Pub Date : 2025-11-14DOI: 10.1038/s42255-025-01399-3
Vinod Tiwari, Byungchang Jin, Olivia Sun, Edwin D. J. Lopez Gonzalez, Min-Hsuan Chen, Xiwei Wu, Hardik Shah, Andrew Zhang, Mark A. Herman, Cassandra N. Spracklen, Russell P. Goodman, Charles Brenner
Citrin deficiency (CD) is caused by the inactivation of SLC25A13, a mitochondrial membrane protein required to move electrons from cytosolic NADH to the mitochondrial matrix in hepatocytes. People with CD do not like sweets. Here we show that SLC25A13 loss causes the accumulation of glycerol-3-phosphate (G3P), which activates the carbohydrate response element-binding protein (ChREBP) to transcribe FGF21, which acts in the brain to restrain intake of sweets and alcohol and to transcribe key genes driving lipogenesis. Mouse and human data suggest that G3P–ChREBP is a mechanistic component of the Randle Cycle that contributes to metabolic-dysfunction-associated steatotic liver disease and forms part of a system that communicates metabolic states from the liver to the brain in a manner that alters food and alcohol choices. The data provide a framework for understanding FGF21 induction in varied conditions, suggest ways to develop FGF21-inducing drugs and suggest potential drug candidates for lean metabolic-dysfunction-associated steatotic liver disease and support of urea cycle function in CD. In a mouse model of the rare disease citrin deficiency, the authors discovered that the accumulation of glycerol-3-phosphate leads to ChREBP activation and FGF21 induction. The study identifies glycerol-3-phosphate as a ChREBP-activating ligand, which could resolve paradoxes of FGF21 expression and clarify the logic of lipogenic transcription.
{"title":"Glycerol-3-phosphate activates ChREBP, FGF21 transcription and lipogenesis in citrin deficiency","authors":"Vinod Tiwari, Byungchang Jin, Olivia Sun, Edwin D. J. Lopez Gonzalez, Min-Hsuan Chen, Xiwei Wu, Hardik Shah, Andrew Zhang, Mark A. Herman, Cassandra N. Spracklen, Russell P. Goodman, Charles Brenner","doi":"10.1038/s42255-025-01399-3","DOIUrl":"10.1038/s42255-025-01399-3","url":null,"abstract":"Citrin deficiency (CD) is caused by the inactivation of SLC25A13, a mitochondrial membrane protein required to move electrons from cytosolic NADH to the mitochondrial matrix in hepatocytes. People with CD do not like sweets. Here we show that SLC25A13 loss causes the accumulation of glycerol-3-phosphate (G3P), which activates the carbohydrate response element-binding protein (ChREBP) to transcribe FGF21, which acts in the brain to restrain intake of sweets and alcohol and to transcribe key genes driving lipogenesis. Mouse and human data suggest that G3P–ChREBP is a mechanistic component of the Randle Cycle that contributes to metabolic-dysfunction-associated steatotic liver disease and forms part of a system that communicates metabolic states from the liver to the brain in a manner that alters food and alcohol choices. The data provide a framework for understanding FGF21 induction in varied conditions, suggest ways to develop FGF21-inducing drugs and suggest potential drug candidates for lean metabolic-dysfunction-associated steatotic liver disease and support of urea cycle function in CD. In a mouse model of the rare disease citrin deficiency, the authors discovered that the accumulation of glycerol-3-phosphate leads to ChREBP activation and FGF21 induction. The study identifies glycerol-3-phosphate as a ChREBP-activating ligand, which could resolve paradoxes of FGF21 expression and clarify the logic of lipogenic transcription.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 11","pages":"2284-2299"},"PeriodicalIF":20.8,"publicationDate":"2025-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s42255-025-01399-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145509020","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}
Pub Date : 2025-11-13DOI: 10.1038/s42255-025-01419-2
Abigail Strefeler, Zakery N. Baker, Sylvain Chollet, Mads M. Foged, Rachel M. Guerra, Julijana Ivanisevic, Hector Gallart-Ayala, David J. Pagliarini, Alexis A. Jourdain
Rapidly proliferating cells require large amounts of nucleotides, making nucleotide metabolism a widely exploited therapeutic target against cancer, autoinflammatory disorders and viral infections. However, regulation of nucleotide metabolism remains incompletely understood. Here, we reveal regulators of de novo pyrimidine synthesis. Using uridine-sensitized CRISPR-Cas9 screening, we show that coenzyme Q (CoQ) is dispensable for pyrimidine synthesis, in the presence of the demethoxy-CoQ intermediate as alternative electron acceptor. We further report that the ADP-ribose pyrophosphatase NUDT5 directly binds PPAT, the rate-limiting enzyme in purine synthesis, which inhibits its activity and preserves the phosphoribosyl pyrophosphate (PRPP) pool. In the absence of NUDT5, hyperactive purine synthesis exhausts the PRPP pool at the expense of pyrimidine synthesis, which promotes resistance to purine and pyrimidine nucleobase analogues. Of note, the interaction between NUDT5 and PPAT is disrupted by PRPP, highlighting an intricate allosteric regulation. Overall, our findings reveal a fundamental mechanism of nucleotide balance and position NUDT5 as a regulator of nucleobase analogue metabolism. A uridine-sensitized CRISPR-Cas9 screening identifies demethoxy-CoQ as an alternative electron acceptor in the absence of CoQ, and NUDT5 as a regulator of de novo pyrimidine synthesis via its interaction with PPAT.
{"title":"Uridine-sensitized screening identifies demethoxy-coenzyme Q and NUDT5 as regulators of nucleotide synthesis","authors":"Abigail Strefeler, Zakery N. Baker, Sylvain Chollet, Mads M. Foged, Rachel M. Guerra, Julijana Ivanisevic, Hector Gallart-Ayala, David J. Pagliarini, Alexis A. Jourdain","doi":"10.1038/s42255-025-01419-2","DOIUrl":"10.1038/s42255-025-01419-2","url":null,"abstract":"Rapidly proliferating cells require large amounts of nucleotides, making nucleotide metabolism a widely exploited therapeutic target against cancer, autoinflammatory disorders and viral infections. However, regulation of nucleotide metabolism remains incompletely understood. Here, we reveal regulators of de novo pyrimidine synthesis. Using uridine-sensitized CRISPR-Cas9 screening, we show that coenzyme Q (CoQ) is dispensable for pyrimidine synthesis, in the presence of the demethoxy-CoQ intermediate as alternative electron acceptor. We further report that the ADP-ribose pyrophosphatase NUDT5 directly binds PPAT, the rate-limiting enzyme in purine synthesis, which inhibits its activity and preserves the phosphoribosyl pyrophosphate (PRPP) pool. In the absence of NUDT5, hyperactive purine synthesis exhausts the PRPP pool at the expense of pyrimidine synthesis, which promotes resistance to purine and pyrimidine nucleobase analogues. Of note, the interaction between NUDT5 and PPAT is disrupted by PRPP, highlighting an intricate allosteric regulation. Overall, our findings reveal a fundamental mechanism of nucleotide balance and position NUDT5 as a regulator of nucleobase analogue metabolism. A uridine-sensitized CRISPR-Cas9 screening identifies demethoxy-CoQ as an alternative electron acceptor in the absence of CoQ, and NUDT5 as a regulator of de novo pyrimidine synthesis via its interaction with PPAT.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 11","pages":"2221-2235"},"PeriodicalIF":20.8,"publicationDate":"2025-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s42255-025-01419-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145498181","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}
Pub Date : 2025-11-12DOI: 10.1038/s42255-025-01397-5
Elia Angelino, Lorenza Bodo, Roberta Sartori, Valeria Malacarne, Beatrice D’Anna, Nicolò Formaggio, Suvham Barua, Tommaso Raiteri, Andrea Lauria, Simone Reano, Alessandra Murabito, Monica Nicolau, Fabiana Ferrero, Camilla Pezzini, Giulia Rossino, Francesco Favero, Michele Valmasoni, Nicoletta Filigheddu, Alessio Menga, Davide Corà, Emilio Hirsch, Salvatore Oliviero, Vittorio Sartorelli, Valentina Proserpio, Alessandra Ghigo, Marco Sandri, Paolo E. Porporato, Daniela Talarico, Giuseppina Caretti, Andrea Graziani
Skeletal muscle wasting is a defining feature of cancer cachexia, a multifactorial syndrome that drastically compromises patient quality of life and treatment outcomes. Mitochondrial dysfunction is a major contributor to skeletal muscle wasting in cancer cachexia, yet the upstream molecular drivers remain elusive. Here we show that cancer impairs the activity of cAMP-dependent protein kinase A (PKA) and of its transcriptional effector CREB1 in skeletal muscle, ultimately contributing to the downregulation of a core transcriptional network that supports mitochondrial integrity and function. The restoration of cAMP–PKA–CREB1 signalling through pharmacological inhibition of the cAMP-hydrolysing phosphodiesterase 4 (PDE4) rescues the expression of mitochondrial-related genes, improves mitochondrial function and mitigates skeletal muscle wasting in male mice. Altogether, our data identify tumour-induced suppression of the cAMP–PKA–CREB1 axis as a central mechanism contributing to mitochondrial dysfunction in skeletal muscle during cancer cachexia. Furthermore, these findings highlight PDE4, particularly the PDE4D isoform, as a potential therapeutic target to preserve muscle mitochondrial function and counteract muscle wasting in cancer cachexia. Tumour-induced dysregulation of cAMP–PKA–CREB1 signalling in skeletal muscle is shown to be a driver of mitochondrial dysfunction, contributing to cancer cachexia in mice.
{"title":"Impaired cAMP–PKA–CREB1 signalling drives mitochondrial dysfunction in skeletal muscle during cancer cachexia","authors":"Elia Angelino, Lorenza Bodo, Roberta Sartori, Valeria Malacarne, Beatrice D’Anna, Nicolò Formaggio, Suvham Barua, Tommaso Raiteri, Andrea Lauria, Simone Reano, Alessandra Murabito, Monica Nicolau, Fabiana Ferrero, Camilla Pezzini, Giulia Rossino, Francesco Favero, Michele Valmasoni, Nicoletta Filigheddu, Alessio Menga, Davide Corà, Emilio Hirsch, Salvatore Oliviero, Vittorio Sartorelli, Valentina Proserpio, Alessandra Ghigo, Marco Sandri, Paolo E. Porporato, Daniela Talarico, Giuseppina Caretti, Andrea Graziani","doi":"10.1038/s42255-025-01397-5","DOIUrl":"10.1038/s42255-025-01397-5","url":null,"abstract":"Skeletal muscle wasting is a defining feature of cancer cachexia, a multifactorial syndrome that drastically compromises patient quality of life and treatment outcomes. Mitochondrial dysfunction is a major contributor to skeletal muscle wasting in cancer cachexia, yet the upstream molecular drivers remain elusive. Here we show that cancer impairs the activity of cAMP-dependent protein kinase A (PKA) and of its transcriptional effector CREB1 in skeletal muscle, ultimately contributing to the downregulation of a core transcriptional network that supports mitochondrial integrity and function. The restoration of cAMP–PKA–CREB1 signalling through pharmacological inhibition of the cAMP-hydrolysing phosphodiesterase 4 (PDE4) rescues the expression of mitochondrial-related genes, improves mitochondrial function and mitigates skeletal muscle wasting in male mice. Altogether, our data identify tumour-induced suppression of the cAMP–PKA–CREB1 axis as a central mechanism contributing to mitochondrial dysfunction in skeletal muscle during cancer cachexia. Furthermore, these findings highlight PDE4, particularly the PDE4D isoform, as a potential therapeutic target to preserve muscle mitochondrial function and counteract muscle wasting in cancer cachexia. Tumour-induced dysregulation of cAMP–PKA–CREB1 signalling in skeletal muscle is shown to be a driver of mitochondrial dysfunction, contributing to cancer cachexia in mice.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 12","pages":"2548-2570"},"PeriodicalIF":20.8,"publicationDate":"2025-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s42255-025-01397-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145492615","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}
Pub Date : 2025-11-12DOI: 10.1038/s42255-025-01417-4
Honglei Ji, Maria Rohm
The question of why muscle wasting persists in cancer cachexia despite adequate nutrition has long since intrigued researchers. Here, the authors identify PDE4D-mediated suppression of cAMP–PKA–CREB1 signalling as a driver of mitochondrial dysfunction and show that PDE4D inhibition preserves muscle bioenergetics and mass in cancer cachexia.
{"title":"Reawakening cAMP signalling in cancer cachexia","authors":"Honglei Ji, Maria Rohm","doi":"10.1038/s42255-025-01417-4","DOIUrl":"10.1038/s42255-025-01417-4","url":null,"abstract":"The question of why muscle wasting persists in cancer cachexia despite adequate nutrition has long since intrigued researchers. Here, the authors identify PDE4D-mediated suppression of cAMP–PKA–CREB1 signalling as a driver of mitochondrial dysfunction and show that PDE4D inhibition preserves muscle bioenergetics and mass in cancer cachexia.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 12","pages":"2388-2389"},"PeriodicalIF":20.8,"publicationDate":"2025-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145492616","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}
Pub Date : 2025-11-10DOI: 10.1038/s42255-025-01369-9
Emma L. Shepherd, Patricia F. Lalor
A new study in mice links ethanol consumption to endogenous fructose generation via hepatic aldose reductase, which enhances alcohol-seeking behaviour and liver damage. Inhibition of ketohexokinase reduced these effects, highlighting potential targets for managing alcohol use disorders.
{"title":"Firewater, fructose and appetite","authors":"Emma L. Shepherd, Patricia F. Lalor","doi":"10.1038/s42255-025-01369-9","DOIUrl":"10.1038/s42255-025-01369-9","url":null,"abstract":"A new study in mice links ethanol consumption to endogenous fructose generation via hepatic aldose reductase, which enhances alcohol-seeking behaviour and liver damage. Inhibition of ketohexokinase reduced these effects, highlighting potential targets for managing alcohol use disorders.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 11","pages":"2187-2188"},"PeriodicalIF":20.8,"publicationDate":"2025-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145478128","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}
Pub Date : 2025-11-10DOI: 10.1038/s42255-025-01402-x
Ana Andres-Hernando, David J. Orlicky, Gabriela E. Garcia, Esteban C. Loetz, Richard Montoya, Vijay Kumar, Devin P. Effinger, Masanari Kuwabara, So Young Bae, Laura Lorenzo-Rebenaque, Elena Fauste, Richard L. Bell, Nicholas Grahame, Suthat Liangpunsakul, Hahn Kim, Sundeep Dugar, Paul Maffuid, Takahiko Nakagawa, Michael F. Wempe, J. Mark Petrash, Dean R. Tolan, Sondra T. Bland, Richard J. Johnson, Miguel A. Lanaspa
Alcohol and sugar share reinforcing properties and both contribute to liver disease progression, ultimately leading to cirrhosis. Emerging evidence suggests that ethanol activates the aldose reductase pathway, resulting in endogenous fructose production. Here we investigated whether alcohol preference and alcohol-associated liver disease (ALD) are mediated through fructose metabolism by ketohexokinase (KHK)-A/C. Using global, conditional and tissue-specific KHK-A/C knockout mice, we assessed ethanol intake, reinforcement behaviours and liver injury. Ethanol consumption increased portal vein osmolality and activated the polyol pathway in the liver and intestine, leading to fructose production metabolized by KHK-A/C. Mice lacking KHK-A/C showed reduced ethanol preference across multiple paradigms, including two-bottle choice, conditioned place preference and operant self-administration, alongside decreased ∆FosB expression in the nucleus accumbens. Both genetic deletion and pharmacologic inhibition of KHK-A/C suppressed ethanol intake. Hepatocyte-specific KHK-A/C knockout mice displayed partially reduced alcohol consumption, potentially linked to altered aldehyde dehydrogenase expression, while intestinal KHK-A/C deletion restored glucagon-like peptide-1 levels—a hormone known to suppress alcohol intake. Under ethanol pair-matched conditions, global and liver-specific KHK-A/C knockout mice were protected from ALD, with marked reductions in hepatic steatosis, inflammation and fibrosis. These findings identify ethanol-induced fructose metabolism as a key driver of excessive alcohol consumption and ALD pathogenesis. Given that ALD and metabolic dysfunction-associated steatotic liver disease share fructose-dependent mechanisms, targeting fructose metabolism may offer a novel therapeutic approach for treating alcohol use disorder and related liver injury. Ethanol-induced fructose metabolism, mediated by KHK-A/C, drives excessive alcohol consumption and pathogenesis of alcoholic liver disease.
{"title":"Identification of a common ketohexokinase-dependent link driving alcohol intake and alcohol-associated liver disease in mice","authors":"Ana Andres-Hernando, David J. Orlicky, Gabriela E. Garcia, Esteban C. Loetz, Richard Montoya, Vijay Kumar, Devin P. Effinger, Masanari Kuwabara, So Young Bae, Laura Lorenzo-Rebenaque, Elena Fauste, Richard L. Bell, Nicholas Grahame, Suthat Liangpunsakul, Hahn Kim, Sundeep Dugar, Paul Maffuid, Takahiko Nakagawa, Michael F. Wempe, J. Mark Petrash, Dean R. Tolan, Sondra T. Bland, Richard J. Johnson, Miguel A. Lanaspa","doi":"10.1038/s42255-025-01402-x","DOIUrl":"10.1038/s42255-025-01402-x","url":null,"abstract":"Alcohol and sugar share reinforcing properties and both contribute to liver disease progression, ultimately leading to cirrhosis. Emerging evidence suggests that ethanol activates the aldose reductase pathway, resulting in endogenous fructose production. Here we investigated whether alcohol preference and alcohol-associated liver disease (ALD) are mediated through fructose metabolism by ketohexokinase (KHK)-A/C. Using global, conditional and tissue-specific KHK-A/C knockout mice, we assessed ethanol intake, reinforcement behaviours and liver injury. Ethanol consumption increased portal vein osmolality and activated the polyol pathway in the liver and intestine, leading to fructose production metabolized by KHK-A/C. Mice lacking KHK-A/C showed reduced ethanol preference across multiple paradigms, including two-bottle choice, conditioned place preference and operant self-administration, alongside decreased ∆FosB expression in the nucleus accumbens. Both genetic deletion and pharmacologic inhibition of KHK-A/C suppressed ethanol intake. Hepatocyte-specific KHK-A/C knockout mice displayed partially reduced alcohol consumption, potentially linked to altered aldehyde dehydrogenase expression, while intestinal KHK-A/C deletion restored glucagon-like peptide-1 levels—a hormone known to suppress alcohol intake. Under ethanol pair-matched conditions, global and liver-specific KHK-A/C knockout mice were protected from ALD, with marked reductions in hepatic steatosis, inflammation and fibrosis. These findings identify ethanol-induced fructose metabolism as a key driver of excessive alcohol consumption and ALD pathogenesis. Given that ALD and metabolic dysfunction-associated steatotic liver disease share fructose-dependent mechanisms, targeting fructose metabolism may offer a novel therapeutic approach for treating alcohol use disorder and related liver injury. Ethanol-induced fructose metabolism, mediated by KHK-A/C, drives excessive alcohol consumption and pathogenesis of alcoholic liver disease.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 11","pages":"2250-2267"},"PeriodicalIF":20.8,"publicationDate":"2025-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s42255-025-01402-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145478127","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}
Pub Date : 2025-11-06DOI: 10.1038/s42255-025-01406-7
Children born to mothers with type 1 diabetes (T1D) are less likely to develop T1D than those with an affected father or sibling. We identified modifications of DNA methylation at multiple T1D risk genes in blood samples from children exposed to maternal T1D. These changes were linked to decreased islet autoimmunity risk.
{"title":"Maternal type 1 diabetes might protect offspring through epigenetic modifications","authors":"","doi":"10.1038/s42255-025-01406-7","DOIUrl":"10.1038/s42255-025-01406-7","url":null,"abstract":"Children born to mothers with type 1 diabetes (T1D) are less likely to develop T1D than those with an affected father or sibling. We identified modifications of DNA methylation at multiple T1D risk genes in blood samples from children exposed to maternal T1D. These changes were linked to decreased islet autoimmunity risk.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 11","pages":"2197-2198"},"PeriodicalIF":20.8,"publicationDate":"2025-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145447660","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}
Pub Date : 2025-11-06DOI: 10.1038/s42255-025-01403-w
Raffael Ott, Jose Zapardiel-Gonzalo, Peter Kreitmaier, Kristina Casteels, Angela Hommel, Olga Kordonouri, Helena Elding Larsson, Agnieszka Szypowska, Manu Vatish, Eleftheria Zeggini, Annette Knopff, Christiane Winkler, Anette-G. Ziegler, Ezio Bonifacio, Sandra Hummel
Exposure to maternal type 1 diabetes (T1D) during pregnancy provides relative protection against T1D in the offspring. This protective effect may be driven by epigenetic mechanisms. Here we conducted an epigenome-wide blood analysis on 790 young children with and 962 children without a T1D-affected mother, and identified differential DNA methylation (q < 0.05) at multiple loci and regions. These included the Homeobox A gene cluster and 15 T1D susceptibility genes. The differential methylation was found in transcriptionally relevant regions associated with immune function, including sites previously linked to T1D-related methylation loci and protein biomarkers. Propensity scores for methylation at T1D susceptibility loci could predict the development of islet autoimmunity in offspring born to mothers without T1D. Together, these findings highlight pathways through which maternal T1D may confer protection against islet autoimmunity in offspring and suggest that environmental factors can influence T1D risk through epigenetic modifications of T1D susceptibility loci. Through an epigenome-wide blood analysis in children of mothers with or without type 1 diabetes, the authors identify epigenetic modifications of type 1 diabetes susceptibility loci through which maternal type 1 diabetes may protect from islet autoimmunity in offspring.
{"title":"Blood methylome signatures in children exposed to maternal type 1 diabetes are linked to protection against islet autoimmunity","authors":"Raffael Ott, Jose Zapardiel-Gonzalo, Peter Kreitmaier, Kristina Casteels, Angela Hommel, Olga Kordonouri, Helena Elding Larsson, Agnieszka Szypowska, Manu Vatish, Eleftheria Zeggini, Annette Knopff, Christiane Winkler, Anette-G. Ziegler, Ezio Bonifacio, Sandra Hummel","doi":"10.1038/s42255-025-01403-w","DOIUrl":"10.1038/s42255-025-01403-w","url":null,"abstract":"Exposure to maternal type 1 diabetes (T1D) during pregnancy provides relative protection against T1D in the offspring. This protective effect may be driven by epigenetic mechanisms. Here we conducted an epigenome-wide blood analysis on 790 young children with and 962 children without a T1D-affected mother, and identified differential DNA methylation (q < 0.05) at multiple loci and regions. These included the Homeobox A gene cluster and 15 T1D susceptibility genes. The differential methylation was found in transcriptionally relevant regions associated with immune function, including sites previously linked to T1D-related methylation loci and protein biomarkers. Propensity scores for methylation at T1D susceptibility loci could predict the development of islet autoimmunity in offspring born to mothers without T1D. Together, these findings highlight pathways through which maternal T1D may confer protection against islet autoimmunity in offspring and suggest that environmental factors can influence T1D risk through epigenetic modifications of T1D susceptibility loci. Through an epigenome-wide blood analysis in children of mothers with or without type 1 diabetes, the authors identify epigenetic modifications of type 1 diabetes susceptibility loci through which maternal type 1 diabetes may protect from islet autoimmunity in offspring.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 11","pages":"2236-2249"},"PeriodicalIF":20.8,"publicationDate":"2025-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s42255-025-01403-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145447658","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}
Pub Date : 2025-11-04DOI: 10.1038/s42255-025-01391-x
Huajun Pan, Fei Yin
By parsing stimulus-responsive sources of astrocytic reactive oxygen species (ROS), Barnett et al. reveal how mitochondrial complex III-derived signals uniquely shape inflammatory responses and astrocyte–neuron crosstalk, linking mitochondrial redox cues to dementia-related neurodegeneration.
Pub Date : 2025-11-04DOI: 10.1038/s42255-025-01390-y
Daniel Barnett, Till S. Zimmer, Caroline Booraem, Fernando Palaguachi, Samantha M. Meadows, Haopeng Xiao, Man Ying Wong, Wenjie Luo, Li Gan, Edward T. Chouchani, Anna G. Orr, Adam L. Orr
Neurodegenerative disorders alter mitochondrial functions, including the production of reactive oxygen species (ROS). Mitochondrial complex III (CIII) generates ROS implicated in redox signalling, but its triggers, temporal dynamics, targets and disease relevance are not clear. Here, using site-selective suppressors and genetic manipulations together with live mitochondrial ROS imaging and multiomic profiling, we show that CIII is a dominant source of ROS production in astrocytes exposed to neuropathology-related stimuli. Astrocytic CIII ROS production is dependent on nuclear factor-κB and the mitochondrial sodium-calcium exchanger (NCLX) and causes oxidation of select cysteines within immune- and metabolism-associated proteins linked to neurological disease. CIII ROS amplify metabolomic and pathology-associated transcriptional changes in astrocytes, with STAT3 activity as a major mediator, and facilitate neuronal toxicity. Therapeutic suppression of CIII ROS in mice decreases dementia-linked tauopathy and neuroimmune cascades and extends lifespan. Our findings establish CIII ROS as an important immunometabolic signal transducer and tractable therapeutic target in neurodegenerative disease. Barnett et al. disentangle the differential contribution of mitochondrial complex I- and complex III-derived ROS to astrocytic function, with CIII-derived ROS being a major driver of neuroinflammatory responses.
{"title":"Mitochondrial complex III-derived ROS amplify immunometabolic changes in astrocytes and promote dementia pathology","authors":"Daniel Barnett, Till S. Zimmer, Caroline Booraem, Fernando Palaguachi, Samantha M. Meadows, Haopeng Xiao, Man Ying Wong, Wenjie Luo, Li Gan, Edward T. Chouchani, Anna G. Orr, Adam L. Orr","doi":"10.1038/s42255-025-01390-y","DOIUrl":"10.1038/s42255-025-01390-y","url":null,"abstract":"Neurodegenerative disorders alter mitochondrial functions, including the production of reactive oxygen species (ROS). Mitochondrial complex III (CIII) generates ROS implicated in redox signalling, but its triggers, temporal dynamics, targets and disease relevance are not clear. Here, using site-selective suppressors and genetic manipulations together with live mitochondrial ROS imaging and multiomic profiling, we show that CIII is a dominant source of ROS production in astrocytes exposed to neuropathology-related stimuli. Astrocytic CIII ROS production is dependent on nuclear factor-κB and the mitochondrial sodium-calcium exchanger (NCLX) and causes oxidation of select cysteines within immune- and metabolism-associated proteins linked to neurological disease. CIII ROS amplify metabolomic and pathology-associated transcriptional changes in astrocytes, with STAT3 activity as a major mediator, and facilitate neuronal toxicity. Therapeutic suppression of CIII ROS in mice decreases dementia-linked tauopathy and neuroimmune cascades and extends lifespan. Our findings establish CIII ROS as an important immunometabolic signal transducer and tractable therapeutic target in neurodegenerative disease. Barnett et al. disentangle the differential contribution of mitochondrial complex I- and complex III-derived ROS to astrocytic function, with CIII-derived ROS being a major driver of neuroinflammatory responses.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 11","pages":"2300-2323"},"PeriodicalIF":20.8,"publicationDate":"2025-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s42255-025-01390-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145434667","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}
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