Nature metabolism最新文献

{"title":"Redox-dependent pathways in the pro-thermogenic effects of cysteine restriction","authors":"Daniele Lettieri-Barbato, Katia Aquilano","doi":"10.1038/s42255-025-01384-w","DOIUrl":"https://doi.org/10.1038/s42255-025-01384-w","url":null,"abstract":"<p>In their recent article, Lee et al.¹ elegantly demonstrate that dietary cysteine restriction induces rapid weight loss and adipose tissue remodelling via a sympathetic nervous system pathway that is independent of UCP1. At the same time, Varghese et al.² report that the same dietary constraint ignites a robust thermogenic programme, with loss of fat mass and activation of the integrated stress response. Notably, circulating GDF15 and FGF21 amplify, but are not indispensable for, the phenotype, which persists — albeit attenuated — in <i>Gdf15</i> and <i>Fgf21</i>-knock-out mice. A marked fall in the cysteine-containing antioxidant glutathione (GSH) in liver and adipose tissue underscores redox imbalance as an early event. Together, the two studies highlight the translational potential of cysteine restriction as a weight loss intervention, yet leave open key questions on the redox mechanisms within adipocytes that couple cysteine availability to thermogenic output.</p><p>Depletion of GSH has been shown to reduce adiposity and is sufficient to improve insulin sensitivity as well as induce thermogenesis in adipocytes and in vivo^3,4,5. Our laboratory demonstrated that pharmacological inhibition of γ-glutamylcysteine ligase with buthionine sulfoximine lowers GSH, boosts mitochondrial reactive oxygen species (mtROS) and activates the redox-sensitive transcription factor FOXO1, thereby inducing <i>Ucp1</i> and <i>Ppargc1a</i> in adipocytes⁵. The gene program triggered in cultured adipocytes mirrors the in vivo response, demonstrating that adipocytes themselves are sufficient redox sensors independent of systemic inputs. These effects were reversed by cysteine supplementation, arguing that the local redox status of adipose tissue constitutes a gatekeeper for thermogenic activation.</p>","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"46 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145035107","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Harmonizing human plasma metabolite annotation with Plasma Benchmark","authors":"Ville Koistinen, Topi Meuronen, Pekka Keski-Rahkonen, Reza Salek, Otto Savolainen, Hany Ahmed, Carl Brunius, Rikard Landberg, Marko Lehtonen, Seppo Auriola, Augustin Scalbert, Kati Hanhineva","doi":"10.1038/s42255-025-01376-w","DOIUrl":"https://doi.org/10.1038/s42255-025-01376-w","url":null,"abstract":"<p>The human plasma metabolome has been extensively characterized: version 5.0 of the Human Metabolome Database (HMDB)¹ currently encompasses 37,229 entries for metabolites reported in human blood. Although the analytical coverage of modern LC–MS platforms enables the detection and identification of 1,000–2,000 plasma metabolites, the number of well-known and regularly detected plasma metabolites is considerably smaller: reference values of 144 plasma metabolites in a healthy population² and 588 lipids in the National Institute of Standards and Technology’s (NIST) reference plasma sample³ have been reported previously. The plasma metabolome also exhibits vast interindividual and intraindividual variability, which is explained by variation in the microbiome, dietary habits and genetics⁴. Challenges in consistently reporting the human plasma metabolome arise from interlaboratory variation in non-targeted LC–MS methodologies and varying practices and capabilities in the annotation of the metabolites themselves⁵.</p><p>To construct Plasma Benchmark, three participating laboratories analysed the same in-house pooled plasma and the NIST1950 human reference plasma⁶ in four analytical modes, including reversed-phase and hydrophilic interaction chromatography in the positive and negative ionization modes followed by data matrix generation in MS-DIAL⁷. We applied a set of inclusion criteria based on signal-to-noise ratio, relative standard deviation, sample-to-blank ratio, and acquisition of MS/MS data and predicted molecular formula to narrow the number of detected molecular features down to 639 robust molecular features that most probably represent actual plasma metabolites. Nearly 88% of the detected molecular features did not fulfil the signal-to-noise ratio and sample-to-blank ratio criteria, probably due to inherent noise and contaminants in LC–MS data but also because of high variability in the detection of many molecular features across laboratories⁸ (Fig. 1b). Manual curation of the robust molecular features resulted in 288 unique metabolites, whereas the rest of the molecular features were classified as redundant molecular features and in-source fragments. The inclusion of four analytical modes was crucial for an extensive coverage of metabolites because most were detected in only one mode (Fig. 1b).</p>","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"42 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145031906","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In vivo itaconate tracing reveals degradation pathway and turnover kinetics","authors":"Hanna F. Willenbockel,&nbsp;Alexander T. Williams,&nbsp;Alfredo Lucas,&nbsp;Mack B. Reynolds,&nbsp;Emeline Joulia,&nbsp;Maureen L. Ruchhoeft,&nbsp;Birte Dowerg,&nbsp;Pedro Cabrales,&nbsp;Christian M. Metallo,&nbsp;Thekla Cordes","doi":"10.1038/s42255-025-01363-1","DOIUrl":"10.1038/s42255-025-01363-1","url":null,"abstract":"Itaconate is an immunomodulatory metabolite that alters mitochondrial metabolism and immune cell function. This organic acid is endogenously synthesized by tricarboxylic acid (TCA) metabolism downstream of TLR signalling. Itaconate-based treatment strategies are under investigation to mitigate numerous inflammatory conditions. However, little is known about the turnover rate of itaconate in circulation, the kinetics of its degradation and the broader consequences on metabolism. By combining mass spectrometry and in vivo 13C itaconate tracing in male mice, we demonstrate that itaconate is rapidly eliminated from plasma, excreted via urine and fuels TCA cycle metabolism specifically in the liver and kidneys. Our results further reveal that itaconate is converted into acetyl-CoA, mesaconate and citramalate. Itaconate administration also influences branched-chain amino acid metabolism and succinate levels, indicating a functional impact on succinate dehydrogenase and methylmalonyl-CoA mutase activity in male rats and mice. Our findings uncover a previously unknown aspect of itaconate metabolism, highlighting its rapid catabolism in vivo that contrasts findings in cultured cells. In this study, Willenbockel et al. trace circulating itaconate in vivo to gain insight into its fate and systemic metabolism.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 9","pages":"1781-1790"},"PeriodicalIF":20.8,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s42255-025-01363-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145025747","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Common genetic variants modify disease risk and clinical presentation in monogenic diabetes","authors":"Jacques Murray Leech,&nbsp;Robin N. Beaumont,&nbsp;Ankit M. Arni,&nbsp;V. Kartik Chundru,&nbsp;Luke N. Sharp,&nbsp;Kevin Colclough,&nbsp;Andrew T. Hattersley,&nbsp;Michael N. Weedon,&nbsp;Kashyap A. Patel","doi":"10.1038/s42255-025-01372-0","DOIUrl":"10.1038/s42255-025-01372-0","url":null,"abstract":"Young-onset monogenic disorders often show variable penetrance, yet the underlying causes remain poorly understood. Uncovering these influences could reveal new biological mechanisms and enhance risk prediction for monogenic diseases. Here we show that polygenic background substantially shapes the clinical presentation of maturity-onset diabetes of the young (MODY), a common monogenic form of diabetes that typically presents in adolescence or early adulthood. We find strong enrichment of type 2 diabetes (T2D) polygenic risk, but not type 1 diabetes risk, in genetically confirmed MODY cases (n = 1,462). This T2D polygenic burden, primarily through beta-cell dysfunction pathways, is strongly associated with earlier age of diagnosis and increased diabetes severity. Common genetic variants collectively account for 24% (P &lt; 0.0001) of the phenotypic variability. Using a large population cohort (n = 424,553), we demonstrate that T2D polygenic burden substantially modifies diabetes onset in individuals with pathogenic variants, with diabetes risk ranging from 11% to 81%. Finally, we show that individuals with MODY-like phenotypes (n = 300) without a causal variant have elevated polygenic burden for T2D and related traits, representing potential polygenic phenocopies. These findings reveal substantial influence of common genetic variation in shaping the clinical presentation of early-onset monogenic disorders. Incorporating these may improve risk estimates for individuals carrying pathogenic variants. In clinical and population-based cohorts, a strong contribution of polygenic risk for type 2 diabetes (T2D) significantly modifies the onset and phenotypic variability of maturity-onset diabetes of the young (MODY). This polygenic T2D burden may also account for MODY-like individuals without identified monogenic causes.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 9","pages":"1819-1829"},"PeriodicalIF":20.8,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s42255-025-01372-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145018067","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cellular pan-chain acyl-CoA profiling reveals SLC25A42/SLC25A16 in mitochondrial CoA import and metabolism","authors":"Ran Liu,&nbsp;Zihan Zhang,&nbsp;Aye K. Kyaw,&nbsp;Kariona A. Grabińska,&nbsp;Hardik Shah,&nbsp;Hongying Shen","doi":"10.1038/s42255-025-01358-y","DOIUrl":"10.1038/s42255-025-01358-y","url":null,"abstract":"The essential cofactor coenzyme A (CoASH) and its thioester derivatives (acyl-CoAs) have pivotal roles in cellular metabolism. However, the mechanism by which different acyl-CoAs are accurately partitioned into different subcellular compartments to support site-specific reactions, and the physiological impact of such compartmentalization, remain poorly understood. Here, we report an optimized liquid chromatography–mass spectrometry-based pan-chain acyl-CoA extraction and profiling method that enables a robust detection of 33 cellular and 23 mitochondrial acyl-CoAs from cultured human cells. We reveal that SLC25A16 and SLC25A42 are critical for mitochondrial import of free CoASH. This CoASH import process supports an enriched mitochondrial CoA pool and CoA-dependent pathways in the matrix, including the high-flux TCA cycle and fatty acid oxidation. Despite a small fraction of the mitochondria-localized CoA synthase COASY, de novo CoA biosynthesis is primarily cytosolic and supports cytosolic lipid anabolism. This mitochondrial acyl-CoA compartmentalization enables a spatial regulation of anabolic and energy-related catabolic processes, which promises to shed light on pathophysiology in the inborn errors of CoA metabolism. By developing a method that allows detection of transient, low-abundance acyl-CoA species, Liu et al. provide a thorough characterization of coenzyme A dynamics and subcellular partitioning.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 9","pages":"1871-1888"},"PeriodicalIF":20.8,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s42255-025-01358-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145018068","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Polygenic determinants of monogenic diabetes","authors":"Rashmi B. Prasad,&nbsp;Tiinamaija Tuomi","doi":"10.1038/s42255-025-01380-0","DOIUrl":"10.1038/s42255-025-01380-0","url":null,"abstract":"In a new study, the polygenic background of type 2 diabetes (T2D) is found to determine the risk of diabetes associated with so-called monogenic forms of β-cell diabetes, as well as the age at onset and severity of diabetes.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 9","pages":"1723-1724"},"PeriodicalIF":20.8,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145018066","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An alternative route for β-hydroxybutyrate metabolism supports cytosolic acetyl-CoA synthesis in cancer cells","authors":"Faith C. Kaluba, Thomas J. Rogers, Yu-Jin Jeong, Rachel ‘Rae’ J. House, Althea Waldhart, Kelly H. Sokol, Samuel R. Daniels, Cameron J. Lee, Joseph Longo, Amy Johnson, Vincent J. Sartori, Ryan D. Sheldon, Russell G. Jones, Evan C. Lien","doi":"10.1038/s42255-025-01366-y","DOIUrl":"https://doi.org/10.1038/s42255-025-01366-y","url":null,"abstract":"<p>Cancer cells are exposed to diverse metabolites in the tumour microenvironment that are used to support the synthesis of nucleotides, amino acids and lipids needed for rapid cell proliferation. In some tumours, ketone bodies such as β-hydroxybutyrate (β-OHB), which are elevated in circulation under fasting conditions or low glycemic diets, can serve as an alternative fuel that is metabolized in the mitochondria to provide acetyl-CoA for the tricarboxylic acid (TCA) cycle. Here we identify a non-canonical route for β-OHB metabolism that bypasses the TCA cycle to generate cytosolic acetyl-CoA. We show that in cancer cells that can metabolize ketones, β-OHB-derived acetoacetate in the mitochondria can be shunted into the cytosol, where acetoacetyl-CoA synthetase (AACS) and thiolase convert it into cytosolic acetyl-CoA. This alternative metabolic routing allows β-OHB to avoid oxidation in the mitochondria and to be used as a major source of cytosolic acetyl-CoA, even when other key cytosolic acetyl-CoA precursors such as glucose are available in excess. Finally, we demonstrate that ketone body metabolism, including this alternative AACS-dependent route, can support the growth of mouse <i>Kras</i>^G12D; <i>Trp53</i>^−/− pancreatic tumours grown orthotopically in the pancreas of male mice, as well as the growth of mouse B16 melanoma tumours in male mice fed a calorie-restricted diet. Together, these data reveal how cancer cells use β-OHB as a major source of cytosolic acetyl-CoA to support cell proliferation and tumour growth.</p>","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 1","pages":""},"PeriodicalIF":20.8,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145009292","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ATF6 activation alters colonic lipid metabolism causing tumour-associated microbial adaptation","authors":"Olivia I. Coleman,&nbsp;Adam Sorbie,&nbsp;Alessandra Riva,&nbsp;Miriam von Stern,&nbsp;Stephanie Kuhls,&nbsp;Denise M. Selegato,&nbsp;Luisa Siegert,&nbsp;Isabel Keidel,&nbsp;Nikolai Köhler,&nbsp;Jakob Wirbel,&nbsp;Tim Kacprowski,&nbsp;Andreas Dunkel,&nbsp;Josch K. Pauling,&nbsp;Johannes Plagge,&nbsp;Diego Mediel-Cuadra,&nbsp;Sophia J. Wagner,&nbsp;Ines Chadly,&nbsp;Sandra Bierwith,&nbsp;Tingying Peng,&nbsp;Thomas Metzler,&nbsp;Xin Li,&nbsp;Mathias Heikenwälder,&nbsp;Clemens Schafmayer,&nbsp;Sebastian Hinz,&nbsp;Christian Röder,&nbsp;Christoph Röcken,&nbsp;Michael Zimmermann,&nbsp;Philip Rosenstiel,&nbsp;Katja Steiger,&nbsp;Moritz Jesinghaus,&nbsp;Gerhard Liebisch,&nbsp;Josef Ecker,&nbsp;Christina Schmidt,&nbsp;Georg Zeller,&nbsp;Klaus-Peter Janssen,&nbsp;Dirk Haller","doi":"10.1038/s42255-025-01350-6","DOIUrl":"10.1038/s42255-025-01350-6","url":null,"abstract":"Endoplasmic reticulum unfolded protein responses contribute to cancer development, with activating transcription factor 6 (ATF6) involved in microbiota-dependent tumorigenesis. Here we show the clinical relevance of ATF6 in individuals with early-onset and late colorectal cancer, and link ATF6 signalling to changes in lipid metabolism and intestinal microbiota. Transcriptional analysis in intestinal epithelial cells of ATF6 transgenic mice (nATF6IEC) identifies bacteria-specific changes in cellular metabolism enriched for fatty acid biosynthesis. Untargeted metabolomics and isotype labelling confirm ATF6-related enrichment of long-chain fatty acids in colonic tissue of humans, mice and organoids. FASN inhibition and microbiota transfer in germ-free nATF6IEC mice confirm the causal involvement of ATF6-induced lipid alterations in tumorigenesis. The selective expansion of tumour-relevant microbial taxa, including Desulfovibrio fairfieldensis, is mechanistically linked to long-chain fatty acid exposure using bioorthogonal non-canonical amino acid tagging, and growth analysis of Desulfovibrio isolates. We postulate chronic ATF6 signalling to select for tumour-promoting microbiota by altering lipid metabolism. The transcription factor ATF6 causes an enrichment in long-chain fatty acids in the colonic epithelium, which leads to changes in the gut microbiota and contributes to the development of colorectal cancer in humans and mice, thereby linking endoplasmic reticulum stress responses to lipid metabolism and tumorigenesis.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 9","pages":"1830-1850"},"PeriodicalIF":20.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s42255-025-01350-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144924214","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondria transfer","authors":"Navdeep S. Chandel,&nbsp;Marni J. Falk,&nbsp;Janine H. Santos,&nbsp;Jonathan R. Brestoff,&nbsp;Ana V. Lechuga-Vieco,&nbsp;Yasemin S. Sancak,&nbsp;Quan Chen,&nbsp;Alvaro A. Elorza,&nbsp;Rubén Quintana-Cabrera","doi":"10.1038/s42255-025-01364-0","DOIUrl":"10.1038/s42255-025-01364-0","url":null,"abstract":"Intercellular mitochondria transfer has recently attracted substantial attention, both from a fundamental and therapeutic point of view. At the same time, the topic continues to be met with scepticism. In this Viewpoint, different experts in mitochondrial biology share their personal view on the topic.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 9","pages":"1716-1719"},"PeriodicalIF":20.8,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144905910","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dual gains from targeting MondoA in T cells","authors":"Ermei Xie,&nbsp;Guideng Li","doi":"10.1038/s42255-025-01329-3","DOIUrl":"10.1038/s42255-025-01329-3","url":null,"abstract":"Lactic acid activates the MondoA–TXNIP pathway, dampening CD8⁺ T cell responses and boosting regulatory T cell function. Inhibiting MondoA revives antitumour immunity and amplifies the effects of anti-PD-1 treatment.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 9","pages":"1725-1727"},"PeriodicalIF":20.8,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144900204","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}