{"title":"AKR1D1 suppresses liver cancer progression by promoting bile acid metabolism-mediated NK cell cytotoxicity","authors":"Haoran Wei, Caixia Suo, Xuemei Gu, Shengqi Shen, Kashuai Lin, Chuxu Zhu, Kai Yan, Zhenhua Bian, Liang Chen, Tong Zhang, Ronghui Yan, Zhiyi Yang, Yingxuan Yu, Zhikun Li, Rui Liu, Junming He, Qiwei He, Xiuying Zhong, Weidong Jia, Chun-Ming Wong, Ping Gao","doi":"10.1016/j.cmet.2025.01.011","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.01.011","url":null,"abstract":"Bile acid metabolism and antitumor immunity are both disrupted during liver cancer progression. However, the complex regulatory relationship between them remains largely unclear. Here, we find that loss of aldo-keto reductase 1D1 (AKR1D1) promotes the accumulation of isolithocholic acid (iso-LCA) through gut microbiome dysregulation, thereby impairing the cytotoxic function of natural killer (NK) cells and leading to the accelerated development of hepatocellular carcinoma (HCC). Mechanistically, AKR1D1 deficiency leads to an increased proportion of <em>Bacteroidetes ovatus</em> (<em>B. ovatus</em>), which breaks down chenodeoxycholic acid (CDCA) into iso-LCA. Moreover, accumulated iso-LCA impairs the antitumor activity of hepatic NK cells in a phosphorylated-CREB1 (p-CREB1)-dependent manner. The potassium-sparing diuretic spironolactone treatment significantly enhances the inhibitory effect of anti-PD1 antibody on HCC progression by targeting iso-LCA-mediated tumor immune escape. Taken together, our results uncover a previously unappreciated link between AKR1D1 and HCC and suggest that targeting iso-LCA produced by <em>B. ovatus</em> might be a promising strategy to activate NK cell cytotoxicity to treat HCC.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"28 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143486524","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}
Cell metabolismPub Date : 2025-02-24DOI: 10.1016/j.cmet.2025.01.017
Giovanni Rigoni, Enrique Calvo, Christina Glytsou, Marta Carro-Alvarellos, Masafumi Noguchi, Martina Semenzato, Charlotte Quirin, Federico Caicci, Natascia Meneghetti, Mattia Sturlese, Takaya Ishihara, Stefano Moro, Chiara Rampazzo, Naotada Ishihara, Fabrizio Bezzo, Leonardo Salviati, Jesùs Vazquez, Gabriele Sales, Chiara Romualdi, Jose Antonio Enriquez, Maria Eugenia Soriano
{"title":"MARIGOLD and MitoCIAO, two searchable compendia to visualize and functionalize protein complexes during mitochondrial remodeling","authors":"Giovanni Rigoni, Enrique Calvo, Christina Glytsou, Marta Carro-Alvarellos, Masafumi Noguchi, Martina Semenzato, Charlotte Quirin, Federico Caicci, Natascia Meneghetti, Mattia Sturlese, Takaya Ishihara, Stefano Moro, Chiara Rampazzo, Naotada Ishihara, Fabrizio Bezzo, Leonardo Salviati, Jesùs Vazquez, Gabriele Sales, Chiara Romualdi, Jose Antonio Enriquez, Maria Eugenia Soriano","doi":"10.1016/j.cmet.2025.01.017","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.01.017","url":null,"abstract":"Mitochondrial proteins assemble dynamically in high molecular weight complexes essential for their functions. We generated and validated two searchable compendia of these mitochondrial complexes. Following identification by mass spectrometry of proteins in complexes separated using blue-native gel electrophoresis from unperturbed, cristae-remodeled, and outer membrane-permeabilized mitochondria, we created MARIGOLD, a mitochondrial apoptotic remodeling complexome database of 627 proteins. MARIGOLD elucidates how dynamically proteins distribute in complexes upon mitochondrial membrane remodeling. From MARIGOLD, we developed MitoCIAO, a mitochondrial complexes interactome tool that, by statistical correlation, calculates the likelihood of protein cooccurrence in complexes. MitoCIAO correctly predicted biologically validated interactions among components of the mitochondrial cristae organization system (MICOS) and optic atrophy 1 (OPA1) complexes. We used MitoCIAO to functionalize two ATPase family AAA domain-containing 3A (ATAD3A) complexes: one with OPA1 that regulates mitochondrial ultrastructure and the second containing ribosomal proteins that is essential for mitoribosome stability. These compendia reveal the dynamic nature of mitochondrial complexes and enable their functionalization.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"8 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143477752","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}
{"title":"Caloric restriction prevents inheritance of polycystic ovary syndrome through oocyte-mediated DNA methylation reprogramming","authors":"Yue Liu, Yi Dong, Yonghui Jiang, Shan Han, Xin Liu, Xin Xu, Aiqing Zhu, Zihe Zhao, Yuan Gao, Yang Zou, Chuanxin Zhang, Yuehong Bian, Yuqing Zhang, Jiang Liu, Shigang Zhao, Han Zhao, Zi-Jiang Chen","doi":"10.1016/j.cmet.2025.01.014","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.01.014","url":null,"abstract":"Polycystic ovary syndrome (PCOS) is a prevalent metabolic and reproductive endocrine disorder with strong heritability. However, the independent role of oocytes in mediating this heritability remains unclear. Utilizing <em>in vitro</em> fertilization-embryo transfer and surrogacy, we demonstrated that oocytes from androgen-exposed mice (F1) transmitted PCOS-like traits to F2 and F3 generations. Notably, caloric restriction (CR) in F1 or F2 effectively prevented this transmission by restoring disrupted DNA methylation in oocyte genes related to insulin secretion and AMPK signaling pathways. Further detection in adult tissues of offspring revealed dysregulated DNA methylation and expression of those genes (e.g., <em>Adcy3</em>, <em>Gnas</em>, and <em>Srebf1</em>) were reversed by maternal CR. Moreover, similar benefits of CR were observed in aberrant embryonic methylome of women with PCOS. These findings elucidate the essential role of CR in preventing PCOS transmission via methylation reprogramming, emphasizing the importance of preconception metabolic management for women with PCOS.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"25 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143463087","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}
Cell metabolismPub Date : 2025-02-21DOI: 10.1016/j.cmet.2025.01.025
Caterina Miro, Annunziata Gaetana Cicatiello, Annarita Nappi, Serena Sagliocchi, Lucia Acampora, Federica Restolfer, Ornella Cuomo, Giulia de Alteris, Gabriella Pugliese, Sepehr Torabinejad, Rosa Maritato, Melania Murolo, Emery Di Cicco, Nunzio Velotti, Marianna Capuano, Evelina La Civita, Daniela Terracciano, Roberto Ciampaglia, Mariano Stornaiuolo, Mario Musella, Monica Dentice
{"title":"Leptin enhances the intracellular thyroid hormone activation in skeletal muscle to boost energy balance","authors":"Caterina Miro, Annunziata Gaetana Cicatiello, Annarita Nappi, Serena Sagliocchi, Lucia Acampora, Federica Restolfer, Ornella Cuomo, Giulia de Alteris, Gabriella Pugliese, Sepehr Torabinejad, Rosa Maritato, Melania Murolo, Emery Di Cicco, Nunzio Velotti, Marianna Capuano, Evelina La Civita, Daniela Terracciano, Roberto Ciampaglia, Mariano Stornaiuolo, Mario Musella, Monica Dentice","doi":"10.1016/j.cmet.2025.01.025","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.01.025","url":null,"abstract":"Thyroid hormones (THs) are key modulators of energy metabolism and cross-talk with other endocrine and metabolic factors. Notably, leptin can increase hypothalamic control of TH synthesis as an adaptive metabolic response regulating body weight. In this study, we found that the TH signal is heightened in overweight humans and is lost with obesity. In mice, systemic and intracerebroventricular leptin injection induces the expression of type 2 deiodinase (D2), the TH-activating enzyme, in skeletal muscle. Mechanistically, leptin enhances the transcription of D2 by a STAT3- and α-melanocyte-stimulating hormone (α-MSH)/cyclic AMP (cAMP)-dependent regulation. Notably, mice lacking D2 or with a mutation in the TH receptor do not exhibit the metabolic effects of leptin, such as increased insulin sensitivity and oxygen consumption, indicating that leptin’s peripheral metabolic effects in skeletal muscle are mediated by TH. These findings underscore the critical role of leptin in integrating the TH-induced metabolic activation, while also contributing to appetite suppression in response to perceived fat stores.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"50 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143463088","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}
Cell metabolismPub Date : 2025-02-20DOI: 10.1016/j.cmet.2025.01.012
Jiawei Zhong, Danae Zareifi, Sophie Weinbrenner, Mattias Hansen, Felix Klingelhuber, Pamela A. Nono Nankam, Scott Frendo-Cumbo, Nayanika Bhalla, Lina Cordeddu, Thais de Castro Barbosa, Peter Arner, Ingrid Dahlman, Maheswary Muniandy, Sini Heinonen, Kirsi H. Pietiläinen, Anne Hoffmann, Adhideb Ghosh, Dorit John, Anke Tönjes, Patrik L. Ståhl, Mikael Rydén
{"title":"adiposetissue.org: A knowledge portal integrating clinical and experimental data from human adipose tissue","authors":"Jiawei Zhong, Danae Zareifi, Sophie Weinbrenner, Mattias Hansen, Felix Klingelhuber, Pamela A. Nono Nankam, Scott Frendo-Cumbo, Nayanika Bhalla, Lina Cordeddu, Thais de Castro Barbosa, Peter Arner, Ingrid Dahlman, Maheswary Muniandy, Sini Heinonen, Kirsi H. Pietiläinen, Anne Hoffmann, Adhideb Ghosh, Dorit John, Anke Tönjes, Patrik L. Ståhl, Mikael Rydén","doi":"10.1016/j.cmet.2025.01.012","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.01.012","url":null,"abstract":"We developed the Adipose Tissue Knowledge Portal by centralizing previously dispersed datasets, integrating clinical and experimental results with transcriptomic and proteomic data from >6,000 women and men. The platform includes multiple adipose depots, resident cell types, and adipocyte perturbation studies. By providing streamlined data access, the portal enables integrative analyses and serves as a powerful tool to interrogate various dimensions of adipose biology down to the single-cell level.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"310 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143451886","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}
Cell metabolismPub Date : 2025-02-20DOI: 10.1016/j.cmet.2025.01.008
Bo Yuan, Will Doxsey, Özlem Tok, Young-Yon Kwon, Yanshan Liang, Karen E. Inouye, Gökhan S. Hotamışlıgil, Sheng Hui
{"title":"An organism-level quantitative flux model of energy metabolism in mice","authors":"Bo Yuan, Will Doxsey, Özlem Tok, Young-Yon Kwon, Yanshan Liang, Karen E. Inouye, Gökhan S. Hotamışlıgil, Sheng Hui","doi":"10.1016/j.cmet.2025.01.008","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.01.008","url":null,"abstract":"Mammalian tissues feed on nutrients in the blood circulation. At the organism level, mammalian energy metabolism is comprised of the oxidation, storage, interconversion, and release of circulating nutrients. Here, by integrating isotope tracer infusion, mass spectrometry, and isotope gas analyzer measurement, we developed a framework to systematically quantify fluxes through these metabolic processes for 10 major circulating energy nutrients in mice, resulting in an organism-level quantitative flux model of energy metabolism. This model revealed in wild-type mice that circulating nutrients have metabolic cycling fluxes dominant to their oxidation fluxes, with distinct partitions between cycling and oxidation for individual circulating nutrients. Applications of this framework in obese mouse models showed extensive elevation of metabolic cycling fluxes in ob/ob mice but not in diet-induced obese mice on a per-animal or per-lean mass basis. Our framework is a valuable tool to reveal new features of energy metabolism in physiological and disease conditions.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"4 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143451882","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}
Cell metabolismPub Date : 2025-02-19DOI: 10.1016/j.cmet.2025.01.007
Zhenyu Wang, Li Tian, Yi Jiang, Lijun Ning, Xiaoqiang Zhu, Xuejie Chen, Baoqin Xuan, Yilu Zhou, Jinmei Ding, Yanru Ma, Ying Zhao, Xiaowen Huang, Muni Hu, Jing-Yuan Fang, Nan Shen, Zhijun Cao, Haoyan Chen, Xiaoyan Wang, Jie Hong
{"title":"Synergistic role of gut-microbial L-ornithine in enhancing ustekinumab efficacy for Crohn’s disease","authors":"Zhenyu Wang, Li Tian, Yi Jiang, Lijun Ning, Xiaoqiang Zhu, Xuejie Chen, Baoqin Xuan, Yilu Zhou, Jinmei Ding, Yanru Ma, Ying Zhao, Xiaowen Huang, Muni Hu, Jing-Yuan Fang, Nan Shen, Zhijun Cao, Haoyan Chen, Xiaoyan Wang, Jie Hong","doi":"10.1016/j.cmet.2025.01.007","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.01.007","url":null,"abstract":"The role of the intestinal microbiome in Crohn’s disease (CD) treatment remains poorly understood. This study investigates microbe-host interactions in CD patients undergoing ustekinumab (UST) therapy. Fecal metagenome, metabolome, and host transcriptome data from 85 CD patients were analyzed using multi-omics integration and mediation analysis. Our findings reveal significant microbiome-metabolite-host interactions. Specifically, <em>Faecalibacterium prausnitzii</em> was linked to altered L-ornithine biosynthesis, resulting in higher L-ornithine levels in patients before UST therapy. <em>In vivo</em> and <em>in vitro</em> studies demonstrated that microbiome-derived L-ornithine enhances UST treatment sensitivity in CD by disrupting the host IL-23 receptor signaling and inhibiting Th17 cell stabilization through the IL-12RB1/TYK2/STAT3 axis. L-ornithine significantly enhances the therapeutic efficacy of UST in CD patients, as demonstrated in a prospective clinical trial. These findings suggest that targeting specific microbe-host metabolic pathways may improve the efficacy of inflammatory bowel disease (IBD) treatments.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"2 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143452146","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}
{"title":"Sweetener aspartame aggravates atherosclerosis through insulin-triggered inflammation","authors":"Weijie Wu, Wenhai Sui, Sizhe Chen, Ziheng Guo, Xu Jing, Xiaolu Wang, Qun Wang, Xinshuang Yu, Wenjing Xiong, Jiansong Ji, Libo Yang, Yuan Zhang, Wenjing Jiang, Guohua Yu, Shuzhen Liu, Wei Tao, Chen Zhao, Yun Zhang, Yuguo Chen, Cheng Zhang, Yihai Cao","doi":"10.1016/j.cmet.2025.01.006","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.01.006","url":null,"abstract":"Consumption of artificial sweeteners (ASWs) in various foods and beverages has been linked to an increased risk of cardiovascular diseases (CVDs). However, molecular mechanisms underlying ASW-associated CVD remain unknown. Here, we show that consumption of 0.15% aspartame (APM) markedly increased insulin secretion in mice and monkeys. Bilateral subdiaphragmatic vagotomy (SDV) obliterated APM-elevated blood insulin levels, demonstrating crucial roles of parasympathetic activation in regulation of insulin secretion. Incessant APM feeding of ApoE<sup>−/</sup><sup>−</sup> mice aggravated atherosclerotic plaque formation and growth via an insulin-dependent mechanism. Implantation of an insulin-slow-release pump in ApoE<sup>−/−</sup> mice exacerbated atherosclerosis. Whole-genome expression profiling discovered that CX3CL1 chemokine was the most upregulated gene in the insulin-stimulated arterial endothelial cells. Specific deletion of a CX3CL1 receptor, <em>Cx3cr1</em> gene, in monocytes/macrophages completely abrogated the APM-exacerbated atherosclerosis. Our findings uncover a novel mechanism of APM-associated atherosclerosis and therapeutic targeting of the endothelial CX3CL1-macrophage CX3CR1 signaling axis provides an approach for treating atherosclerotic CVD.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"2 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143451892","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}
Cell metabolismPub Date : 2025-02-17DOI: 10.1016/j.cmet.2025.01.013
Phillip A. Dumesic, Sarah E. Wilensky, Symanthika Bose, Jonathan G. Van Vranken, Steven P. Gygi, Bruce M. Spiegelman
{"title":"RBM43 controls PGC1α translation and a PGC1α-STING signaling axis","authors":"Phillip A. Dumesic, Sarah E. Wilensky, Symanthika Bose, Jonathan G. Van Vranken, Steven P. Gygi, Bruce M. Spiegelman","doi":"10.1016/j.cmet.2025.01.013","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.01.013","url":null,"abstract":"Obesity is associated with systemic inflammation that impairs mitochondrial function. This disruption curtails oxidative metabolism, limiting adipocyte lipid metabolism and thermogenesis, a metabolically beneficial program that dissipates chemical energy as heat. Here, we show that PGC1α, a key governor of mitochondrial biogenesis, is negatively regulated at the level of its mRNA translation by the RNA-binding protein RBM43. RBM43 is induced by inflammatory cytokines and suppresses mitochondrial biogenesis in a PGC1α-dependent manner. In mice, adipocyte-selective <em>Rbm43</em> disruption elevates PGC1α translation and oxidative metabolism. In obesity, <em>Rbm43</em> loss improves glucose tolerance, reduces adipose inflammation, and suppresses activation of the innate immune sensor cGAS-STING in adipocytes. We further identify a role for PGC1α in safeguarding against cytoplasmic accumulation of mitochondrial DNA, a cGAS ligand. The action of RBM43 defines a translational regulatory axis by which inflammatory signals dictate cellular energy metabolism and contribute to metabolic disease pathogenesis.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"64 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143427467","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}
Cell metabolismPub Date : 2025-02-17DOI: 10.1016/j.cmet.2025.01.024
Hans-Georg Sprenger, Melanie J. Mittenbühler, Yizhi Sun, Jonathan G. Van Vranken, Sebastian Schindler, Abhilash Jayaraj, Sumeet A. Khetarpal, Amanda L. Smythers, Ariana Vargas-Castillo, Anna M. Puszynska, Jessica B. Spinelli, Andrea Armani, Tenzin Kunchok, Birgitta Ryback, Hyuk-Soo Seo, Kijun Song, Luke Sebastian, Coby O’Young, Chelsea Braithwaite, Sirano Dhe-Paganon, Bruce M. Spiegelman
{"title":"Ergothioneine controls mitochondrial function and exercise performance via direct activation of MPST","authors":"Hans-Georg Sprenger, Melanie J. Mittenbühler, Yizhi Sun, Jonathan G. Van Vranken, Sebastian Schindler, Abhilash Jayaraj, Sumeet A. Khetarpal, Amanda L. Smythers, Ariana Vargas-Castillo, Anna M. Puszynska, Jessica B. Spinelli, Andrea Armani, Tenzin Kunchok, Birgitta Ryback, Hyuk-Soo Seo, Kijun Song, Luke Sebastian, Coby O’Young, Chelsea Braithwaite, Sirano Dhe-Paganon, Bruce M. Spiegelman","doi":"10.1016/j.cmet.2025.01.024","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.01.024","url":null,"abstract":"Ergothioneine (EGT) is a diet-derived, atypical amino acid that accumulates to high levels in human tissues. Reduced EGT levels have been linked to age-related disorders, including neurodegenerative and cardiovascular diseases, while EGT supplementation is protective in a broad range of disease and aging models. Despite these promising data, the direct and physiologically relevant molecular target of EGT has remained elusive. Here, we use a systematic approach to identify how mitochondria remodel their metabolome in response to exercise training. From these data, we find that EGT accumulates in muscle mitochondria upon exercise training. Proteome-wide thermal stability studies identify 3-mercaptopyruvate sulfurtransferase (MPST) as a direct molecular target of EGT; EGT binds to and activates MPST, thereby boosting mitochondrial respiration and exercise training performance in mice. Together, these data identify the first physiologically relevant EGT target and establish the EGT-MPST axis as a molecular mechanism for regulating mitochondrial function and exercise performance.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"10 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143427468","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}
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