Cell metabolismPub Date : 2025-02-01DOI: 10.1016/j.cmet.2025.01.023
Dunja Petrovic, Luke Slade, Yiorgos Paikopoulos, Davide D’Andrea, Nevena Savic, Ana Stancic, Jan Lj Miljkovic, Thibaut Vignane, Maria Kyriaki Drekolia, Dusan Mladenovic, Nikola Sutulovic, Alice Refeyton, Milica Kolakovic, Vladimir M. Jovanovic, Jasmina Zivanovic, Marko Miler, Valentina Vellecco, Vincenzo Brancaleone, Mariarosaria Bucci, Alva M. Casey, Milos R. Filipovic
{"title":"Ergothioneine improves healthspan of aged animals by enhancing cGPDH activity through CSE-dependent persulfidation","authors":"Dunja Petrovic, Luke Slade, Yiorgos Paikopoulos, Davide D’Andrea, Nevena Savic, Ana Stancic, Jan Lj Miljkovic, Thibaut Vignane, Maria Kyriaki Drekolia, Dusan Mladenovic, Nikola Sutulovic, Alice Refeyton, Milica Kolakovic, Vladimir M. Jovanovic, Jasmina Zivanovic, Marko Miler, Valentina Vellecco, Vincenzo Brancaleone, Mariarosaria Bucci, Alva M. Casey, Milos R. Filipovic","doi":"10.1016/j.cmet.2025.01.023","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.01.023","url":null,"abstract":"(Cell Metabolism <em>37</em>, 1–15.e1–e14; February 4, 2025)","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"25 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143072633","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 : 2025-01-31DOI: 10.1016/j.cmet.2024.12.004
Yanbo Zhang, Kai Luo, Brandilyn A. Peters, Yasmin Mossavar-Rahmani, Jee-Young Moon, Yi Wang, Martha L. Daviglus, Linda Van Horn, Amanda C. McClain, Christina Cordero, James S. Floyd, Bing Yu, Ryan W. Walker, Robert D. Burk, Robert C. Kaplan, Qibin Qi
{"title":"Sugar-sweetened beverage intake, gut microbiota, circulating metabolites, and diabetes risk in Hispanic Community Health Study/Study of Latinos","authors":"Yanbo Zhang, Kai Luo, Brandilyn A. Peters, Yasmin Mossavar-Rahmani, Jee-Young Moon, Yi Wang, Martha L. Daviglus, Linda Van Horn, Amanda C. McClain, Christina Cordero, James S. Floyd, Bing Yu, Ryan W. Walker, Robert D. Burk, Robert C. Kaplan, Qibin Qi","doi":"10.1016/j.cmet.2024.12.004","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.12.004","url":null,"abstract":"No population-based studies examined gut microbiota and related metabolites associated with sugar-sweetened beverage (SSB) intake among US adults. In this cohort of US Hispanic/Latino adults, higher SSB intake was associated with nine gut bacterial species, including lower abundances of several short-chain-fatty-acid producers, previously shown to be altered by fructose and glucose in animal studies, and higher abundances of fructose- and glucose-utilizing <em>Clostridium bolteae</em> and <em>Anaerostipes caccae</em>. Fifty-six serum metabolites were correlated with SSB intake and a gut microbiota score based on these SSB-related species in consistent directions. These metabolites were clustered into several modules, including a glycerophospholipid module, two modules comprising branched-chain amino acid (BCAA) and aromatic amino acid (AAA) derivatives from microbial metabolism, etc. Higher glycerophospholipid and BCAA derivative levels and lower AAA derivative levels were associated with higher incident diabetes risk during follow-up. These findings suggest a potential role of gut microbiota in the association between SSB intake and diabetes.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"60 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143072105","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 : 2025-01-30DOI: 10.1016/j.cmet.2024.12.009
Won Dong Lee, Daniel R. Weilandt, Lingfan Liang, Michael R. MacArthur, Natasha Jaiswal, Olivia Ong, Charlotte G. Mann, Qingwei Chu, Craig J. Hunter, Rolf-Peter Ryseck, Wenyun Lu, Anna M. Oschmann, Alexis J. Cowan, Tara A. TeSlaa, Caroline R. Bartman, Cholsoon Jang, Joseph A. Baur, Paul M. Titchenell, Joshua D. Rabinowitz
{"title":"Lactate homeostasis is maintained through regulation of glycolysis and lipolysis","authors":"Won Dong Lee, Daniel R. Weilandt, Lingfan Liang, Michael R. MacArthur, Natasha Jaiswal, Olivia Ong, Charlotte G. Mann, Qingwei Chu, Craig J. Hunter, Rolf-Peter Ryseck, Wenyun Lu, Anna M. Oschmann, Alexis J. Cowan, Tara A. TeSlaa, Caroline R. Bartman, Cholsoon Jang, Joseph A. Baur, Paul M. Titchenell, Joshua D. Rabinowitz","doi":"10.1016/j.cmet.2024.12.009","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.12.009","url":null,"abstract":"Lactate is among the highest flux circulating metabolites. It is made by glycolysis and cleared by both tricarboxylic acid (TCA) cycle oxidation and gluconeogenesis. Severe lactate elevations are life-threatening, and modest elevations predict future diabetes. How lactate homeostasis is maintained, however, remains poorly understood. Here, we identify, in mice, homeostatic circuits regulating lactate production and consumption. Insulin induces lactate production by upregulating glycolysis. We find that hyperlactatemia inhibits insulin-induced glycolysis, thereby suppressing excess lactate production. Unexpectedly, insulin also promotes lactate TCA cycle oxidation. The mechanism involves lowering circulating fatty acids, which compete with lactate for mitochondrial oxidation. Similarly, lactate can promote its own consumption by lowering circulating fatty acids via the adipocyte-expressed G-protein-coupled receptor hydroxycarboxylic acid receptor 1 (HCAR1). Quantitative modeling suggests that these mechanisms suffice to produce lactate homeostasis, with robustness to noise and perturbation of individual regulatory mechanisms. Thus, through regulation of glycolysis and lipolysis, lactate homeostasis is maintained.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"84 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143071940","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 : 2025-01-28DOI: 10.1016/j.cmet.2024.12.007
Andrew T. Frisch, Yiyang Wang, Bingxian Xie, Aaron Yang, B. Rhodes Ford, Supriya Joshi, Katarzyna M. Kedziora, Ronal Peralta, Drew Wilfahrt, Steven J. Mullett, Kellie Spahr, Konstantinos Lontos, Jessica A. Jana, Victoria G. Dean, William G. Gunn, Stacy Gelhaus, Amanda C. Poholek, Dayana B. Rivadeneira, Greg M. Delgoffe
{"title":"Redirecting glucose flux during in vitro expansion generates epigenetically and metabolically superior T cells for cancer immunotherapy","authors":"Andrew T. Frisch, Yiyang Wang, Bingxian Xie, Aaron Yang, B. Rhodes Ford, Supriya Joshi, Katarzyna M. Kedziora, Ronal Peralta, Drew Wilfahrt, Steven J. Mullett, Kellie Spahr, Konstantinos Lontos, Jessica A. Jana, Victoria G. Dean, William G. Gunn, Stacy Gelhaus, Amanda C. Poholek, Dayana B. Rivadeneira, Greg M. Delgoffe","doi":"10.1016/j.cmet.2024.12.007","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.12.007","url":null,"abstract":"Cellular therapies are living drugs whose efficacy depends on persistence and survival. Expansion of therapeutic T cells employs hypermetabolic culture conditions to promote T cell expansion. We show that typical <em>in vitro</em> expansion conditions generate metabolically and functionally impaired T cells more reliant on aerobic glycolysis than those expanding <em>in vivo</em>. We used dichloroacetate (DCA) to modulate glycolytic metabolism during expansion, resulting in elevated mitochondrial capacity, stemness, and improved antitumor efficacy in murine T cell receptor (TCR)-Tg and human CAR-T cells. DCA-conditioned T cells surprisingly show no elevated intratumoral effector function but rather have improved engraftment. DCA conditioning decreases reliance on glucose, promoting usage of serum-prevalent physiologic carbon sources. Further, DCA conditioning promotes metabolic flux from mitochondria to chromatin, resulting in increased histone acetylation at key longevity genes. Thus, hyperglycemic culture conditions promote expansion at the expense of metabolic flexibility and suggest pharmacologic metabolic rewiring as a beneficial strategy for improvement of cellular immunotherapies.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"40 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143049939","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 : 2025-01-28DOI: 10.1016/j.cmet.2024.12.005
Ya Liu, Rui Zhou, Yifan Guo, Biao Hu, Lingqi Xie, Yuze An, Jie Wen, Zheyu Liu, Min Zhou, Weihong Kuang, Yao Xiao, Min Wang, Genqing Xie, Haiyan Zhou, Renbin Lu, Hui Peng, Yan Huang
{"title":"Muscle-derived small extracellular vesicles induce liver fibrosis during overtraining","authors":"Ya Liu, Rui Zhou, Yifan Guo, Biao Hu, Lingqi Xie, Yuze An, Jie Wen, Zheyu Liu, Min Zhou, Weihong Kuang, Yao Xiao, Min Wang, Genqing Xie, Haiyan Zhou, Renbin Lu, Hui Peng, Yan Huang","doi":"10.1016/j.cmet.2024.12.005","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.12.005","url":null,"abstract":"The benefits of exercise for metabolic health occur in a dose-dependent manner. However, the adverse effects of overtraining and their underlying mechanisms remain unclear. Here, we show that overtraining induces hepatic fibrosis. Mechanistically, we find that excessive lactate accumulation in skeletal muscle leads to the lactylation of SH3 domain-containing 3 (SORBS3), triggering its liquid-liquid phase separation (LLPS). LLPS of SORBS3 enhances its interaction with flotillin 1 and selectively facilitates the sorting of F-box protein 2 (FBXO2) into small extracellular vesicles, referred to as “lactate bodies.” Lactate bodies induce hepatocyte apoptosis followed by hepatic stellate cell activation via myeloid cell leukemia sequence 1 (MCL1)-BAX/BAK signaling. Inhibition of SORBS3 lactylation or FBXO2 disrupts lactate bodies formation and alleviates overtraining-triggered liver fibrosis. Likewise, reduction of muscle lactate bodies formation by salidroside attenuates overtraining-induced liver fibrosis. Collectively, we identify a process by which overtraining induces hepatic fibrosis, highlighting a potential therapeutic target for liver health.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"8 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143049940","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":"Akkermansia muciniphila supplementation in patients with overweight/obese type 2 diabetes: Efficacy depends on its baseline levels in the gut","authors":"Yifei Zhang, Ruixin Liu, Yufei Chen, Zhiwen Cao, Cong Liu, Riqiang Bao, Yufan Wang, Shan Huang, Shijia Pan, Li Qin, Jiqiu Wang, Guang Ning, Weiqing Wang","doi":"10.1016/j.cmet.2024.12.010","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.12.010","url":null,"abstract":"<em>Akkermansia muciniphila</em> is a promising target for managing obesity and type 2 diabetes (T2D), but human studies are limited. We conducted a 12-week randomized, double-blind, placebo-controlled trial involving 58 participants with overweight or obese T2D, who received <em>A. muciniphila</em> (AKK-WST01) or placebo, along with routine lifestyle guidance. Both groups showed decreases in body weight and glycated hemoglobin (HbA1c), without significant between-group differences. In participants with low baseline <em>A. muciniphila</em>, AKK-WST01 supplementation showed high colonization efficiency and significant reductions in body weight, fat mass, and HbA1c, which were not found in the placebo group. However, AKK-WST01 supplementation showed poor colonization and no significant clinical improvements in participants with high baseline <em>A. muciniphila</em>. These findings were verified in germ-free mice receiving feces with low or high <em>A. muciniphila</em>. Our study indicates that metabolic benefits of <em>A. muciniphila</em> supplementation could depend on its baseline intestinal levels, supporting the potential for gut microbiota-guided probiotic supplementation. (<span><span>ClinicalTrials.gov</span><svg aria-label=\"Opens in new window\" focusable=\"false\" height=\"20\" viewbox=\"0 0 8 8\"><path d=\"M1.12949 2.1072V1H7V6.85795H5.89111V2.90281L0.784057 8L0 7.21635L5.11902 2.1072H1.12949Z\"></path></svg></span> number, NCT04797442).","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"19 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143049938","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 : 2025-01-21DOI: 10.1016/j.cmet.2024.12.008
Dunja Petrovic, Luke Slade, Yiorgos Paikopoulos, Davide D’Andrea, Nevena Savic, Ana Stancic, Jan Lj Miljkovic, Thibaut Vignane, Maria Kyriaki Drekolia, Dusan Mladenovic, Nikola Sutulovic, Alice Refeyton, Milica Kolakovic, Vladimir M. Jovanovic, Jasmina Zivanovic, Marko Miler, Valentina Vellecco, Vincenzo Brancaleone, Mariarosaria Bucci, Alva M. Casey, Milos R. Filipovic
{"title":"Ergothioneine improves healthspan of aged animals by enhancing cGPDH activity through CSE-dependent persulfidation","authors":"Dunja Petrovic, Luke Slade, Yiorgos Paikopoulos, Davide D’Andrea, Nevena Savic, Ana Stancic, Jan Lj Miljkovic, Thibaut Vignane, Maria Kyriaki Drekolia, Dusan Mladenovic, Nikola Sutulovic, Alice Refeyton, Milica Kolakovic, Vladimir M. Jovanovic, Jasmina Zivanovic, Marko Miler, Valentina Vellecco, Vincenzo Brancaleone, Mariarosaria Bucci, Alva M. Casey, Milos R. Filipovic","doi":"10.1016/j.cmet.2024.12.008","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.12.008","url":null,"abstract":"Ergothioneine (ET), a dietary thione/thiol, is receiving growing attention for its possible benefits in healthy aging and metabolic resilience. Our study investigates ET’s effects on healthspan in aged animals, revealing lifespan extension and enhanced mobility in <em>Caenorhabditis elegans</em>, accompanied by improved stress resistance and reduced age-associated biomarkers. In aged rats, ET administration enhances exercise endurance, muscle mass, and vascularization, concomitant with higher NAD<sup>+</sup> levels in muscle. Mechanistically, ET acts as an alternative substrate for cystathionine gamma-lyase (CSE), stimulating H<sub>2</sub>S production, which increases protein persulfidation of more than 300 protein targets. Among these, protein-persulfidation-driven activation of cytosolic glycerol-3-phosphate dehydrogenase (cGPDH) primarily contributes to the ET-induced NAD<sup>+</sup> increase. ET’s effects are abolished in models lacking CSE or cGPDH, highlighting the essential role of H<sub>2</sub>S signaling and protein persulfidation. These findings elucidate ET’s multifaceted actions and provide insights into its therapeutic potential for combating age-related muscle decline and metabolic perturbations.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"12 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142991967","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 : 2025-01-17DOI: 10.1016/j.cmet.2024.12.014
Jingwei Ma, Shuai Tong, Jingxuan Xiao, Bo Huang
{"title":"Mannose: A game-changer for T cell immunotherapy","authors":"Jingwei Ma, Shuai Tong, Jingxuan Xiao, Bo Huang","doi":"10.1016/j.cmet.2024.12.014","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.12.014","url":null,"abstract":"Metabolism influences the behavior of various immune cell types. In a recent <em>Cancer Cell</em> study, Qiu et al. revealed mannose metabolism as a prominent metabolic feature of tumor precursor exhausted T cells (Tpex) that is crucial for maintaining T cell stemness. Their work uncovers a novel metabolic mechanism that decouples T cell proliferation from differentiation, providing valuable insights into how metabolic modulation can be used to generate “better” T cells during the manufacturing process.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"10 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142987466","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 : 2025-01-15DOI: 10.1016/j.cmet.2024.11.013
Youkun Bi, Xinlong Qiao, Zhaokui Cai, Hailian Zhao, Rong Ye, Qun Liu, Lin Gao, Yingqi Liu, Bo Liang, Yixuan Liu, Yaning Zhang, Zhiguang Yang, Yanyun Wu, Huiwen Wang, Wei Jia, Changqing Zeng, Ce Jia, Hongjin Wu, Yuanchao Xue, Guangju Ji
{"title":"Exosomal miR-302b rejuvenates aging mice by reversing the proliferative arrest of senescent cells","authors":"Youkun Bi, Xinlong Qiao, Zhaokui Cai, Hailian Zhao, Rong Ye, Qun Liu, Lin Gao, Yingqi Liu, Bo Liang, Yixuan Liu, Yaning Zhang, Zhiguang Yang, Yanyun Wu, Huiwen Wang, Wei Jia, Changqing Zeng, Ce Jia, Hongjin Wu, Yuanchao Xue, Guangju Ji","doi":"10.1016/j.cmet.2024.11.013","DOIUrl":"https://doi.org/10.1016/j.cmet.2024.11.013","url":null,"abstract":"Cellular senescence, a hallmark of aging, involves a stable exit from the cell cycle. Senescent cells (SnCs) are closely associated with aging and aging-related disorders, making them potential targets for anti-aging interventions. In this study, we demonstrated that human embryonic stem cell-derived exosomes (hESC-Exos) reversed senescence by restoring the proliferative capacity of SnCs <em>in vitro</em>. In aging mice, hESC-Exos treatment remodeled the proliferative landscape of SnCs, leading to rejuvenation, as evidenced by extended lifespan, improved physical performance, and reduced aging markers. Ago2 Clip-seq analysis identified miR-302b enriched in hESC-Exos that specifically targeted the cell cycle inhibitors <em>Cdkn1a</em> and <em>Ccng2</em>. Furthermore, miR-302b treatment reversed the proliferative arrest of SnCs <em>in vivo</em>, resulting in rejuvenation without safety concerns over a 24-month observation period. These findings demonstrate that exosomal miR-302b has the potential to reverse cellular senescence, offering a promising approach to mitigate senescence-related pathologies and aging.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"36 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142981361","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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