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":"体内衣康酸示踪揭示了降解途径和转化动力学","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":null,"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":20.8000,"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":"0","resultStr":"{\"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\":null,\"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\":20.8000,\"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\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Nature metabolism\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.nature.com/articles/s42255-025-01363-1\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"ENDOCRINOLOGY & METABOLISM\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nature metabolism","FirstCategoryId":"3","ListUrlMain":"https://www.nature.com/articles/s42255-025-01363-1","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ENDOCRINOLOGY & METABOLISM","Score":null,"Total":0}
In vivo itaconate tracing reveals degradation pathway and turnover kinetics
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.
期刊介绍:
Nature Metabolism is a peer-reviewed scientific journal that covers a broad range of topics in metabolism research. It aims to advance the understanding of metabolic and homeostatic processes at a cellular and physiological level. The journal publishes research from various fields, including fundamental cell biology, basic biomedical and translational research, and integrative physiology. It focuses on how cellular metabolism affects cellular function, the physiology and homeostasis of organs and tissues, and the regulation of organismal energy homeostasis. It also investigates the molecular pathophysiology of metabolic diseases such as diabetes and obesity, as well as their treatment. Nature Metabolism follows the standards of other Nature-branded journals, with a dedicated team of professional editors, rigorous peer-review process, high standards of copy-editing and production, swift publication, and editorial independence. The journal has a high impact factor, has a certain influence in the international area, and is deeply concerned and cited by the majority of scholars.