American journal of physiology. Cell physiology最新文献

{"title":"The molecular circadian clock of eosinophils: a potential therapeutic target for asthma.","authors":"Julia Teppan, Thomas Bärnthaler, Aitak Farzi, Hannah Durrington, Gael Gioan-Tavernier, Hazel Platt, Peter Wolf, Akos Heinemann, Eva Böhm","doi":"10.1152/ajpcell.00149.2025","DOIUrl":"10.1152/ajpcell.00149.2025","url":null,"abstract":"<p><p>Asthma is a chronic inflammatory airway disease exhibiting time-of-day variability in symptoms and severity. Eosinophils, pivotal players and biomarkers in asthma, are regulated by the molecular circadian clock. This study aimed to investigate the impact of the molecular circadian clock on eosinophil effector function and its potential as a diagnostic biomarker and therapeutic target. We monitored clock proteins by flow cytometry in peripheral blood eosinophils from participants with mild asthma over a 24-h period. The observed decreased protein levels were confirmed in a cohort of patients with moderate asthma. To assess the interaction between inflammation and the molecular circadian clock, eosinophils were stimulated with patients' sera, inflammatory mediators, and clock-modulating ligands. The therapeutic potential of the inverse retinoic acid receptor-related-related orphan receptor (ROR) agonist SR1001 was evaluated in vitro and in a murine model of allergen-induced airway inflammation. Altered protein levels of circadian locomotor output cycles kaput (CLOCK), Brain and muscle Arnt-like protein-1 (BMAL1), REV-ERBs, and RORs in eosinophils from participants with asthma reflected the disease severity and allergy status of the patients. Mimicking an inflammatory environment in vitro resulted in similar changes. Blocking C-C chemokine receptor type 3 (CCR3)/ERK and epidermal growth factor receptor (EGFR) signaling with an inverse ROR agonist SR1001 reset the molecular circadian clock in eosinophils and exhibited anti-inflammatory effects by inhibiting eosinophil migration in vitro. In addition, we confirmed the therapeutic potential of the clock-modulating SR1001, bronchoprotective effects in two in vivo models. This study suggests that clock proteins could serve as therapeutic targets in asthma. Pharmacological inhibition of ROR signaling demonstrated significant anti-inflammatory and bronchoprotective properties, indicating its potential as a novel treatment strategy for asthma and other eosinophilic diseases.<b>NEW & NOTEWORTHY</b> Our findings highlight the role of the circadian system as an immunomodulatory regulator, biomarker, and therapeutic target in chronic inflammatory diseases. The observed inflammation-driven downregulation of the molecular circadian clock may also represent a key mechanism that triggers the switch from homeostatic to pro-inflammatory eosinophils. Furthermore, we demonstrate for the first time that pharmacologic inhibition of ROR resets the molecular circadian clock and induces anti-inflammatory and lung-protective effects without disrupting circadian rhythms.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1394-C1408"},"PeriodicalIF":5.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143699376","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":"Sex hormone-binding globulin dampens growth and metastasis of breast cancer in an estrogen-independent manner.","authors":"Sang R Lee, Na Rim Kim, Moeka Mukae, Young Suk Won, Eui-Ju Hong","doi":"10.1152/ajpcell.00747.2024","DOIUrl":"https://doi.org/10.1152/ajpcell.00747.2024","url":null,"abstract":"<p><p>Early studies have shown that sex hormone-binding globulin (SHBG) suppresses breast cancer by decreasing estrogen activity. However, the sex hormone-independent role of SHBG in breast cancer has received limited attention. Building on our previous research linking SHBG with tumor-associated macrophage (TYRO3, AXL, and MerTK) receptors, we aimed to explore SHBG's sex hormone-independent involvement in breast cancer progression. Analysis of public datasets and tumor slides from patients with breast cancer revealed that invasive breast cancer was associated with a significant decrease in SHBG, and lower SHBG levels correlated with poor cancer prognosis. In the polyomavirus middle T antigen overexpression mouse model (MMTV-PyMT), SHBG-Tg mice exhibited extended survival both under naïve and ovariectomized conditions. Although SHBG-Tg tumors had an estrogenic environment, their growth was suppressed, which correlated with reduced AXL levels. SHBG plasma treatment inhibited proliferation, tumorsphere growth, and invasion in MDA-MB-231 cells, accompanied by a decrease in AXL levels. In subcutaneous allograft models, SHBG-Tg mice showed reduced tumor growth and metastasis, and intraperitoneal injection of SHBG plasma significantly delayed tumor progression in PyMT mice compared with WT plasma. In summary, our study highlights SHBG's inhibitory role in breast cancer growth and metastasis, which may be particularly relevant for estrogen-independent patients with triple-negative breast cancer.<b>NEW & NOTEWORTHY</b> Our study is the first in vivo experiment using polyomavirus middle T antigen-sex hormone-binding globulin (PyMT-SHBG) mouse model to assess the physiological role of SHBG in breast cancer development. We show that SHBG presence in PyMT model restrains breast cancer development and progression in sex hormone-independent manner.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":"328 5","pages":"C1685-C1698"},"PeriodicalIF":5.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143955784","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":"Pathophysiological underpinnings of metabolic dysfunction-associated steatotic liver disease.","authors":"Mohammad Shafi Kuchay, Narendra Singh Choudhary, Bruno Ramos-Molina","doi":"10.1152/ajpcell.00951.2024","DOIUrl":"https://doi.org/10.1152/ajpcell.00951.2024","url":null,"abstract":"<p><p>Metabolic dysfunction-associated steatotic liver disease (MASLD) is emerging as the leading cause of chronic liver disease worldwide, reflecting the global epidemics of obesity, metabolic syndrome, and type 2 diabetes. Beyond its strong association with excess adiposity, MASLD encompasses a heterogeneous population that includes individuals with normal body weight (\"lean MASLD\") highlighting the complexity of its pathogenesis. This disease results from a complex interplay between genetic susceptibility, epigenetic modifications, and environmental factors, which converge to disrupt metabolic homeostasis. Adipose tissue dysfunction and insulin resistance trigger an overflow of lipids to the liver, leading to mitochondrial dysfunction, oxidative stress, and hepatocellular injury. These processes promote hepatic inflammation and fibrogenesis, driven by cross talk among hepatocytes, immune cells, and hepatic stellate cells, with key contributions from gut-liver axis perturbations. Recent advances have unraveled pivotal molecular pathways, such as transforming growth factor-β signaling, Notch-induced osteopontin, and sphingosine kinase 1-mediated responses, that orchestrate fibrogenic activation. Understanding these interconnected mechanisms is crucial for developing targeted therapies. This review integrates current knowledge on the pathophysiology of MASLD, emphasizing emerging concepts such as lean metabolic dysfunction-associated steatohepatitis (MASH), epigenetic alterations, hepatic extracellular vesicles, and the relevance of extrahepatic signals. It also discusses novel therapeutic strategies under investigation, aiming to provide a comprehensive and structured overview of the evolving MASLD landscape for both basic scientists and clinicians.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":"328 5","pages":"C1637-C1666"},"PeriodicalIF":5.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143970314","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":"Mitochondrial metabolism and hypoxic signaling in differentiated human cardiomyocyte AC16 cell line.","authors":"Lukas Alan, Barbora Opletalova, Habiba Hayat, Aleksandra Markovic, Marketa Hlavackova, Marek Vrbacky, Tomas Mracek, Petra Alanova","doi":"10.1152/ajpcell.00083.2025","DOIUrl":"https://doi.org/10.1152/ajpcell.00083.2025","url":null,"abstract":"<p><p>Cardiovascular diseases are associated with an altered cardiomyocyte metabolism. Because of a shortage of human heart tissue, experimental studies mostly rely on alternative approaches including animal and cell culture models. Since the use of isolated primary cardiomyocytes is limited, immortalized cardiomyocyte cell lines may represent a useful tool as they closely mimic human cardiomyocytes. This study is focused on the AC16 cell line generated from adult human ventricular cardiomyocytes. Despite an increasing number of studies employing AC16 cells, a comprehensive proteomic, bioenergetic, and oxygen-sensing characterization of proliferating vs. differentiated cells is still lacking. Here, we provide a comparison of these two stages, particularly emphasizing cell metabolism, mitochondrial function, and hypoxic signaling. Label-free quantitative mass spectrometry revealed a decrease in autophagy and cytoplasmic translation in differentiated AC16, confirming their phenotype. Cell differentiation led to global increase in mitochondrial proteins [e.g. oxidative phosphorylation (OXPHOS) proteins, TFAM, VWA8] reflected by elevated mitochondrial respiration. Fatty acid oxidation proteins were increased in differentiated cells, whereas the expression levels of proteins associated with fatty acid synthesis were unchanged and glycolytic proteins were decreased. There was a profound difference between proliferating and differentiated cells in their response to hypoxia and anoxia-reoxygenation. We conclude that AC16 differentiation leads to proteomic and metabolic shifts and altered cell response to oxygen deprivation. This underscores the requirement for proper selection of the particular differentiation state during experimental planning.<b>NEW & NOTEWORTHY</b> Proliferating and differentiated AC16 cell lines exhibit distinct proteomic and metabolic profiles with critical implications for experimental design. Proliferating cells predominantly utilize glycolysis and are highly sensitive to hypoxia, whereas differentiated cells display enhanced mitochondrial biogenesis, oxidative phosphorylation, and resistance to anoxia-reoxygenation. These findings provide novel insights into the metabolic adaptations during differentiation and highlight the necessity of selecting the appropriate cellular stage to ensure accurate experimental outcomes.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":"328 5","pages":"C1571-C1585"},"PeriodicalIF":5.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143952239","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":"Physiological function of cyclic nucleotide phosphodiesterases in atrial myocytes and their potential as therapeutic targets for atrial fibrillation.","authors":"Matthew John Read, Andreas Koschinski, Samuel Jitu Bose, Rebecca A B Burton","doi":"10.1152/ajpcell.00782.2024","DOIUrl":"10.1152/ajpcell.00782.2024","url":null,"abstract":"<p><p>Cyclic nucleotide hydrolyzing phosphodiesterases (PDEs) are key regulators of cyclic nucleotide (e.g., cAMP and cGMP) signaling. Here, we examine the role of PDEs in the physiology of atrial myocytes (AMs), the pathogenesis of atrial fibrillation (AF), and the potential of PDEs as therapeutic targets for AF. PDE1-5 and 8 are present and functional in AMs. PDE2-4 are important regulators of AM contraction but their role beyond atrial contractility is unclear. The role of PDE1,5 and 8 in healthy AMs is unknown but of interest because of their roles in ventricular myocytes. We propose that PDE2-5 and PDE8 are potential targets to prevent the triggering of AF considering their effects on Ca²⁺ handling and/or electrical activity. PDE1-5 are possible targets to treat patients with paroxysmal or persistent AF caused by pulmonary vein automaticity. PDE8B2 is a possible target for patients with persistent AF due to its altered expression. Research should aim to identify the presence, localization, and function of specific PDE isoforms in human atria. Ultimately, the paucity of PDE isoform-specific small molecule modulators and the difficulty of delivering PDE-targeted medications or therapies to particular cell types limit current research and its application.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1423-C1454"},"PeriodicalIF":5.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584307","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":"Blocking dopamine receptor 2 decreases gastrin levels in <i>H. pylori</i>-infected mice through increasing gastric somatostatin content.","authors":"Qian-Ying Shen, Yue-Yue Zhou, Yan-Lin Wang, Yao Qi, Dong-Bo Lian, Zhe-Hong Li, Meng-Fei Chen, Xiao-Li Zhang, Yue Zhang, Jin Song, Li-Fei Zheng, Jin-Xia Zhu","doi":"10.1152/ajpcell.00993.2024","DOIUrl":"10.1152/ajpcell.00993.2024","url":null,"abstract":"<p><p>Long-term infection with <i>Helicobacter pylori</i> (<i>H. pylori</i>) leads to elevated serum gastrin levels, which are closely related to gastric cancer. It is important to reduce serum gastrin levels after <i>H. pylori</i> infection. Dopamine (DA) receptor 1 (D₁R) is expressed on G cells in the gastric antrum. Parietal cells produce DA, which inhibits somatostatin (SOM) release through D₂R on D cells in the gastric mucosa. Whether targeted intervention in DRs can improve high gastrin levels after <i>H. pylori</i> infection remains to be explored. In this study, human gastric tissue, <i>H. pylori</i>-infected mice, D₁R and D₂R knockout mice, RT-qPCR, enzyme-linked immunosorbent assay (ELISA), immunohistochemical (IHC), Western blot, and ex vivo incubation of gastric mucosae were used. We found that <i>H. pylori</i> infection destroyed the mitochondria of parietal cells and reduced DA content in the gastric mucosa at 10 wk after infection. Moreover, gastrin-positive cell numbers and serum gastrin levels were increased. D₁R, but not D₂R, was observed in G cells. DA promoted gastric gastrin secretion. Interestingly, both D1- and D2-like agonists mimicked the effect of DA on the gastrin secretion, which was antagonized by their antagonists. Blocking D₂R with domperidone or knocking out D₂R resulted in decreased gastrin-positive cell numbers and gastrin levels but increased SOM levels at 10 wk after <i>H. pylori</i> infection. Our findings highlight the key regulatory effect of D₂R on gastrin secretion and elucidate the role of domperidone in reducing the elevated gastrin level associated with <i>H. pylori</i> infection.<b>NEW & NOTEWORTHY</b> We report novel findings that blocking D₂Rs, not D₁Rs, decreased the number of gastric gastrin-positive cells and gastrin levels in <i>H. pylori</i>-infected mice. Gastric gastrin secretion induced by DA was indirectly mediated via D₂Rs, which suppressed SOM release. These results provide an experimental basis for local regulation of gastric gastrin secretion by DA through D₂Rs, offering a potential strategy for preventing and treating high gastrin levels in <i>H. pylori</i> infection.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1409-C1422"},"PeriodicalIF":5.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143646891","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":"A history of omics discoveries reveals the correlates and mechanisms of loading-induced hypertrophy in adult skeletal muscle. 2024 CaMPS young investigator award invited review.","authors":"Toby L Chambers, Kevin A Murach","doi":"10.1152/ajpcell.00968.2024","DOIUrl":"10.1152/ajpcell.00968.2024","url":null,"abstract":"<p><p>Since the early 2000s, omics approaches to study skeletal muscle hypertrophy consequent to loading (e.g., resistance exercise) have expanded dramatically. Beginning with genomics and transcriptomics, there are now omics datasets from hypertrophying skeletal muscle spanning methylomics, proteomics, and phosphoproteomics, with further integration of single cell/nucleus-specific omics, among others. The purpose of this review is to explore the history of leveraging omics to enable understanding and discovery with respect to loading-induced hypertrophy in adult skeletal muscle. We elaborate on key historical and contemporary studies and findings, highlight specific examples where omics discoveries led to a mechanistic understanding of skeletal muscle growth, and provide background on established and emerging omic technologies. We focus on findings from human skeletal muscle tissue but also provide context and support from the rodent literature, including insights from gain- and loss-of-function experiments. Moving forward, the computational integration of omics datasets will provide unprecedented information and exciting new directions for studying how resistance exercise mediates skeletal muscle health. This information will help inform how to target key factors influencing muscle mass with a deep, comprehensive, and integrated multilayered understanding of their molecular regulation.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1535-C1557"},"PeriodicalIF":5.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143762643","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":"Potential of synergist ablation to study mechanisms of skeletal muscle hypertrophy in rodent disease models.","authors":"Fabio Sarto, Christopher S Fry, Marco V Narici, Lee L Rubin, Feodor D Price","doi":"10.1152/ajpcell.00076.2025","DOIUrl":"10.1152/ajpcell.00076.2025","url":null,"abstract":"<p><p>Synergist ablation (SA) is a well-established model of mechanical overload-induced hypertrophy in rodents, commonly used to infer skeletal muscle adaptation to resistance training in humans. Given the critical role of skeletal muscle atrophy in chronic conditions such as neuromuscular, metabolic, and cardiopulmonary disorders, SA represents a promising preclinical tool to study muscle hypertrophy mechanisms in pathological states. However, although extensively characterized in healthy animals, the potential applications of SA in disease models remain largely overlooked. This Mini-Review summarizes existing studies employing SA in rodent disease models, highlighting the diverse hypertrophic responses observed across conditions, including Duchenne muscular dystrophy, obesity, diabetes, cancer cachexia, and chronic kidney disease. Although hypertrophy gains are generally attenuated in diseased animals compared to healthy controls, SA-induced overload provides valuable insights into disease-specific regulatory mechanisms, including alterations in intracellular signaling, fiber type transitions, and disease phenotype. We also discuss the strengths and limitations of SA as a preclinical model for resistance training in disease contexts and propose its broader adoption for mechanistic investigations into skeletal muscle plasticity under pathological conditions.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1389-C1393"},"PeriodicalIF":5.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143690799","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":"Aquaporin-1 acts as an O₂ channel. The permeability of human and mouse red cell membranes for oxygen.","authors":"Samer Al-Samir, Despoina Kyriazi, Andrea J Yool, Inês Moser, Kallirroi Kyriazi, Gerolf Gros, Georgios Tsiavaliaris, Volker Endeward","doi":"10.1152/ajpcell.00858.2024","DOIUrl":"10.1152/ajpcell.00858.2024","url":null,"abstract":"<p><p>It has been demonstrated that aquaporin-1 (AQP1), one of the most abundant red cell membrane proteins, constitutes a functionally important channel for CO₂ in red cell membranes. We ask here, whether AQP1 and other gas channel proteins play a role also in red cell oxygen transport. We use a stopped-flow technique to: <i>1</i>) compare the oxygen permeability, [Formula: see text], of AQP1-deficient (Colton Null) with that of normal human red cell membranes, <i>2</i>) compare the [Formula: see text] of <i>Aqp1</i>^-/- with that of normal mouse red cells, <i>3</i>) study the effect of the gas channel inhibitor 4,4'-diisothiocyanato-2,2'-stilbenedisulfonate (DIDS) on [Formula: see text] of human and mouse red cells, and <i>4</i>) investigate all three effects at various temperatures between 7 and 37°C, because O₂ transfer across channels and across membrane lipids may depend differently on temperature. We find that at 7°C/10°C lack of AQP1 in the red cell membrane causes significant reductions of [Formula: see text], by 20% in human and by 37% in mouse red cells. DIDS causes reductions in [Formula: see text] by 34% in human and by 88% in mouse red cells. In addition, the AQP1 inhibitor 5-(phenoxymethyl)furan-2-carbaldehyde (5-PMFC) decreases human red cell [Formula: see text] by ∼40%. All these effects are highly visible at 7°C/10°C, but minor or absent at 25 and 37°C, suggesting that O₂ passage through the channel(s) increases less with temperature than O₂ permeation through membrane lipids. Lack of AQP1 and exposure to DIDS or 5-PMFC indicate that AQP1-possibly along with other gas channels-at <25°C acts as an efficient channel for O₂.<b>NEW & NOTEWORTHY</b> Aquaporin-1 is a membrane protein that conducts CO₂ at 37°C very efficiently. Here, we show that aquaporin-1 also conducts O₂, but mainly at lower temperatures of around 10°C. Although O₂ transfer across the red cell membrane is accelerated by aquaporin-1 significantly at 10°C, a temperature occurring in poikilotherms, aquaporin-1 apparently does not contribute to O₂ passage at 37°C as it occurs in homoiotherms.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1605-C1622"},"PeriodicalIF":5.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143762674","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":"Umbilical cord mesenchymal stem cell-derived extracellular vesicles improve excessive autophagy of granulosa cells through <i>METTL3</i>.","authors":"Weiqin Zhou, Ju Zhang, Xuanping Lu, Ziwei Zhao, Yujing Weng, Chunrong Zhu","doi":"10.1152/ajpcell.00785.2024","DOIUrl":"10.1152/ajpcell.00785.2024","url":null,"abstract":"<p><p>Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder impacting women's fertility. We assessed the effect of umbilical cord mesenchymal stem cell-derived extracellular vesicles (UC-MSC-EVs) on PTEN-induced kinase 1 (<i>PINK1</i>)/<i>Parkin</i>-mediated excessive autophagy of ovarian granulosa cells (GCs) through methyltransferase-like 3 (<i>METTL3</i>). Human ovarian GC line KGN was cultured and treated with dehydroepiandrosterone (DHEA) and UC-MSC-EVs. Cell apoptosis and viability, autophagy-related protein levels, adenosine triphosphate (ATP) and mitochondrial membrane potential (MMP) level, and microtubule-associated protein 1 light chain 3 β (LC3B) and translocase of outer mitochondrial membrane 20 (TOMM20) colocalization were assessed by flow cytometry, CCK-8, Western blot, kit, and immunofluorescence. <i>PINK1</i> N6-methyladenosine (m6A) modification, <i>METTL3</i> levels, and <i>PINK1</i> mRNA stability were determined by methylated RNA immunoprecipitation, reverse transcription quantitative polymerase chain reaction, and Western blot. The PCOS mouse model was established and treated with UC-MSC-EVs. Serum hormone and ovarian tissue autophagy-related protein levels were determined by enzyme-linked immunosorbent assay. DHEA decreased KGN cell viability and p62 level, increased <i>PINK1</i>, <i>Parkin</i>, LC3BII/I, and Beclin-1 protein levels, ATP content, MMP level, TOMM20⁺LC3B⁺ cell number, and apoptosis, which were partly abrogated by UC-MSC-EV treatment. PINK1 had m6A modification sites. METTL3 was a <i>PINK1</i> m6A-modified writer protein. After DHEA treatment, KGN cells showed elevated <i>METTL3</i> and <i>PINK1</i> m6A modification levels and mRNA stability, whereas UC-MSC-EV treatment caused the opposite results. METTL3 overexpression partly averted UC-MSC-EVs-improved <i>PINK1</i>/<i>Parkin</i>-mediated mitophagy. UC-MSC-EVs curbed PINK1/Parkin-mediated excessive autophagy through <i>METTL3</i> and improved ovarian function in PCOS mice. In conclusion, UC-MSC-EVs suppressed PINK1/Parkin-mediated mitophagy of ovarian GCs through METTL3, thereby improving PCOS.<b>NEW & NOTEWORTHY</b> Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder impacting women's fertility. The authors in this study using DHEA-induced granulosa cells (GCs) demonstrated that umbilical cord mesenchymal stem cell-derived extracellular vesicles (UC-MSC-EVs) suppressed <i>PINK1</i>/<i>Parkin</i>-mediated mitophagy of ovarian GCs through METTL3, thereby improving PCOS.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1586-C1604"},"PeriodicalIF":5.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143662035","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}