Cell metabolism最新文献

Machine-learning-guided discovery of SLC25A45 as a mediator of mitochondrial methylated amino acid import and carnitine synthesis 机器学习引导下发现SLC25A45作为线粒体甲基化氨基酸输入和肉毒碱合成的中介

IF 29 1区生物学

Cell metabolism Pub Date : 2025-10-10 DOI: 10.1016/j.cmet.2025.09.015

Artem Khan, Frederick S. Yen, Gokhan Unlu, Nicole L. DelGaudio, Ranya Erdal, Michael Xiao, Khando Wangdu, Kevin Cho, Eric R. Gamazon, Gary J. Patti, Kıvanç Birsoy

{"title":"Machine-learning-guided discovery of SLC25A45 as a mediator of mitochondrial methylated amino acid import and carnitine synthesis","authors":"Artem Khan, Frederick S. Yen, Gokhan Unlu, Nicole L. DelGaudio, Ranya Erdal, Michael Xiao, Khando Wangdu, Kevin Cho, Eric R. Gamazon, Gary J. Patti, Kıvanç Birsoy","doi":"10.1016/j.cmet.2025.09.015","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.09.015","url":null,"abstract":"Solute carriers (SLCs) regulate cellular and organismal metabolism by transporting small molecules and ions across membranes, yet the physiological substrates of ∼20% remain elusive. To address this, we developed a machine-learning platform to predict gene-metabolite associations. This approach identifies UNC93A and SLC45A4 as candidate plasma membrane transporters for acetylglucosamine and polyamines, respectively. Additionally, we uncover SLC25A45 as a mitochondrial transporter linked to serum levels of methylated basic amino acids, products of protein catabolism. Mechanistically, SLC25A45 is necessary for the mitochondrial import of methylated basic amino acids, including ADMA and TML, the latter serving as a precursor for carnitine synthesis. In line with this observation, SLC25A45 loss impairs carnitine synthesis and blunts upregulation of carnitine-containing metabolites under fasted conditions. By facilitating mitochondrial TML import, SLC25A45 connects protein catabolism to carnitine production, sustaining β-oxidation during fasting. Altogether, our study identifies putative substrates for three SLCs and provides a resource for transporter deorphanization.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"37 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145254946","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

Mitochondrial sodium-calcium exchange—Can TMEM65 do it alone? 线粒体钠钙交换——TMEM65能单独完成吗？

IF 29 1区生物学

Cell metabolism Pub Date : 2025-10-07 DOI: 10.1016/j.cmet.2025.09.005

Joanne F. Garbincius, John W. Elrod

引用次数: 0

An “electric” microbial cue to control food intake behavior 一种控制食物摄入行为的“电”微生物提示

IF 29 1区生物学

Cell metabolism Pub Date : 2025-10-07 DOI: 10.1016/j.cmet.2025.09.007

Huixian Li, Daniel Mucida

引用次数: 0

Imidazole propionate: Cause and cure in atherosclerosis? 丙酸咪唑：动脉粥样硬化的病因与治疗？

IF 29 1区生物学

Cell metabolism Pub Date : 2025-10-07 DOI: 10.1016/j.cmet.2025.08.006

Xiangqi Chen, Xiaoqiang Tang, Yanping Li, Jinhan He

引用次数: 0

AMPKα2 signals amino acid insufficiency to inhibit protein synthesis AMPKα2信号氨基酸不足，抑制蛋白质合成

IF 29 1区生物学

Cell metabolism Pub Date : 2025-10-07 DOI: 10.1016/j.cmet.2025.09.004

Yunzi Mao, Mei Cui, Yanfeng Jiang, Haowen Yu, Meng Wang, Gang Li, Haihui Zhang, Cheng Zhao, Yanxin Shen, Yupeng Hu, Yanpeng An, Yan Lin, Yiyuan Yuan, Pengcheng Lin, Xingdong Chen, Wei Xu, Shi-Min Zhao

{"title":"AMPKα2 signals amino acid insufficiency to inhibit protein synthesis","authors":"Yunzi Mao, Mei Cui, Yanfeng Jiang, Haowen Yu, Meng Wang, Gang Li, Haihui Zhang, Cheng Zhao, Yanxin Shen, Yupeng Hu, Yanpeng An, Yan Lin, Yiyuan Yuan, Pengcheng Lin, Xingdong Chen, Wei Xu, Shi-Min Zhao","doi":"10.1016/j.cmet.2025.09.004","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.09.004","url":null,"abstract":"The functional difference between the two catalytic subunits, α1 and α2, of AMP-activated protein kinase (AMPK) complexes remains elusive. Herein, we report that AMPKα2 specifically transduces amino acid insufficiency signals to protein synthesis. Low amino acid levels, high protein levels, and reduced phosphorylation of AMPKα threonine 172 (p-T172) are observed in blood samples in patients with Alzheimer’s disease (AD) from a cohort of 1,000,000 Chinese individuals. Loss of α2, but not α1, recaptures these observations and induces AD-like cognitive dysfunction in mice. Mechanistically, low amino acid-activated general control nonderepressible 2 (GCN2) specifically phosphorylates α2 at T172 independent of AMP and fructose 1,6-bisphosphate to inhibit protein synthesis. α2-p-T172 loss renders protein over-synthesis and AD-pathologic protein aggregation in cells and in mouse brain. AMPK activators metformin and 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR), as well as branched-chain amino acid (BCAA) or protein restriction, α2-p-T172-dependently prevent AD-like symptoms in mice. We identify AMPKα2 as a specific amino acid abundance detector for protein synthesis.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"128 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145241311","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

The energy resistance principle 能量阻力原理

IF 29 1区生物学

Cell metabolism Pub Date : 2025-10-06 DOI: 10.1016/j.cmet.2025.09.002

Martin Picard, Nirosha J. Murugan

引用次数: 0

Paternal exercise confers endurance capacity to offspring through sperm microRNAs 父亲的运动通过精子微rna赋予后代耐力

IF 29 1区生物学

Cell metabolism Pub Date : 2025-10-06 DOI: 10.1016/j.cmet.2025.09.003

Xin Yin, Azhar Anwar, Linbo Yan, Ranran Yu, Yang Luo, Liang Shi, Botao Li, Jiehao Chen, Gaoli Liang, Yongci Chen, Jie Tang, Jie Liang, Yansheng Kan, Zhihao Zhang, Xiahuan Zhou, Jizheng Ma, Chenbo Ji, Yanbo Wang, Qipeng Zhang, Jing Li, Xi Chen

{"title":"Paternal exercise confers endurance capacity to offspring through sperm microRNAs","authors":"Xin Yin, Azhar Anwar, Linbo Yan, Ranran Yu, Yang Luo, Liang Shi, Botao Li, Jiehao Chen, Gaoli Liang, Yongci Chen, Jie Tang, Jie Liang, Yansheng Kan, Zhihao Zhang, Xiahuan Zhou, Jizheng Ma, Chenbo Ji, Yanbo Wang, Qipeng Zhang, Jing Li, Xi Chen","doi":"10.1016/j.cmet.2025.09.003","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.09.003","url":null,"abstract":"Paternal exercise influences exercise capacity and metabolic health of offspring, but the underlying mechanisms remain poorly understood. We demonstrate that offspring sired by exercise-trained fathers display intrinsic exercise adaptations and improved metabolic parameters compared with those sired by sedentary fathers. Similarly, offspring born to transgenic mice with muscle-specific overexpression of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), a booster of mitochondrial function, exhibit improved endurance capacity and metabolic traits, even in the absence of the inherited PGC-1α transgene. Injecting sperm small RNAs from exercised fathers into normal zygotes recapitulates exercise-trained phenotypes in offspring at the behavioral, metabolic, and molecular levels. Mechanistically, exercise training and muscular PGC-1α overexpression remodel sperm microRNAs, which directly suppress nuclear receptor corepressor 1 (NCoR1), a functional antagonist of PGC-1α, in early embryos, thereby reprogramming transcriptional networks to promote mitochondrial biogenesis and oxidative metabolism. Overall, this study underscores a causal role for paternal PGC-1α, sperm microRNAs, and embryonic NCoR1 in transmitting exercise-induced phenotypes and metabolic adaptations to offspring.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"16 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145229363","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

Catenibacterium mitsuokai promotes hepatocellular carcinogenesis by binding to hepatocytes and generating quinolinic acid Catenibacterium mitsuokai通过与肝细胞结合并产生喹啉酸促进肝细胞癌变

IF 29 1区生物学

Cell metabolism Pub Date : 2025-09-25 DOI: 10.1016/j.cmet.2025.09.001

Ying Zhang, Weixin Liu, Chi Chun Wong, Qian Song, Xinyue Zhang, Qianying Zhou, Xuxin Ren, Xiaoxue Ren, Ruiyan Xuan, Yutong Zhao, Linfu Xu, Xiaoxing Li, Lixia Xu, Xiang Zhang, Ming Kuang, Jun Yu

{"title":"Catenibacterium mitsuokai promotes hepatocellular carcinogenesis by binding to hepatocytes and generating quinolinic acid","authors":"Ying Zhang, Weixin Liu, Chi Chun Wong, Qian Song, Xinyue Zhang, Qianying Zhou, Xuxin Ren, Xiaoxue Ren, Ruiyan Xuan, Yutong Zhao, Linfu Xu, Xiaoxing Li, Lixia Xu, Xiang Zhang, Ming Kuang, Jun Yu","doi":"10.1016/j.cmet.2025.09.001","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.09.001","url":null,"abstract":"The role of gut microbes in the pathogenesis of hepatocellular carcinoma (HCC) remains unclear. Here, we identified that Catenibacterium is enriched in both the feces and tumors of patients with HCC. C. mitsuokai accelerated HCC carcinogenesis in both conventional and germ-free mice. Furthermore, C. mitsuokai disrupted the gut barrier and translocated to the liver as live bacteria. Critically, the C. mitsuokai surface protein Gtr1/RagA interacts with the γ-catenin receptor on HCC cells, facilitating its attachment and colonization in the mouse liver. We further revealed that the pro-tumorigenic effect of C. mitsuokai depends on its secreted metabolite, quinolinic acid. Mechanistically, quinolinic acid binds to and activates the tyrosine kinase with immunoglobulin and epidermal growth factor homology domains 2 (TIE2) on HCC cells. Phosphorylated TIE2 subsequently activates the downstream oncogenic phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathway, thereby promoting HCC progression. In summary, C. mitsuokai disrupts the gut barrier, colonizes HCC cells via Gtr1/RagA-γ-catenin, and secretes quinolinic acid, which binds to TIE2 and drives the PI3K/AKT pathway to promote HCC development.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"73 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145134335","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

Liver-breast communication of adipocyte-oriented exosomes drives primary mammary cancer progression 脂肪细胞导向外泌体的肝-乳腺通讯驱动原发性乳腺癌的进展

IF 29 1区生物学

Cell metabolism Pub Date : 2025-09-24 DOI: 10.1016/j.cmet.2025.08.012

Chunni Li, Yiwen Lu, Yihong Li, Ting Liu, Hong Deng, Mingchao Gao, Boxuan Zhou, Jiayu Liu, Junchao Cai, Di Huang, Linbin Yang, Jin Jin, Dongming Kuang, Shicheng Su

{"title":"Liver-breast communication of adipocyte-oriented exosomes drives primary mammary cancer progression","authors":"Chunni Li, Yiwen Lu, Yihong Li, Ting Liu, Hong Deng, Mingchao Gao, Boxuan Zhou, Jiayu Liu, Junchao Cai, Di Huang, Linbin Yang, Jin Jin, Dongming Kuang, Shicheng Su","doi":"10.1016/j.cmet.2025.08.012","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.08.012","url":null,"abstract":"The incidence of certain types of extrahepatic cancers significantly increases in nonalcoholic fatty liver disease (NAFLD), the mechanisms of which are elusive. Here, we demonstrate that NAFLD is correlated with a higher risk of breast cancer in individuals with atypical hyperplasia and poor prognosis in patients with breast cancer. In mice, fatty liver exosomes are preferentially accumulated in adipocytes, and their enrichment in mammary adipocytes fosters a pro-tumor breast microenvironment. Adipocyte tropism is dictated by the binding of exosomal ErbB4 to neuregulin 4 (Nrg4). tRNA methyltransferase 10 homolog C (TRMT10C) in fatty liver exosomes translocates to mitochondria and inhibits Nd5 and Nd6 mRNA translation by inducing N1-methyladenosine modifications in adipocytes. ND5 and ND6 reduction increases reactive oxygen species and consequently enhances free fatty acid release, which fuels tumor progression. Plasma ErbB4+ exosomes are an independent prognostic factor for patients with breast cancer and comorbid NAFLD. Collectively, we reveal a liver-breast metabolic remote interaction that drives cancer development.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"59 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145127338","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

HEBP2-governed glutamine competition between tumor and macrophages dictates immunotherapy efficacy in triple-negative breast cancer hebp2调控的肿瘤和巨噬细胞之间的谷氨酰胺竞争决定了三阴性乳腺癌的免疫治疗效果

IF 29 1区生物学

Cell metabolism Pub Date : 2025-09-23 DOI: 10.1016/j.cmet.2025.08.009

Yi Xiao, Ying Xu, Han Wang, Fan Yang, Xiao-Hong Ding, Tong Fu, Li Chen, Xi Jin, Ya-Xin Zhao, Ying Wang, Fenfang Chen, Zhi-Ming Shao, Yi-Zhou Jiang

{"title":"HEBP2-governed glutamine competition between tumor and macrophages dictates immunotherapy efficacy in triple-negative breast cancer","authors":"Yi Xiao, Ying Xu, Han Wang, Fan Yang, Xiao-Hong Ding, Tong Fu, Li Chen, Xi Jin, Ya-Xin Zhao, Ying Wang, Fenfang Chen, Zhi-Ming Shao, Yi-Zhou Jiang","doi":"10.1016/j.cmet.2025.08.009","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.08.009","url":null,"abstract":"Immunotherapy demonstrates limited efficacy in triple-negative breast cancer (TNBC), influenced by intricate metabolic interactions within the tumor microenvironment. Here, we developed a single-cell RNA sequencing (scRNA-seq) immunotherapy cohort (N = 27) and a spatial transcriptomics cohort (N = 88) to elucidate metabolic crosstalk associated with therapeutic efficacy in TNBC. We illustrated that heme binding protein 2 (HEBP2)high tumor cells (featured by active glutathione metabolism) and CCL3+ macrophages (characterized by oxidative metabolism) indicated immunotherapy efficacy and were quantitatively and spatially negatively correlated. HEBP2-mediated glutamine face-off between these cell types induced this phenomenon. Mechanistically, HEBP2 disrupted FOXA1 cytoplasmic phase separation, promoting its nuclear translocation to upregulate glutathione S-transferase P1 (GSTP1) expression and glutamine consumption in tumor cells. This metabolic shift induced ferroptosis of CCL3+ macrophages, impairing the antitumor immunity. The utilization of a GSTP1 inhibitor sensitized TNBC to immunotherapy. Collectively, we delineate a tumor-macrophage metabolic checkpoint governed by the HEBP2/GSTP1 axis and pioneer single-cell-level immunometabolism as a paradigm for evaluating immunotherapeutic vulnerabilities.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"35 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145116504","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