Pub Date : 2025-12-09DOI: 10.1038/s42255-025-01415-6
Brandon M. Oswald, Lisa M. DeCamp, Joseph Longo, Michael S. Dahabieh, Nicholas Bunda, Benjamin K. Johnson, McLane J. Watson, Shixin Ma, Samuel E. J. Preston, Ryan D. Sheldon, Michael P. Vincent, Abigail E. Ellis, Molly T. Soper-Hopper, Christine Isaguirre, Dahlya Kamarudin, Hui Shen, Kelsey S. Williams, Peter A. Crawford, Susan Kaech, H. Josh Jang, Evan C. Lien, Connie M. Krawczyk, Russell G. Jones
Reducing calorie intake through dietary restriction (DR) slows tumour growth in mammals, yet the underlying mechanisms are poorly defined. Here, we show that DR enhances anti-tumour immunity by optimizing CD8+ T cell function within the tumour microenvironment (TME). Using syngeneic xenograft tumour models, we found that DR induces a profound reprogramming of CD8+ T cell fate in the TME, favouring the expansion of effector T cell subsets with enhanced metabolic capacity and cytotoxic potential, while limiting the accumulation of terminally exhausted T cells. This metabolic reprogramming is driven by enhanced ketone body oxidation, particularly β-hydroxybutyrate (βOHB), which is elevated in both the circulation and tumour tissues of DR-fed mice. βOHB fuels T cell oxidative metabolism under DR, increasing mitochondrial membrane potential and tricarboxylic acid cycle-dependent pathways critical for T cell effector function, including acetyl-CoA production. By contrast, T cells deficient for ketone body oxidation exhibit reduced mitochondrial function, increased exhaustion and fail to control tumour growth under DR conditions. Importantly, DR synergizes with anti-PD1 immunotherapy, further augmenting anti-tumour T cell responses and limiting tumour progression. Our findings reveal that T cell metabolic reprogramming is central to the anti-tumour effects of DR, highlighting nutritional control of CD8+ T cell fate as a key driver of anti-tumour immunity. Dietary restriction promotes the expansion of effector T cells via ketone bodies, which enhances anti-tumour immunity and synergizes with immunotherapy in mice.
{"title":"Dietary restriction reprograms CD8+ T cell fate to enhance anti-tumour immunity and immunotherapy responses","authors":"Brandon M. Oswald, Lisa M. DeCamp, Joseph Longo, Michael S. Dahabieh, Nicholas Bunda, Benjamin K. Johnson, McLane J. Watson, Shixin Ma, Samuel E. J. Preston, Ryan D. Sheldon, Michael P. Vincent, Abigail E. Ellis, Molly T. Soper-Hopper, Christine Isaguirre, Dahlya Kamarudin, Hui Shen, Kelsey S. Williams, Peter A. Crawford, Susan Kaech, H. Josh Jang, Evan C. Lien, Connie M. Krawczyk, Russell G. Jones","doi":"10.1038/s42255-025-01415-6","DOIUrl":"10.1038/s42255-025-01415-6","url":null,"abstract":"Reducing calorie intake through dietary restriction (DR) slows tumour growth in mammals, yet the underlying mechanisms are poorly defined. Here, we show that DR enhances anti-tumour immunity by optimizing CD8+ T cell function within the tumour microenvironment (TME). Using syngeneic xenograft tumour models, we found that DR induces a profound reprogramming of CD8+ T cell fate in the TME, favouring the expansion of effector T cell subsets with enhanced metabolic capacity and cytotoxic potential, while limiting the accumulation of terminally exhausted T cells. This metabolic reprogramming is driven by enhanced ketone body oxidation, particularly β-hydroxybutyrate (βOHB), which is elevated in both the circulation and tumour tissues of DR-fed mice. βOHB fuels T cell oxidative metabolism under DR, increasing mitochondrial membrane potential and tricarboxylic acid cycle-dependent pathways critical for T cell effector function, including acetyl-CoA production. By contrast, T cells deficient for ketone body oxidation exhibit reduced mitochondrial function, increased exhaustion and fail to control tumour growth under DR conditions. Importantly, DR synergizes with anti-PD1 immunotherapy, further augmenting anti-tumour T cell responses and limiting tumour progression. Our findings reveal that T cell metabolic reprogramming is central to the anti-tumour effects of DR, highlighting nutritional control of CD8+ T cell fate as a key driver of anti-tumour immunity. Dietary restriction promotes the expansion of effector T cells via ketone bodies, which enhances anti-tumour immunity and synergizes with immunotherapy in mice.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 12","pages":"2489-2509"},"PeriodicalIF":20.8,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s42255-025-01415-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145705133","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 : 2025-12-08DOI: 10.1038/s42255-025-01413-8
Julien Chilloux, Francois Brial, Amandine Everard, David Smyth, Petros Andrikopoulos, Liyong Zhang, Hubert Plovier, Antonis Myridakis, Lesley Hoyles, José Maria Moreno-Navarrete, Jèssica Latorre Luque, Viviana Casagrande, Rossella Menghini, Blerina Ahmetaj-Shala, Christine Blancher, Laura Martinez-Gili, Selin Gencer, Jane F. Fearnside, Richard H. Barton, Ana Luisa Neves, Alice R. Rothwell, Christelle Gérard, Sophie Calderari, Mark J. Williamson, Julian E. Fuchs, Lata Govada, Claire L. Boulangé, Saroor Patel, James Scott, Mark Thursz, Naomi Chayen, Robert C. Glen, Nigel J. Gooderham, Jeremy K. Nicholson, Massimo Federici, José Manuel Fernández-Real, Dominique Gauguier, Peter P. Liu, Patrice D. Cani, Marc-Emmanuel Dumas
The global type 2 diabetes epidemic is a major health crisis. Although the microbiome has roles in the onset of insulin resistance (IR), low-grade inflammation and diabetes, the microbial compounds controlling these processes remain to be discovered. Here, we show that the microbial metabolite trimethylamine (TMA) decouples inflammation and IR from diet-induced obesity by inhibiting interleukin-1 receptor-associated kinase 4 (IRAK4), a central kinase in the Toll-like receptor pathway sensing danger signals. TMA blunts TLR4 signalling in primary human hepatocytes and peripheral blood monocytic cells and rescues mouse survival after lipopolysaccharide-induced septic shock. Genetic deletion and chemical inhibition of IRAK4 result in metabolic and immune improvements in high-fat diets. Remarkably, our results suggest that TMA—unlike its liver co-metabolite trimethylamine N-oxide, which is associated with cardiovascular disease—improves immune tone and glycemic control in diet-induced obesity. Altogether, this study supports the emerging role of the kinome in the microbial–mammalian chemical crosstalk. The microbial metabolite trimethylamine (TMA), the precursor of TMAO, which is associated with adverse cardiometabolic outcomes, is shown to have beneficial metabolic and anti-inflammatory effects in the host in the context of obesity.
{"title":"Inhibition of IRAK4 by microbial trimethylamine blunts metabolic inflammation and ameliorates glycemic control","authors":"Julien Chilloux, Francois Brial, Amandine Everard, David Smyth, Petros Andrikopoulos, Liyong Zhang, Hubert Plovier, Antonis Myridakis, Lesley Hoyles, José Maria Moreno-Navarrete, Jèssica Latorre Luque, Viviana Casagrande, Rossella Menghini, Blerina Ahmetaj-Shala, Christine Blancher, Laura Martinez-Gili, Selin Gencer, Jane F. Fearnside, Richard H. Barton, Ana Luisa Neves, Alice R. Rothwell, Christelle Gérard, Sophie Calderari, Mark J. Williamson, Julian E. Fuchs, Lata Govada, Claire L. Boulangé, Saroor Patel, James Scott, Mark Thursz, Naomi Chayen, Robert C. Glen, Nigel J. Gooderham, Jeremy K. Nicholson, Massimo Federici, José Manuel Fernández-Real, Dominique Gauguier, Peter P. Liu, Patrice D. Cani, Marc-Emmanuel Dumas","doi":"10.1038/s42255-025-01413-8","DOIUrl":"10.1038/s42255-025-01413-8","url":null,"abstract":"The global type 2 diabetes epidemic is a major health crisis. Although the microbiome has roles in the onset of insulin resistance (IR), low-grade inflammation and diabetes, the microbial compounds controlling these processes remain to be discovered. Here, we show that the microbial metabolite trimethylamine (TMA) decouples inflammation and IR from diet-induced obesity by inhibiting interleukin-1 receptor-associated kinase 4 (IRAK4), a central kinase in the Toll-like receptor pathway sensing danger signals. TMA blunts TLR4 signalling in primary human hepatocytes and peripheral blood monocytic cells and rescues mouse survival after lipopolysaccharide-induced septic shock. Genetic deletion and chemical inhibition of IRAK4 result in metabolic and immune improvements in high-fat diets. Remarkably, our results suggest that TMA—unlike its liver co-metabolite trimethylamine N-oxide, which is associated with cardiovascular disease—improves immune tone and glycemic control in diet-induced obesity. Altogether, this study supports the emerging role of the kinome in the microbial–mammalian chemical crosstalk. The microbial metabolite trimethylamine (TMA), the precursor of TMAO, which is associated with adverse cardiometabolic outcomes, is shown to have beneficial metabolic and anti-inflammatory effects in the host in the context of obesity.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 12","pages":"2531-2547"},"PeriodicalIF":20.8,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s42255-025-01413-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145708752","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 : 2025-12-05DOI: 10.1038/s42255-025-01410-x
Amy E. Stewart, Derek K. Zachman, Pol Castellano-Escuder, Lois M. Kelly, Ben Zolyomi, Michael D. I. Aiduk, Christopher D. Delaney, Ian C. Lock, Claudie Bosc, John Bradley, Shane T. Killarney, J. Darren Stuart, Paul A. Grimsrud, Olga R. Ilkayeva, Christopher B. Newgard, Navdeep S. Chandel, Alexandre Puissant, Kris C. Wood, Matthew D. Hirschey
Understanding how cellular pathways interact is crucial for treating complex diseases like cancer. Individual gene–gene interaction studies have provided valuable insights, but may miss pathways working together. Here we develop a multi-gene approach to pathway mapping which reveals that acute myeloid leukaemia (AML) depends on an unexpected link between complex II and purine metabolism. Through stable-isotope metabolomic tracing, we show that complex II directly supports de novo purine biosynthesis and that exogenous purines rescue AML cells from complex II inhibition. The mechanism involves a metabolic circuit where glutamine provides nitrogen to build the purine ring, producing glutamate that complex II metabolizes to sustain purine synthesis. This connection translates into a metabolic vulnerability whereby increasing intracellular glutamate levels suppresses purine production and sensitizes AML cells to complex II inhibition. In a syngeneic AML mouse model, targeting complex II leads to rapid disease regression and extends survival. In individuals with AML, higher complex II gene expression correlates with resistance to BCL-2 inhibition and worse survival. These findings establish complex II as a central regulator of de novo purine biosynthesis and a promising therapeutic target in AML. A machine-learning-based computational approach to probe pathway coessentiality reveals that complex II of the electron transport chain regulates de novo purine synthesis, and can be targeted to treat acute myeloid leukaemia.
{"title":"Pathway coessentiality mapping reveals complex II is required for de novo purine biosynthesis in acute myeloid leukaemia","authors":"Amy E. Stewart, Derek K. Zachman, Pol Castellano-Escuder, Lois M. Kelly, Ben Zolyomi, Michael D. I. Aiduk, Christopher D. Delaney, Ian C. Lock, Claudie Bosc, John Bradley, Shane T. Killarney, J. Darren Stuart, Paul A. Grimsrud, Olga R. Ilkayeva, Christopher B. Newgard, Navdeep S. Chandel, Alexandre Puissant, Kris C. Wood, Matthew D. Hirschey","doi":"10.1038/s42255-025-01410-x","DOIUrl":"10.1038/s42255-025-01410-x","url":null,"abstract":"Understanding how cellular pathways interact is crucial for treating complex diseases like cancer. Individual gene–gene interaction studies have provided valuable insights, but may miss pathways working together. Here we develop a multi-gene approach to pathway mapping which reveals that acute myeloid leukaemia (AML) depends on an unexpected link between complex II and purine metabolism. Through stable-isotope metabolomic tracing, we show that complex II directly supports de novo purine biosynthesis and that exogenous purines rescue AML cells from complex II inhibition. The mechanism involves a metabolic circuit where glutamine provides nitrogen to build the purine ring, producing glutamate that complex II metabolizes to sustain purine synthesis. This connection translates into a metabolic vulnerability whereby increasing intracellular glutamate levels suppresses purine production and sensitizes AML cells to complex II inhibition. In a syngeneic AML mouse model, targeting complex II leads to rapid disease regression and extends survival. In individuals with AML, higher complex II gene expression correlates with resistance to BCL-2 inhibition and worse survival. These findings establish complex II as a central regulator of de novo purine biosynthesis and a promising therapeutic target in AML. A machine-learning-based computational approach to probe pathway coessentiality reveals that complex II of the electron transport chain regulates de novo purine synthesis, and can be targeted to treat acute myeloid leukaemia.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 12","pages":"2474-2488"},"PeriodicalIF":20.8,"publicationDate":"2025-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s42255-025-01410-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145680192","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 : 2025-12-03DOI: 10.1038/s42255-025-01412-9
Olaya Santiago-Fernández, Luisa Coletto, Inmaculada Tasset, Susmita Kaushik, Axel R. Concepcion, Rizwan Qaisar, Adrián Macho-González, Kristen Lindenau, Antonio Diaz, Rabia R. Khawaja, Stefano Donega, Nirad Banskota, Ceereena Ubaida-Mohien, Gavin Pharaoh, Bumsoo Ahn, Lisa M. Hartnell, Ignacio Ramírez-Pardo, Bhakti Chavda, Aiara Gazteluiturri, Michael Kinter, Luigi Ferrucci, Julie A. Reisz, Angelo D’Alessandro, Holly Van Remmen, Pura Muñoz-Cánoves, Stefan Feske, Ana Maria Cuervo
Chaperone-mediated autophagy (CMA) contributes to proteostasis maintenance by selectively degrading a subset of proteins in lysosomes. CMA declines with age in most tissues, including skeletal muscle. However, the role of CMA in skeletal muscle and the consequences of its decline remain poorly understood. Here we demonstrate that CMA regulates skeletal muscle function. We show that CMA is upregulated in skeletal muscle in response to starvation, exercise and tissue repair, but declines in ageing and obesity. Using a muscle-specific CMA-deficient mouse model, we show that CMA loss leads to progressive myopathy, including reduced muscle force and degenerative myofibre features. Comparative proteomic analyses reveal CMA-dependent changes in the mitochondrial proteome and identify the sarcoplasmic–endoplasmic reticulum Ca2+-ATPase (SERCA) as a CMA substrate. Impaired SERCA turnover in CMA-deficient skeletal muscle is associated with defective calcium (Ca2+) storage and dysregulated Ca2+ dynamics. We confirm that CMA is also downregulated with age in human skeletal muscle. Remarkably, genetic upregulation of CMA activity in old mice partially ameliorates skeletal muscle ageing phenotypes. Together, our work highlights the contribution of CMA to skeletal muscle homoeostasis and myofibre integrity. Chaperone-mediated autophagy declines with age in skeletal muscle of humans and mice, leading to muscle dysfunction characterized by impaired calcium homoeostasis and mitochondrial function.
{"title":"Age-related decline of chaperone-mediated autophagy in skeletal muscle leads to progressive myopathy","authors":"Olaya Santiago-Fernández, Luisa Coletto, Inmaculada Tasset, Susmita Kaushik, Axel R. Concepcion, Rizwan Qaisar, Adrián Macho-González, Kristen Lindenau, Antonio Diaz, Rabia R. Khawaja, Stefano Donega, Nirad Banskota, Ceereena Ubaida-Mohien, Gavin Pharaoh, Bumsoo Ahn, Lisa M. Hartnell, Ignacio Ramírez-Pardo, Bhakti Chavda, Aiara Gazteluiturri, Michael Kinter, Luigi Ferrucci, Julie A. Reisz, Angelo D’Alessandro, Holly Van Remmen, Pura Muñoz-Cánoves, Stefan Feske, Ana Maria Cuervo","doi":"10.1038/s42255-025-01412-9","DOIUrl":"10.1038/s42255-025-01412-9","url":null,"abstract":"Chaperone-mediated autophagy (CMA) contributes to proteostasis maintenance by selectively degrading a subset of proteins in lysosomes. CMA declines with age in most tissues, including skeletal muscle. However, the role of CMA in skeletal muscle and the consequences of its decline remain poorly understood. Here we demonstrate that CMA regulates skeletal muscle function. We show that CMA is upregulated in skeletal muscle in response to starvation, exercise and tissue repair, but declines in ageing and obesity. Using a muscle-specific CMA-deficient mouse model, we show that CMA loss leads to progressive myopathy, including reduced muscle force and degenerative myofibre features. Comparative proteomic analyses reveal CMA-dependent changes in the mitochondrial proteome and identify the sarcoplasmic–endoplasmic reticulum Ca2+-ATPase (SERCA) as a CMA substrate. Impaired SERCA turnover in CMA-deficient skeletal muscle is associated with defective calcium (Ca2+) storage and dysregulated Ca2+ dynamics. We confirm that CMA is also downregulated with age in human skeletal muscle. Remarkably, genetic upregulation of CMA activity in old mice partially ameliorates skeletal muscle ageing phenotypes. Together, our work highlights the contribution of CMA to skeletal muscle homoeostasis and myofibre integrity. Chaperone-mediated autophagy declines with age in skeletal muscle of humans and mice, leading to muscle dysfunction characterized by impaired calcium homoeostasis and mitochondrial function.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 12","pages":"2589-2611"},"PeriodicalIF":20.8,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s42255-025-01412-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145664338","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 : 2025-12-03DOI: 10.1038/s42255-025-01418-3
Vittorio Sartorelli
Two studies in Nature Metabolism reveal a critical role of chaperone-mediated autophagy in maintaining homeostasis and promoting regeneration of skeletal muscle.
{"title":"A dedicated recycling bin keeps muscle healthy","authors":"Vittorio Sartorelli","doi":"10.1038/s42255-025-01418-3","DOIUrl":"10.1038/s42255-025-01418-3","url":null,"abstract":"Two studies in Nature Metabolism reveal a critical role of chaperone-mediated autophagy in maintaining homeostasis and promoting regeneration of skeletal muscle.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 12","pages":"2390-2392"},"PeriodicalIF":20.8,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145664013","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 : 2025-12-03DOI: 10.1038/s42255-025-01411-w
Ignacio Ramírez-Pardo, Silvia Campanario, Bhakti Chavda, Olaya Santiago-Fernández, Marta Flández, Mercedes Grima-Terrén, Andrés Cisneros, Aina Calls-Cobos, Daniel N. Itzhak, Bryan Ngo, Sudha Janaki-Raman, Edward D. Kantz, Laura Ortet, Antonio Diaz, Kristen Lindenau, Julio Doménech-Fernández, Mari Carmen Gómez-Cabrera, Emilio Camafeita, Jesús Vázquez, Marta Martinez-Vicente, Antonio L. Serrano, Eusebio Perdiguero, Joan Isern, Ana Maria Cuervo, Pura Muñoz-Cánoves
Proteostasis supports stemness, and its loss correlates with the functional decline of diverse stem cell types. Chaperone-mediated autophagy (CMA) is a selective autophagy pathway implicated in proteostasis, but whether it plays a role in muscle stem cell (MuSC) function is unclear. Here we show that CMA is necessary for MuSC regenerative capacity throughout life. Genetic loss of CMA in young MuSCs, or failure of CMA in aged MuSCs, causes proliferative impairment resulting in defective skeletal muscle regeneration. Using comparative proteomics to identify CMA substrates, we find that actin cytoskeleton organization and glycolytic metabolism are key processes altered in aged murine and human MuSCs. CMA reactivation and glycolysis enhancement restore the proliferative capacity of aged mouse and human MuSCs, and improve their regenerative ability. Overall, our results show that CMA is a decisive stem cell-fate regulator, with implications in fostering muscle regeneration in old age. Age-related decline of chaperone-mediated autophagy blunts the regenerative capacity of muscle stem cells, partly due to impaired glycolytic shift required for normal stem cell expansion.
{"title":"Chaperone-mediated autophagy sustains muscle stem cell regenerative functions but declines with age","authors":"Ignacio Ramírez-Pardo, Silvia Campanario, Bhakti Chavda, Olaya Santiago-Fernández, Marta Flández, Mercedes Grima-Terrén, Andrés Cisneros, Aina Calls-Cobos, Daniel N. Itzhak, Bryan Ngo, Sudha Janaki-Raman, Edward D. Kantz, Laura Ortet, Antonio Diaz, Kristen Lindenau, Julio Doménech-Fernández, Mari Carmen Gómez-Cabrera, Emilio Camafeita, Jesús Vázquez, Marta Martinez-Vicente, Antonio L. Serrano, Eusebio Perdiguero, Joan Isern, Ana Maria Cuervo, Pura Muñoz-Cánoves","doi":"10.1038/s42255-025-01411-w","DOIUrl":"10.1038/s42255-025-01411-w","url":null,"abstract":"Proteostasis supports stemness, and its loss correlates with the functional decline of diverse stem cell types. Chaperone-mediated autophagy (CMA) is a selective autophagy pathway implicated in proteostasis, but whether it plays a role in muscle stem cell (MuSC) function is unclear. Here we show that CMA is necessary for MuSC regenerative capacity throughout life. Genetic loss of CMA in young MuSCs, or failure of CMA in aged MuSCs, causes proliferative impairment resulting in defective skeletal muscle regeneration. Using comparative proteomics to identify CMA substrates, we find that actin cytoskeleton organization and glycolytic metabolism are key processes altered in aged murine and human MuSCs. CMA reactivation and glycolysis enhancement restore the proliferative capacity of aged mouse and human MuSCs, and improve their regenerative ability. Overall, our results show that CMA is a decisive stem cell-fate regulator, with implications in fostering muscle regeneration in old age. Age-related decline of chaperone-mediated autophagy blunts the regenerative capacity of muscle stem cells, partly due to impaired glycolytic shift required for normal stem cell expansion.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 12","pages":"2571-2588"},"PeriodicalIF":20.8,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145664339","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 : 2025-12-01DOI: 10.1038/s42255-025-01405-8
Laura Casanueva Reimon, Ayden Gouveia, André Carvalho, Joscha N. Schmehr, Mouna El Mehdi, Rolando D. Moreira-Soto, Carlos G. Ardanaz, Janice Bulk, Lionel Rigoux, Paul Klemm, Anna Lena Cremer, Frederik Dethloff, Yvonne Hinze, Heiko Backes, Patrick Giavalisco, Sophie M. Steculorum
Maternal obesity predisposes offspring to metabolic diseases. Here, we show that non-nutritive sensory components of a high-fat diet (HFD), beyond its hypercaloric, obesogenic effects, are sufficient to alter metabolic health in the offspring. To dissociate the caloric and sensory components of HFD, we fed dams a bacon-flavoured diet, isonutritional to a normal chow diet but enriched with fat-related odours. Offspring exposed to these fat-related odours during development display metabolic inflexibility and increased adiposity when fed HFD in adulthood independently of maternal metabolic health. Developmental exposure to fat-related odours shifts mesolimbic dopaminergic circuits and Agouti-related peptide (AgRP) hunger neurons’ responses to phenocopy those of obese mice, including a desensitization of AgRP neurons to dietary fat. While neither neonatal optogenetic activation of sensory circuits nor passive exposure to fat-related odours is sufficient to alter metabolic responses to HFD, coupling optogenetic stimulation of sensory circuits with caloric intake exacerbates obesity. Collectively, we report that fat-related sensory cues during development act as signals that can prime central responses to food cues and whole-body metabolism regulation. Non-nutritive sensory components of high-fat diet, such as bacon flavour, are sufficient to impair metabolic health in offspring in mice.
{"title":"Fat sensory cues in early life program central response to food and obesity","authors":"Laura Casanueva Reimon, Ayden Gouveia, André Carvalho, Joscha N. Schmehr, Mouna El Mehdi, Rolando D. Moreira-Soto, Carlos G. Ardanaz, Janice Bulk, Lionel Rigoux, Paul Klemm, Anna Lena Cremer, Frederik Dethloff, Yvonne Hinze, Heiko Backes, Patrick Giavalisco, Sophie M. Steculorum","doi":"10.1038/s42255-025-01405-8","DOIUrl":"10.1038/s42255-025-01405-8","url":null,"abstract":"Maternal obesity predisposes offspring to metabolic diseases. Here, we show that non-nutritive sensory components of a high-fat diet (HFD), beyond its hypercaloric, obesogenic effects, are sufficient to alter metabolic health in the offspring. To dissociate the caloric and sensory components of HFD, we fed dams a bacon-flavoured diet, isonutritional to a normal chow diet but enriched with fat-related odours. Offspring exposed to these fat-related odours during development display metabolic inflexibility and increased adiposity when fed HFD in adulthood independently of maternal metabolic health. Developmental exposure to fat-related odours shifts mesolimbic dopaminergic circuits and Agouti-related peptide (AgRP) hunger neurons’ responses to phenocopy those of obese mice, including a desensitization of AgRP neurons to dietary fat. While neither neonatal optogenetic activation of sensory circuits nor passive exposure to fat-related odours is sufficient to alter metabolic responses to HFD, coupling optogenetic stimulation of sensory circuits with caloric intake exacerbates obesity. Collectively, we report that fat-related sensory cues during development act as signals that can prime central responses to food cues and whole-body metabolism regulation. Non-nutritive sensory components of high-fat diet, such as bacon flavour, are sufficient to impair metabolic health in offspring in mice.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 12","pages":"2451-2473"},"PeriodicalIF":20.8,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s42255-025-01405-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145655252","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 : 2025-11-24DOI: 10.1038/s42255-025-01414-7
We show that the size of the mitochondrial NAD+ pool in hepatocytes is regulated by SLC25A51 expression in vivo. We further find that selectively increasing mitochondrial NAD+ is sufficient to improve liver regeneration after partial hepatectomy, equivalent to the effect of systemic high-dose NAD+ precursor supplementation.
{"title":"Mitochondrial NAD+ drives liver regeneration","authors":"","doi":"10.1038/s42255-025-01414-7","DOIUrl":"10.1038/s42255-025-01414-7","url":null,"abstract":"We show that the size of the mitochondrial NAD+ pool in hepatocytes is regulated by SLC25A51 expression in vivo. We further find that selectively increasing mitochondrial NAD+ is sufficient to improve liver regeneration after partial hepatectomy, equivalent to the effect of systemic high-dose NAD+ precursor supplementation.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 12","pages":"2393-2394"},"PeriodicalIF":20.8,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145582933","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}
Cognitive impairment is associated with perturbations of fine-tuned neuroimmune interactions. At the molecular level, alterations in cellular metabolism can compromise brain function, driving structural damage and cognitive deficits. In this Review, we focus on the bidirectional interactions between microglia, the brain-resident immune cells and neurons to dissect the metabolic determinants of brain resilience and cognition. We first outline these metabolic pathways during development and adult life. Then, we delineate how these processes are perturbed in ageing, as well as in metabolic, neuroinflammatory and neurodegenerative disorders. By doing so, we provide a mechanistic understanding of the metabolic pathways relevant to cognitive function in health and disease, thus paving the way for novel therapeutic targets based on the emerging field of neuroimmunometabolism. This Review highlights how metabolic interactions between microglia and neurons shape brain health, and how their disruption in ageing and disease contributes to cognitive decline.
{"title":"The metabolic engine of cognition: microglia–neuron interactions in health, ageing and disease","authors":"Evridiki Asimakidou, Stefano Pluchino, Bianca Ambrogina Silva, Luca Peruzzotti-Jametti","doi":"10.1038/s42255-025-01409-4","DOIUrl":"10.1038/s42255-025-01409-4","url":null,"abstract":"Cognitive impairment is associated with perturbations of fine-tuned neuroimmune interactions. At the molecular level, alterations in cellular metabolism can compromise brain function, driving structural damage and cognitive deficits. In this Review, we focus on the bidirectional interactions between microglia, the brain-resident immune cells and neurons to dissect the metabolic determinants of brain resilience and cognition. We first outline these metabolic pathways during development and adult life. Then, we delineate how these processes are perturbed in ageing, as well as in metabolic, neuroinflammatory and neurodegenerative disorders. By doing so, we provide a mechanistic understanding of the metabolic pathways relevant to cognitive function in health and disease, thus paving the way for novel therapeutic targets based on the emerging field of neuroimmunometabolism. This Review highlights how metabolic interactions between microglia and neurons shape brain health, and how their disruption in ageing and disease contributes to cognitive decline.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 12","pages":"2395-2413"},"PeriodicalIF":20.8,"publicationDate":"2025-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145559900","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 : 2025-11-20DOI: 10.1038/s42255-025-01408-5
Sarmistha Mukherjee, Ricardo A. Velázquez Aponte, Caroline E. Perry, Won Dong Lee, Kevin A. Janssen, Marc Niere, Gabriel K. Adzika, Mu-Jie Lu, Hsin-Ru Chan, Xiangyu Zou, Beishan Chen, Nicole Bye, Teresa Xiao, Jin-Seon Yook, Oniel Salik, David W. Frederick, Ryan B. Gaspar, Khanh V. Doan, James G. Davis, Joshua D. Rabinowitz, Douglas C. Wallace, Nathaniel W. Snyder, Shingo Kajimura, Xiaolu A. Cambronne, Mathias Ziegler, Joseph A. Baur
Nicotinamide adenine dinucleotide (NAD+) precursor supplementation shows metabolic and functional benefits in rodent models of disease and is being explored as potential therapeutic strategy in humans. However, the wide range of processes that involve NAD+ in every cell and subcellular compartment make it difficult to narrow down the mechanisms of action. Here we show that the rate of liver regeneration is closely associated with the concentration of NAD+ in hepatocyte mitochondria. We find that the mitochondrial NAD+ concentration in hepatocytes of male mice is determined by the expression of the transporter SLC25A51 (MCART1). The heterozygous loss of SLC25A51 modestly decreases mitochondrial NAD+ content in multiple tissues and impairs liver regeneration, whereas the hepatocyte-specific overexpression of SLC25A51 is sufficient to enhance liver regeneration comparably to the effect of systemic NAD+ precursor supplements. This benefit is observed even though NAD+ levels are increased only in mitochondria. Thus, the hepatocyte mitochondrial NAD+ pool is a key determinant of the rate of liver regeneration. Modulating mitochondrial NAD+ levels by changing the expression of the mitochondrial NAD+ transporter, SLC25A51, Mukherjee et al. demonstrate that mitochondrial, rather than cytosolic or nuclear, NAD+ levels are a key determinant of the rate of liver regeneration.
{"title":"Hepatocyte mitochondrial NAD+ content is limiting for liver regeneration","authors":"Sarmistha Mukherjee, Ricardo A. Velázquez Aponte, Caroline E. Perry, Won Dong Lee, Kevin A. Janssen, Marc Niere, Gabriel K. Adzika, Mu-Jie Lu, Hsin-Ru Chan, Xiangyu Zou, Beishan Chen, Nicole Bye, Teresa Xiao, Jin-Seon Yook, Oniel Salik, David W. Frederick, Ryan B. Gaspar, Khanh V. Doan, James G. Davis, Joshua D. Rabinowitz, Douglas C. Wallace, Nathaniel W. Snyder, Shingo Kajimura, Xiaolu A. Cambronne, Mathias Ziegler, Joseph A. Baur","doi":"10.1038/s42255-025-01408-5","DOIUrl":"10.1038/s42255-025-01408-5","url":null,"abstract":"Nicotinamide adenine dinucleotide (NAD+) precursor supplementation shows metabolic and functional benefits in rodent models of disease and is being explored as potential therapeutic strategy in humans. However, the wide range of processes that involve NAD+ in every cell and subcellular compartment make it difficult to narrow down the mechanisms of action. Here we show that the rate of liver regeneration is closely associated with the concentration of NAD+ in hepatocyte mitochondria. We find that the mitochondrial NAD+ concentration in hepatocytes of male mice is determined by the expression of the transporter SLC25A51 (MCART1). The heterozygous loss of SLC25A51 modestly decreases mitochondrial NAD+ content in multiple tissues and impairs liver regeneration, whereas the hepatocyte-specific overexpression of SLC25A51 is sufficient to enhance liver regeneration comparably to the effect of systemic NAD+ precursor supplements. This benefit is observed even though NAD+ levels are increased only in mitochondria. Thus, the hepatocyte mitochondrial NAD+ pool is a key determinant of the rate of liver regeneration. Modulating mitochondrial NAD+ levels by changing the expression of the mitochondrial NAD+ transporter, SLC25A51, Mukherjee et al. demonstrate that mitochondrial, rather than cytosolic or nuclear, NAD+ levels are a key determinant of the rate of liver regeneration.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"7 12","pages":"2424-2437"},"PeriodicalIF":20.8,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s42255-025-01408-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145554404","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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