Nature metabolismPub Date : 2025-09-16DOI: 10.1038/s42255-025-01352-4
Francesca Rizzollo, Abril Escamilla-Ayala, Nicola Fattorelli, Natalia Barbara Lysiak, Sanket More, Pablo Hernández Varas, Lucia Barazzuol, Chris Van den Haute, Joris Van Asselberghs, David Nittner, Jonathan Coene, Vivek Venkataramani, Bernhard Michalke, Christine Gaillet, Tatiana Cañeque, Irwin Davidson, Steven H. L. Verhelst, Peter Vangheluwe, Tito Calì, Jean-Christophe Marine, Raphaël Rodriguez, Julie Bonnereau, Patrizia Agostinis
{"title":"BDH2-driven lysosome-to-mitochondria iron transfer shapes ferroptosis vulnerability of the melanoma cell states","authors":"Francesca Rizzollo, Abril Escamilla-Ayala, Nicola Fattorelli, Natalia Barbara Lysiak, Sanket More, Pablo Hernández Varas, Lucia Barazzuol, Chris Van den Haute, Joris Van Asselberghs, David Nittner, Jonathan Coene, Vivek Venkataramani, Bernhard Michalke, Christine Gaillet, Tatiana Cañeque, Irwin Davidson, Steven H. L. Verhelst, Peter Vangheluwe, Tito Calì, Jean-Christophe Marine, Raphaël Rodriguez, Julie Bonnereau, Patrizia Agostinis","doi":"10.1038/s42255-025-01352-4","DOIUrl":"10.1038/s42255-025-01352-4","url":null,"abstract":"Iron sustains cancer cell plasticity, yet it also sensitizes the mesenchymal, drug-tolerant phenotype to ferroptosis. This posits that iron compartmentalization must be tightly regulated. However, the molecular machinery governing organelle Fe(II) compartmentalization remains elusive. Here, we show that BDH2 is a key effector of inter-organelle Fe(II) redistribution and ferroptosis vulnerability during melanoma transition from a melanocytic (MEL) to a mesenchymal-like (MES) phenotype. In MEL cells, BDH2 localizes at the mitochondria–lysosome contacts (MLCs) to generate the siderophore 2,5-dihydroxybenzoic acid (2,5-DHBA), which ferries iron into the mitochondria. Fe(II) transfer by BDH2 supports mitochondrial bioenergetics, which is required to maintain lysosomal acidification and MLC formation. Loss of BDH2 alters lysosomal pH and MLC tethering dynamics, causing lysosomal iron sequestration, which primes MES cells for ferroptosis. Rescuing BDH2 expression, or supplementing 2,5-DHBA, rectifies lysosomal pH and MLCs, protecting MES cells from ferroptosis and enhancing their ability to metastasize. Thus, we unveil a BDH2-dependent mechanism that orchestrates inter-organelle Fe(II) transfer, linking metabolic regulation of lysosomal pH to the ferroptosis vulnerability of the mesenchymal, drug-tolerant cancer cells. Rizzollo et al. show that BDH2 participates in iron distribution between cellular compartments, which sets the threshold for the ferroptosis vulnerability of the melanoma cell phenotypes, ultimately affecting their metastatic capacity","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 9","pages":"1851-1870"},"PeriodicalIF":20.8,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s42255-025-01352-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145067695","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}
Nature metabolismPub Date : 2025-09-16DOI: 10.1038/s42255-025-01377-9
Hailan Liu, Veronica L. Li, Qingzhuo Liu, Yao Liu, Cunjin Su, Hueyxian Wong, Na Yin, Hesong Liu, Xing Fang, Kristine M. McDermott, Hueyzhong Wong, Meng Yu, Longlong Tu, Jonathan C. Bean, Yongxiang Li, Mengjie Wang, Yue Deng, Yuhan Shi, Olivia Z. Ginnard, Yuxue Yang, Junying Han, Megan E. Burt, Sanika V. Jossy, Chunmei Wang, Yongjie Yang, Benjamin R. Arenkiel, Dong Kong, Yang He, Jonathan Z. Long, Yong Xu
{"title":"Lac-Phe induces hypophagia by inhibiting AgRP neurons in mice","authors":"Hailan Liu, Veronica L. Li, Qingzhuo Liu, Yao Liu, Cunjin Su, Hueyxian Wong, Na Yin, Hesong Liu, Xing Fang, Kristine M. McDermott, Hueyzhong Wong, Meng Yu, Longlong Tu, Jonathan C. Bean, Yongxiang Li, Mengjie Wang, Yue Deng, Yuhan Shi, Olivia Z. Ginnard, Yuxue Yang, Junying Han, Megan E. Burt, Sanika V. Jossy, Chunmei Wang, Yongjie Yang, Benjamin R. Arenkiel, Dong Kong, Yang He, Jonathan Z. Long, Yong Xu","doi":"10.1038/s42255-025-01377-9","DOIUrl":"10.1038/s42255-025-01377-9","url":null,"abstract":"N-Lactoyl-phenylalanine (Lac-Phe) is a lactate-derived circulating metabolite that reduces feeding and obesity, but the molecular mechanisms that underlie the metabolic benefits of Lac-Phe remain unknown. Here we show that Lac-Phe directly inhibits hypothalamic neurons that express Agouti-related protein (AgRP), resulting in an indirect activation of anorexigenic neurons in the paraventricular nucleus of the hypothalamus (PVH). Both AgRP inhibition and PVH activation are required to mediate Lac-Phe-induced hypophagia. Lac-Phe-mediated inhibition of AgRP neurons occurs through activation of the ATP-sensitive potassium (KATP) channel, whereas inhibition of the KATP channel blunts the effects of Lac-Phe to suppress feeding. Together, these results reveal the molecular and neurobiological mechanisms by which Lac-Phe mediates metabolic improvements and suggest this exercise-induced metabolite might have therapeutic benefits in various human diseases. This study reveals neuronal targets of Lac-Phe in the hypothalamus that mediate its suppression of food intake.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 10","pages":"2004-2017"},"PeriodicalIF":20.8,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145067694","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}
Nature metabolismPub Date : 2025-09-15DOI: 10.1038/s42255-025-01374-y
Hallie R. Wachsmuth, Frank A. Duca
{"title":"Small but mighty: inulin promotes small intestinal bacterial fructose feeding","authors":"Hallie R. Wachsmuth, Frank A. Duca","doi":"10.1038/s42255-025-01374-y","DOIUrl":"10.1038/s42255-025-01374-y","url":null,"abstract":"Although the gut microbiome contributes to the development of metabolic disease, beneficially altering the gut microbiome via increased fibre intake improves metabolic outcomes in rodents and humans. A new study by Jung et al. describes a novel mechanism by which the prebiotic fibre, inulin, can prevent and reverse hepatic steatosis via adaptations in the small intestinal microbiome.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 9","pages":"1720-1722"},"PeriodicalIF":20.8,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145059252","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}
Nature metabolismPub Date : 2025-09-15DOI: 10.1038/s42255-025-01356-0
Sunhee Jung, Hosung Bae, Won-Suk Song, Yujin Chun, Johnny Le, Yasmine Alam, Amandine Verlande, Sung Kook Chun, Joohwan Kim, Miranda E. Kelly, Miranda L. Lopez, Sang Hee Park, Daniel Onofre, Jongwon Baek, Ki-Hong Jang, Varvara I. Rubtsova, Alexis Anica, Selma Masri, Gina Lee, Cholsoon Jang
{"title":"Dietary fibre-adapted gut microbiome clears dietary fructose and reverses hepatic steatosis","authors":"Sunhee Jung, Hosung Bae, Won-Suk Song, Yujin Chun, Johnny Le, Yasmine Alam, Amandine Verlande, Sung Kook Chun, Joohwan Kim, Miranda E. Kelly, Miranda L. Lopez, Sang Hee Park, Daniel Onofre, Jongwon Baek, Ki-Hong Jang, Varvara I. Rubtsova, Alexis Anica, Selma Masri, Gina Lee, Cholsoon Jang","doi":"10.1038/s42255-025-01356-0","DOIUrl":"10.1038/s42255-025-01356-0","url":null,"abstract":"Excessive consumption of the simple sugar fructose, which induces excessive hepatic lipogenesis and gut dysbiosis, is a risk factor for cardiometabolic diseases. Here we show in male mice that the gut microbiome, when adapted to dietary fibre inulin, catabolizes dietary fructose and mitigates or reverses insulin resistance, hepatic steatosis and fibrosis. Specifically, inulin supplementation, without affecting the host’s small intestinal fructose catabolism, promotes the small intestinal microbiome to break down incoming fructose, thereby decreasing hepatic lipogenesis and fructose spillover to the colonic microbiome. Inulin also activates hepatic de novo serine synthesis and cystine uptake, augmenting glutathione production and protecting the liver from fructose-induced lipid peroxidation. These multi-modal effects of inulin are transmittable by the gut microbiome, where Bacteroides acidifaciens acts as a key player. Thus, the gut microbiome, adapted to use inulin (a fructose polymer), efficiently catabolizes dietary monomeric fructose, thereby protecting the host. These findings provide a mechanism for how fibre can facilitate the gut microbiome to mitigate the host’s exposure to harmful nutrients and disease progression. The dietary fibre inulin is shown to promote fructose catabolism by the small intestinal microbiome, thereby mitigating fructose-induced hepatic lipogenesis and steatosis.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 9","pages":"1801-1818"},"PeriodicalIF":20.8,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s42255-025-01356-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145059253","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}
Nature metabolismPub Date : 2025-09-12DOI: 10.1038/s42255-025-01385-9
{"title":"Nutritional advice on social media: clicks over credibility","authors":"","doi":"10.1038/s42255-025-01385-9","DOIUrl":"10.1038/s42255-025-01385-9","url":null,"abstract":"Social media has become a go-to source for nutritional advice, and a space in which influencers compete with, and often drown out, evidence-based guidance. The scientific community should counter this viral spread of misinformation by making trustworthy information more accessible.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 9","pages":"1715-1715"},"PeriodicalIF":20.8,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s42255-025-01385-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145035108","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}
Nature metabolismPub Date : 2025-09-12DOI: 10.1038/s42255-025-01384-w
Daniele Lettieri-Barbato, Katia Aquilano
{"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":"10.1038/s42255-025-01384-w","url":null,"abstract":"","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 10","pages":"1958-1959"},"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}
Nature metabolismPub Date : 2025-09-11DOI: 10.1038/s42255-025-01376-w
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
Nature metabolismPub Date : 2025-09-10DOI: 10.1038/s42255-025-01363-1
Hanna F. Willenbockel, Alexander T. Williams, Alfredo Lucas, Mack B. Reynolds, Emeline Joulia, Maureen L. Ruchhoeft, Birte Dowerg, Pedro Cabrales, Christian M. Metallo, Thekla Cordes
{"title":"In vivo itaconate tracing reveals degradation pathway and turnover kinetics","authors":"Hanna F. Willenbockel, Alexander T. Williams, Alfredo Lucas, Mack B. Reynolds, Emeline Joulia, Maureen L. Ruchhoeft, Birte Dowerg, Pedro Cabrales, Christian M. Metallo, 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}
Nature metabolismPub Date : 2025-09-09DOI: 10.1038/s42255-025-01372-0
Jacques Murray Leech, Robin N. Beaumont, Ankit M. Arni, V. Kartik Chundru, Luke N. Sharp, Kevin Colclough, Andrew T. Hattersley, Michael N. Weedon, Kashyap A. Patel
{"title":"Common genetic variants modify disease risk and clinical presentation in monogenic diabetes","authors":"Jacques Murray Leech, Robin N. Beaumont, Ankit M. Arni, V. Kartik Chundru, Luke N. Sharp, Kevin Colclough, Andrew T. Hattersley, Michael N. Weedon, 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 < 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}
Nature metabolismPub Date : 2025-09-09DOI: 10.1038/s42255-025-01358-y
Ran Liu, Zihan Zhang, Aye K. Kyaw, Kariona A. Grabińska, Hardik Shah, Hongying Shen
{"title":"Cellular pan-chain acyl-CoA profiling reveals SLC25A42/SLC25A16 in mitochondrial CoA import and metabolism","authors":"Ran Liu, Zihan Zhang, Aye K. Kyaw, Kariona A. Grabińska, Hardik Shah, 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}