZFHX3 in the central clock that orchestrates daily timekeeping in mammals.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11928027/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143673177","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Emergence of ion-channel-mediated electrical oscillations in Escherichia coli biofilms. 大肠杆菌生物膜中离子通道介导的电振荡的出现。
IF 6.4 1区 生物学
eLife Pub Date : 2025-03-21 DOI: 10.7554/eLife.92525
Emmanuel Akabuogu, Victor Carneiro da Cunha Martorelli, Rok Krašovec, Ian S Roberts, Thomas A Waigh
{"title":"Emergence of ion-channel-mediated electrical oscillations in <i>Escherichia coli</i> biofilms.","authors":"Emmanuel Akabuogu, Victor Carneiro da Cunha Martorelli, Rok Krašovec, Ian S Roberts, Thomas A Waigh","doi":"10.7554/eLife.92525","DOIUrl":"10.7554/eLife.92525","url":null,"abstract":"<p><p>Bacterial biofilms are communities of bacteria usually attached to solid strata and often differentiated into complex structures. Communication across biofilms has been shown to involve chemical signaling and, more recently, electrical signaling in Gram-positive biofilms. We report for the first time, community-level synchronized membrane potential dynamics in three-dimensional <i>Escherichia coli</i> biofilms. Two hyperpolarization events are observed in response to light stress. The first requires mechanically sensitive ion channels (MscK, MscL, and MscS) and the second needs the Kch-potassium channel. The channels mediated both local spiking of single <i>E. coli</i> biofilms and long-range coordinated electrical signaling in <i>E. coli</i> biofilms. The electrical phenomena are explained using Hodgkin-Huxley and 3D fire-diffuse-fire agent-based models. These data demonstrate that electrical wavefronts based on potassium ions are a mechanism by which signaling occurs in Gram-negative biofilms and as such may represent a conserved mechanism for communication across biofilms.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11928028/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143673029","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Single-cell RNA sequencing of the holothurian regenerating intestine reveals the pluripotency of the coelomic epithelium. holothurian再生肠的单细胞RNA测序揭示了体腔上皮的多能性。
IF 6.4 1区 生物学
eLife Pub Date : 2025-03-20 DOI: 10.7554/eLife.100796
Joshua G Medina-Feliciano, Griselle Valentín-Tirado, Kiara Luna-Martínez, Alejandra Beltran-Rivera, Yamil Miranda-Negrón, José E Garcia-Arraras
{"title":"Single-cell RNA sequencing of the holothurian regenerating intestine reveals the pluripotency of the coelomic epithelium.","authors":"Joshua G Medina-Feliciano, Griselle Valentín-Tirado, Kiara Luna-Martínez, Alejandra Beltran-Rivera, Yamil Miranda-Negrón, José E Garcia-Arraras","doi":"10.7554/eLife.100796","DOIUrl":"10.7554/eLife.100796","url":null,"abstract":"<p><p>In holothurians, the regenerative process following evisceration involves the development of a 'rudiment' or 'anlage' at the injured end of the mesentery. This regenerating anlage plays a pivotal role in the formation of a new intestine. Despite its significance, our understanding of the molecular characteristics inherent to the constituent cells of this structure has remained limited. To address this gap, we employed state-of-the-art scRNA-seq and hybridization chain reaction fluorescent in situ hybridization analyses to discern the distinct cellular populations associated with the regeneration anlage. Through this approach, we successfully identified 13 distinct cell clusters. Among these, two clusters exhibit characteristics consistent with putative mesenchymal cells, while another four show features akin to coelomocyte cell populations. The remaining seven cell clusters collectively form a large group encompassing the coelomic epithelium of the regenerating anlage and mesentery. Within this large group of clusters, we recognized previously documented cell populations such as muscle precursors, neuroepithelial cells, and actively proliferating cells. Strikingly, our analysis provides data for identifying at least four other cellular populations that we define as the precursor cells of the growing anlage. Consequently, our findings strengthen the hypothesis that the coelomic epithelium of the anlage is a pluripotent tissue that gives rise to diverse cell types of the regenerating intestinal organ. Moreover, our results provide the initial view into the transcriptomic analysis of cell populations responsible for the amazing regenerative capabilities of echinoderms.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11925454/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143669303","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Two long-axis dimensions of hippocampal-cortical integration support memory function across the adult lifespan. 海马体-皮层整合的两个长轴维度支持成人一生的记忆功能。
IF 6.4 1区 生物学
eLife Pub Date : 2025-03-20 DOI: 10.7554/eLife.97658
Kristin Nordin, Robin Pedersen, Farshad Falahati, Jarkko Johansson, Filip Grill, Micael Andersson, Saana M Korkki, Lars Bäckman, Andrew Zalesky, Anna Rieckmann, Lars Nyberg, Alireza Salami
{"title":"Two long-axis dimensions of hippocampal-cortical integration support memory function across the adult lifespan.","authors":"Kristin Nordin, Robin Pedersen, Farshad Falahati, Jarkko Johansson, Filip Grill, Micael Andersson, Saana M Korkki, Lars Bäckman, Andrew Zalesky, Anna Rieckmann, Lars Nyberg, Alireza Salami","doi":"10.7554/eLife.97658","DOIUrl":"10.7554/eLife.97658","url":null,"abstract":"<p><p>The hippocampus is a complex structure critically involved in numerous behavior-regulating systems. In young adults, multiple overlapping spatial modes along its longitudinal and transverse axes describe the organization of its functional integration with neocortex, extending the traditional framework emphasizing functional differences between sharply segregated hippocampal subregions. Yet, it remains unknown whether these modes (i.e. gradients) persist across the adult human lifespan, and relate to memory and molecular markers associated with brain function and cognition. In two independent samples, we demonstrate that the principal anteroposterior and second-order, mid-to-anterior/posterior hippocampal modes of neocortical functional connectivity, representing distinct dimensions of macroscale cortical organization, manifest across the adult lifespan. Specifically, individual differences in topography of the second-order gradient predicted episodic memory and mirrored dopamine D1 receptor distribution, capturing shared functional and molecular organization. Older age was associated with less distinct transitions along gradients (i.e. increased functional homogeneity). Importantly, a youth-like gradient profile predicted preserved episodic memory - emphasizing age-related gradient dedifferentiation as a marker of cognitive decline. Our results underscore a critical role of mapping multidimensional hippocampal organization in understanding the neural circuits that support memory across the adult lifespan.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11925452/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143663040","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Tissue inflammation induced by constitutively active STING is mediated by enhanced TNF signaling. 组成型活性STING诱导的组织炎症是由TNF信号增强介导的。
IF 6.4 1区 生物学
eLife Pub Date : 2025-03-20 DOI: 10.7554/eLife.101350
Hella Luksch, Felix Schulze, David Geißler-Lösch, David Sprott, Lennart Höfs, Eva M Szegö, Wulf Tonnus, Stefan Winkler, Claudia Günther, Andreas Linkermann, Rayk Behrendt, Lino L Teichmann, Björn H Falkenburger, Angela Rösen-Wolff
{"title":"Tissue inflammation induced by constitutively active STING is mediated by enhanced TNF signaling.","authors":"Hella Luksch, Felix Schulze, David Geißler-Lösch, David Sprott, Lennart Höfs, Eva M Szegö, Wulf Tonnus, Stefan Winkler, Claudia Günther, Andreas Linkermann, Rayk Behrendt, Lino L Teichmann, Björn H Falkenburger, Angela Rösen-Wolff","doi":"10.7554/eLife.101350","DOIUrl":"https://doi.org/10.7554/eLife.101350","url":null,"abstract":"<p><p>Constitutive activation of STING by gain-of-function mutations triggers manifestation of the systemic autoinflammatory disease STING-associated vasculopathy with onset in infancy (SAVI). In order to investigate the role of signaling by tumor necrosis factor (TNF) in SAVI, we used genetic inactivation of TNF receptors 1 and 2 in murine SAVI, which is characterized by T cell lymphopenia, inflammatory lung disease and neurodegeneration. Genetic inactivation of TNFR1 and TNFR2, however, rescued the loss of thymocytes, reduced interstitial lung disease and neurodegeneration. Furthermore, genetic inactivation of TNFR1 and TNFR2 blunted transcription of cytokines, chemokines and adhesions proteins, which result from chronic STING activation in SAVI mice. In addition, increased transendothelial migration of neutrophils was ameliorated. Taken together, our results demonstrate a pivotal role of TNFR-signaling in the pathogenesis of SAVI in mice and suggest that available TNFR antagonists could ameliorate SAVI in patients.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143669317","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Mesoscale functional organization and connectivity of color, disparity, and naturalistic texture in human second visual area. 人类第二视觉区域颜色、色差和自然纹理的中尺度功能组织和连通性。
IF 6.4 1区 生物学
eLife Pub Date : 2025-03-20 DOI: 10.7554/eLife.93171
Hailin Ai, Weiru Lin, Chengwen Liu, Nihong Chen, Peng Zhang
{"title":"Mesoscale functional organization and connectivity of color, disparity, and naturalistic texture in human second visual area.","authors":"Hailin Ai, Weiru Lin, Chengwen Liu, Nihong Chen, Peng Zhang","doi":"10.7554/eLife.93171","DOIUrl":"10.7554/eLife.93171","url":null,"abstract":"<p><p>Although parallel processing has been extensively studied in the low-level geniculostriate pathway and the high-level dorsal and ventral visual streams, less is known at the intermediate-level visual areas. In this study, we employed high-resolution fMRI at 7T to investigate the columnar and laminar organizations for color, disparity, and naturalistic texture in the human secondary visual cortex (V2), and their informational connectivity with lower- and higher-order visual areas. Although fMRI activations in V2 showed reproducible interdigitated color-selective thin and disparity-selective thick 'stripe' columns, we found no clear evidence of columnar organization for naturalistic textures. Cortical depth-dependent analyses revealed the strongest color-selectivity in the superficial layers of V2, along with both feedforward and feedback informational connectivity with V1 and V4. Disparity selectivity was similar across different cortical depths of V2, which showed significant feedforward and feedback connectivity with V1 and V3ab. Interestingly, the selectivity for naturalistic texture was strongest in the deep layers of V2, with significant feedback connectivity from V4. Thus, while local circuitry within cortical columns is crucial for processing color and disparity information, feedback signals from V4 are involved in generating the selectivity for naturalistic textures in area V2.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11925451/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143663032","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
The domesticated transposon protein L1TD1 associates with its ancestor L1 ORF1p to promote LINE-1 retrotransposition. 驯化的转座子蛋白L1TD1与其祖先L1 ORF1p结合,促进LINE-1逆转录转座。
IF 6.4 1区 生物学
eLife Pub Date : 2025-03-20 DOI: 10.7554/eLife.96850
Gülnihal Kavaklioglu, Alexandra Podhornik, Terezia Vcelkova, Jelena Marjanovic, Mirjam A Beck, Trinh Phan-Canh, Theresia Mair, Claudia Miccolo, Aleksej Drino, Mirko Doni, Gerda Egger, Susanna Chiocca, Miha Modic, Christian Seiser
{"title":"The domesticated transposon protein L1TD1 associates with its ancestor L1 ORF1p to promote LINE-1 retrotransposition.","authors":"Gülnihal Kavaklioglu, Alexandra Podhornik, Terezia Vcelkova, Jelena Marjanovic, Mirjam A Beck, Trinh Phan-Canh, Theresia Mair, Claudia Miccolo, Aleksej Drino, Mirko Doni, Gerda Egger, Susanna Chiocca, Miha Modic, Christian Seiser","doi":"10.7554/eLife.96850","DOIUrl":"10.7554/eLife.96850","url":null,"abstract":"<p><p>Repression of retrotransposition is crucial for the successful fitness of a mammalian organism. The domesticated transposon protein L1TD1, derived from LINE-1 (L1) ORF1p, is an RNA-binding protein that is expressed only in some cancers and early embryogenesis. In human embryonic stem cells, it is found to be essential for maintaining pluripotency. In cancer, L1TD1 expression is highly correlative with malignancy progression and as such considered a potential prognostic factor for tumors. However, its molecular role in cancer remains largely unknown. Our findings reveal that DNA hypomethylation induces the expression of L1TD1 in HAP1 human tumor cells. L1TD1 depletion significantly modulates both the proteome and transcriptome and thereby reduces cell viability. Notably, L1TD1 associates with L1 transcripts and interacts with L1 ORF1p protein, thereby facilitating L1 retrotransposition. Our data suggest that L1TD1 collaborates with its ancestral L1 ORF1p as an RNA chaperone, ensuring the efficient retrotransposition of L1 retrotransposons, rather than directly impacting the abundance of L1TD1 targets. In this way, L1TD1 might have an important role not only during early development but also in tumorigenesis.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11925450/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143669306","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Mapping out overlapping connectivity patterns. 绘制重叠的连接模式。
IF 6.4 1区 生物学
eLife Pub Date : 2025-03-20 DOI: 10.7554/eLife.106507
Myrthe Faber, Koen V Haak
{"title":"Mapping out overlapping connectivity patterns.","authors":"Myrthe Faber, Koen V Haak","doi":"10.7554/eLife.106507","DOIUrl":"10.7554/eLife.106507","url":null,"abstract":"<p><p>Untangling the functional organisation of a brain region crucial for memory and learning helps reveal how individual differences are linked to variations in recall ability, aging and dopamine receptor distribution.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11925448/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143663042","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Genetic diversity affects ecosystem functions across trophic levels as much as species diversity, but in an opposite direction. 遗传多样性对生态系统功能的影响与物种多样性一样多,但方向相反。
IF 6.4 1区 生物学
eLife Pub Date : 2025-03-20 DOI: 10.7554/eLife.100041
Laura Fargeot, Camille Poesy, Maxim Lefort, Jerome G Prunier, Madoka Krick, Rik Verdonck, Charlotte Veyssiere, Murielle Richard, Delphine Legrand, Geraldine Loot, Blanchet Simon
{"title":"Genetic diversity affects ecosystem functions across trophic levels as much as species diversity, but in an opposite direction.","authors":"Laura Fargeot, Camille Poesy, Maxim Lefort, Jerome G Prunier, Madoka Krick, Rik Verdonck, Charlotte Veyssiere, Murielle Richard, Delphine Legrand, Geraldine Loot, Blanchet Simon","doi":"10.7554/eLife.100041","DOIUrl":"10.7554/eLife.100041","url":null,"abstract":"<p><p>Understanding the relationships between biodiversity and ecosystem functioning stands as a cornerstone in ecological research. Extensive evidence now underscores the profound impact of species loss on the stability and dynamics of ecosystem functions. However, it remains unclear whether the loss of genetic diversity within key species yields similar consequences. Here, we delve into the intricate relationship between species diversity, genetic diversity, and ecosystem functions across three trophic levels - primary producers, primary consumers, and secondary consumers - in natural aquatic ecosystems. Our investigation involves estimating species diversity and genome-wide diversity - gauged within three pivotal species - within each trophic level, evaluating seven key ecosystem functions, and analyzing the magnitude of the relationships between biodiversity and ecosystem functions (BEFs). We found that, overall, the absolute effect size of genetic diversity on ecosystem functions mirrors that of species diversity in natural ecosystems. We nonetheless unveil a striking dichotomy: while genetic diversity was positively correlated with various ecosystem functions, species diversity displays a negative correlation with these functions. These intriguing antagonist effects of species and genetic diversity persist across the three trophic levels (underscoring its systemic nature), but were apparent only when BEFs were assessed within trophic levels rather than across them. This study reveals the complexity of predicting the consequences of genetic and species diversity loss under natural conditions, and emphasizes the need for further mechanistic models integrating these two facets of biodiversity.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11925449/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143663025","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Novel mechanism for tubular injury in nephropathic cystinosis. 肾病型胱氨酸病肾小管损伤的新机制。
IF 6.4 1区 生物学
eLife Pub Date : 2025-03-20 DOI: 10.7554/eLife.94169
Swastika Sur, Maggie Kerwin, Silvia Pineda, Poonam Sansanwal, Tara K Sigdel, Marina Sirota, Minnie M Sarwal
{"title":"Novel mechanism for tubular injury in nephropathic cystinosis.","authors":"Swastika Sur, Maggie Kerwin, Silvia Pineda, Poonam Sansanwal, Tara K Sigdel, Marina Sirota, Minnie M Sarwal","doi":"10.7554/eLife.94169","DOIUrl":"10.7554/eLife.94169","url":null,"abstract":"<p><p>Understanding the unique susceptibility of the human kidney to pH dysfunction and injury in cystinosis is paramount to developing new therapies to preserve renal function. Renal proximal tubular epithelial cells (RPTECs) and fibroblasts isolated from patients with cystinosis were transcriptionally profiled. Lysosomal fractionation, immunoblotting, confocal microscopy, intracellular pH, TEM, and mitochondrial stress test were performed for validation. CRISPR, <i>CTNS</i> <sup>-/-</sup> RPTECs were generated. Alterations in cell stress, pH, autophagic turnover, and mitochondrial energetics highlighted key changes in the V-ATPases in patient-derived and <i>CTNS</i><sup>-/-</sup> RPTECs. ATP6V0A1 was significantly downregulated in cystinosis and highly co-regulated with loss of <i>CTNS</i>. Correction of ATP6V0A1 rescued cell stress and mitochondrial function. Treatment of <i>CTNS</i> <sup>-/-</sup> RPTECs with antioxidants ATX induced ATP6V0A1 expression and improved autophagosome turnover and mitochondrial integrity. Our exploratory transcriptional and in vitro cellular and functional studies confirm that loss of Cystinosin in RPTECs, results in a reduction in ATP6V0A1 expression, with changes in intracellular pH, mitochondrial integrity, mitochondrial function, and autophagosome-lysosome clearance. The novel findings are ATP6V0A1's role in cystinosis-associated renal pathology and among other antioxidants, ATX specifically upregulated ATP6V0A1, improved autophagosome turnover or reduced autophagy and mitochondrial integrity. This is a pilot study highlighting a novel mechanism of tubular injury in cystinosis.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11925453/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143663035","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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