Nature metabolismPub Date : 2024-12-13DOI: 10.1038/s42255-024-01160-2
Fiona M. Fitzpatrick, Nora Kory
{"title":"Guardians of the cell: mitochondria as a rheostat for cellular NAD+ levels","authors":"Fiona M. Fitzpatrick, Nora Kory","doi":"10.1038/s42255-024-01160-2","DOIUrl":"10.1038/s42255-024-01160-2","url":null,"abstract":"A new study reveals that subcellular NAD+ pools are interconnected, with mitochondria acting as a buffer to maintain NAD+-dependent processes in overconsuming organelles, highlighting the critical role of mitochondria in NAD+ homeostasis.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"6 12","pages":"2215-2217"},"PeriodicalIF":18.9,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142815658","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 : 2024-12-13DOI: 10.1038/s42255-024-01174-w
Lena E. Høyland, Magali R. VanLinden, Marc Niere, Øyvind Strømland, Suraj Sharma, Jörn Dietze, Ingvill Tolås, Eva Lucena, Ersilia Bifulco, Lars J. Sverkeli, Camila Cimadamore-Werthein, Hanan Ashrafi, Kjellfrid F. Haukanes, Barbara van der Hoeven, Christian Dölle, Cédric Davidsen, Ina K. N. Pettersen, Karl J. Tronstad, Svein A. Mjøs, Faisal Hayat, Mikhail V. Makarov, Marie E. Migaud, Ines Heiland, Mathias Ziegler
{"title":"Subcellular NAD+ pools are interconnected and buffered by mitochondrial NAD+","authors":"Lena E. Høyland, Magali R. VanLinden, Marc Niere, Øyvind Strømland, Suraj Sharma, Jörn Dietze, Ingvill Tolås, Eva Lucena, Ersilia Bifulco, Lars J. Sverkeli, Camila Cimadamore-Werthein, Hanan Ashrafi, Kjellfrid F. Haukanes, Barbara van der Hoeven, Christian Dölle, Cédric Davidsen, Ina K. N. Pettersen, Karl J. Tronstad, Svein A. Mjøs, Faisal Hayat, Mikhail V. Makarov, Marie E. Migaud, Ines Heiland, Mathias Ziegler","doi":"10.1038/s42255-024-01174-w","DOIUrl":"10.1038/s42255-024-01174-w","url":null,"abstract":"The coenzyme NAD+ is consumed by signalling enzymes, including poly-ADP-ribosyltransferases (PARPs) and sirtuins. Ageing is associated with a decrease in cellular NAD+ levels, but how cells cope with persistently decreased NAD+ concentrations is unclear. Here, we show that subcellular NAD+ pools are interconnected, with mitochondria acting as a rheostat to maintain NAD+ levels upon excessive consumption. To evoke chronic, compartment-specific overconsumption of NAD+, we engineered cell lines stably expressing PARP activity in mitochondria, the cytosol, endoplasmic reticulum or peroxisomes, resulting in a decline of cellular NAD+ concentrations by up to 50%. Isotope-tracer flux measurements and mathematical modelling show that the lowered NAD+ concentration kinetically restricts NAD+ consumption to maintain a balance with the NAD+ biosynthesis rate, which remains unchanged. Chronic NAD+ deficiency is well tolerated unless mitochondria are directly targeted. Mitochondria maintain NAD+ by import through SLC25A51 and reversibly cleave NAD+ to nicotinamide mononucleotide and ATP when NMNAT3 is present. Thus, these organelles can maintain an additional, virtual NAD+ pool. Our results are consistent with a well-tolerated ageing-related NAD+ decline as long as the vulnerable mitochondrial pool is not directly affected. By increasing NAD+ consumption in various organelles, mitochondria are revealed to act as buffers that help maintain subcellular NAD+ levels. At the same time, cells are found to be particularly sensitive to a decline in NAD+ levels originating from mitochondria themselves.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"6 12","pages":"2319-2337"},"PeriodicalIF":18.9,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142815705","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 : 2024-12-12DOI: 10.1038/s42255-024-01204-7
Shane M O'Carroll, Christian G Peace, Juliana E Toller-Kawahisa, Yukun Min, Alexander Hooftman, Sara Charki, Louise Kehoe, Maureen J O'Sullivan, Aline Zoller, Anne F Mcgettrick, Alessia Zotta, Emily A Day, Maria Simarro, Neali Armstrong, Justin P Annes, Luke A J O'Neill
{"title":"Author Correction: Itaconate drives mtRNA-mediated type I interferon production through inhibition of succinate dehydrogenase.","authors":"Shane M O'Carroll, Christian G Peace, Juliana E Toller-Kawahisa, Yukun Min, Alexander Hooftman, Sara Charki, Louise Kehoe, Maureen J O'Sullivan, Aline Zoller, Anne F Mcgettrick, Alessia Zotta, Emily A Day, Maria Simarro, Neali Armstrong, Justin P Annes, Luke A J O'Neill","doi":"10.1038/s42255-024-01204-7","DOIUrl":"https://doi.org/10.1038/s42255-024-01204-7","url":null,"abstract":"","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":" ","pages":""},"PeriodicalIF":18.9,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142818790","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 : 2024-12-06DOI: 10.1038/s42255-024-01172-y
Adam J. Sellers, Sten M. M. van Beek, Dzhansel Hashim, Rosalie Baak, Hannah Pallubinsky, Esther Moonen-Kornips, Gert Schaart, Anne Gemmink, Johanna A. Jörgensen, Tineke van de Weijer, Eric Kalkhoven, Guido J. Hooiveld, Sander Kersten, Matthijs K. C. Hesselink, Patrick Schrauwen, Joris Hoeks, Wouter D. van Marken Lichtenbelt
{"title":"Cold acclimation with shivering improves metabolic health in adults with overweight or obesity","authors":"Adam J. Sellers, Sten M. M. van Beek, Dzhansel Hashim, Rosalie Baak, Hannah Pallubinsky, Esther Moonen-Kornips, Gert Schaart, Anne Gemmink, Johanna A. Jörgensen, Tineke van de Weijer, Eric Kalkhoven, Guido J. Hooiveld, Sander Kersten, Matthijs K. C. Hesselink, Patrick Schrauwen, Joris Hoeks, Wouter D. van Marken Lichtenbelt","doi":"10.1038/s42255-024-01172-y","DOIUrl":"10.1038/s42255-024-01172-y","url":null,"abstract":"Cold acclimation increases insulin sensitivity, and some level of muscle contraction appears to be needed for provoking this effect. Here 15 men and (postmenopausal) women with overweight or obesity, the majority of whom had impaired glucose tolerance, were intermittently exposed to cold to induce 1 h of shivering per day over 10 days. We determined the effect of cold acclimation with shivering on overnight fasted oral glucose tolerance (primary outcome) and on skeletal muscle glucose transporter 4 translocation (secondary outcome). We find that cold acclimation with shivering improves oral glucose tolerance, fasting glucose, triglycerides, non-esterified fatty acid concentrations and blood pressure. Cold acclimation with shivering may thus represent an alternative lifestyle approach for the prevention and treatment of obesity-related metabolic disorders. ClinicalTrials.gov registration: NCT04516018 . Sellers, van Beek and colleagues show that intermittent cold exposure for 10 days, which induced 1 h of shivering per day, improves glucose homeostasis, lipid metabolism and blood pressure in adults with overweight or obesity.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"6 12","pages":"2246-2253"},"PeriodicalIF":18.9,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142783280","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 : 2024-12-06DOI: 10.1038/s42255-024-01147-z
Rodrigo Fernández-Verdejo, Jose E. Galgani
{"title":"Cold-induced shivering for metabolic health","authors":"Rodrigo Fernández-Verdejo, Jose E. Galgani","doi":"10.1038/s42255-024-01147-z","DOIUrl":"10.1038/s42255-024-01147-z","url":null,"abstract":"This proof-of-concept study shows that 1 hour of cold exposure with shivering for 10 consecutive days improves glucose tolerance and other metabolic health outcomes in humans with overweight or obesity.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"6 12","pages":"2218-2219"},"PeriodicalIF":18.9,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142783279","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 : 2024-12-03DOI: 10.1038/s42255-024-01168-8
Addison N. Webster, Jordan J. Becker, Chia Li, Dana C. Schwalbe, Damien Kerspern, Eva O. Karolczak, Catherine B. Bundon, Roberta A. Onoharigho, Maisie Crook, Maira Jalil, Elizabeth N. Godschall, Emily G. Dame, Adam Dawer, Dylan Matthew Belmont-Rausch, Tune H. Pers, Andrew Lutas, Naomi Habib, Ali D. Güler, Michael J. Krashes, John N. Campbell
{"title":"Molecular connectomics reveals a glucagon-like peptide 1-sensitive neural circuit for satiety","authors":"Addison N. Webster, Jordan J. Becker, Chia Li, Dana C. Schwalbe, Damien Kerspern, Eva O. Karolczak, Catherine B. Bundon, Roberta A. Onoharigho, Maisie Crook, Maira Jalil, Elizabeth N. Godschall, Emily G. Dame, Adam Dawer, Dylan Matthew Belmont-Rausch, Tune H. Pers, Andrew Lutas, Naomi Habib, Ali D. Güler, Michael J. Krashes, John N. Campbell","doi":"10.1038/s42255-024-01168-8","DOIUrl":"10.1038/s42255-024-01168-8","url":null,"abstract":"Liraglutide and other glucagon-like peptide 1 receptor agonists (GLP-1RAs) are effective weight loss drugs, but how they suppress appetite remains unclear. One potential mechanism is by activating neurons that inhibit the hunger-promoting Agouti-related peptide (AgRP) neurons of the arcuate hypothalamus (Arc). To identify these afferents, we developed a method combining rabies-based connectomics with single-nucleus transcriptomics. Here, we identify at least 21 afferent subtypes of AgRP neurons in the mouse mediobasal and paraventricular hypothalamus, which are predicted by our method. Among these are thyrotropin-releasing hormone (TRH)+ Arc (TRHArc) neurons, inhibitory neurons that express the Glp1r gene and are activated by the GLP-1RA liraglutide. Activating TRHArc neurons inhibits AgRP neurons and feeding, probably in an AgRP neuron-dependent manner. Silencing TRHArc neurons causes overeating and weight gain and attenuates liraglutide’s effect on body weight. Our results demonstrate a widely applicable method for molecular connectomics, comprehensively identify local inputs to AgRP neurons and reveal a circuit through which GLP-1RAs suppress appetite. Combining rabies-based connectomics with single-nucleus transcriptomics, the authors identify a neural circuit through which GLP-1 receptor agonists suppress appetite in mice.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"6 12","pages":"2354-2373"},"PeriodicalIF":18.9,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142760666","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 : 2024-11-26DOI: 10.1038/s42255-024-01166-w
Minwoo Nam, Wenxin Xia, Abdul Hannan Mir, Alexandra Jerrett, Jessica B. Spinelli, Tony T. Huang, Richard Possemato
{"title":"Glucose limitation protects cancer cells from apoptosis induced by pyrimidine restriction and replication inhibition","authors":"Minwoo Nam, Wenxin Xia, Abdul Hannan Mir, Alexandra Jerrett, Jessica B. Spinelli, Tony T. Huang, Richard Possemato","doi":"10.1038/s42255-024-01166-w","DOIUrl":"10.1038/s42255-024-01166-w","url":null,"abstract":"Cancer cells often experience nutrient-limiting conditions because of their robust proliferation and inadequate tumour vasculature, which results in metabolic adaptation to sustain proliferation. Most cancer cells rapidly consume glucose, which is severely reduced in the nutrient-scarce tumour microenvironment. In CRISPR-based genetic screens to identify metabolic pathways influenced by glucose restriction, we find that tumour-relevant glucose concentrations (low glucose) protect cancer cells from inhibition of de novo pyrimidine biosynthesis, a pathway that is frequently targeted by chemotherapy. We identify two mechanisms to explain this result, which is observed broadly across cancer types. First, low glucose limits uridine-5-diphosphate-glucose synthesis, preserving pyrimidine nucleotide availability and thereby prolonging the time to replication fork stalling. Second, low glucose directly modulates apoptosis downstream of replication fork stalling by suppressing BAK activation and subsequent cytochrome c release, key events that activate caspase-9-dependent mitochondrial apoptosis. These results indicate that the low glucose levels frequently observed in tumours may limit the efficacy of specific chemotherapeutic agents, highlighting the importance of considering the effects of the tumour nutrient environment on cancer therapy. Nam et al. show that limited glucose availability similar to the tumour microenvironment confers resistance against chemotherapeutic drugs that target DNA synthesis.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"6 12","pages":"2338-2353"},"PeriodicalIF":18.9,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142712795","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 : 2024-11-25DOI: 10.1038/s42255-024-01157-x
Anna Castells-Nobau, Irene Puig, Anna Motger-Albertí, Lisset de la Vega-Correa, Marisel Rosell-Díaz, María Arnoriaga-Rodríguez, Anira Escrichs, Josep Garre-Olmo, Josep Puig, Rafael Ramos, Lluís Ramió-Torrentà, Vicente Pérez-Brocal, Andrés Moya, Reinald Pamplona, Mariona Jové, Joaquim Sol, Elena Martin-Garcia, Manuel Martinez-Garcia, Gustavo Deco, Rafael Maldonado, José Manuel Fernández-Real, Jordi Mayneris-Perxachs
{"title":"Microviridae bacteriophages influence behavioural hallmarks of food addiction via tryptophan and tyrosine signalling pathways","authors":"Anna Castells-Nobau, Irene Puig, Anna Motger-Albertí, Lisset de la Vega-Correa, Marisel Rosell-Díaz, María Arnoriaga-Rodríguez, Anira Escrichs, Josep Garre-Olmo, Josep Puig, Rafael Ramos, Lluís Ramió-Torrentà, Vicente Pérez-Brocal, Andrés Moya, Reinald Pamplona, Mariona Jové, Joaquim Sol, Elena Martin-Garcia, Manuel Martinez-Garcia, Gustavo Deco, Rafael Maldonado, José Manuel Fernández-Real, Jordi Mayneris-Perxachs","doi":"10.1038/s42255-024-01157-x","DOIUrl":"10.1038/s42255-024-01157-x","url":null,"abstract":"Food addiction contributes to the obesity pandemic, but the connection between how the gut microbiome is linked to food addiction remains largely unclear. Here we show that Microviridae bacteriophages, particularly Gokushovirus WZ-2015a, are associated with food addiction and obesity across multiple human cohorts. Further analyses reveal that food addiction and Gokushovirus are linked to serotonin and dopamine metabolism. Mice receiving faecal microbiota and viral transplantation from human donors with the highest Gokushovirus load exhibit increased food addiction along with changes in tryptophan, serotonin and dopamine metabolism in different regions of the brain, together with alterations in dopamine receptors. Mechanistically, targeted tryptophan analysis shows lower anthranilic acid (AA) concentrations associated with Gokushovirus. AA supplementation in mice decreases food addiction and alters pathways related to the cycle of neurotransmitter synthesis release. In Drosophila, AA regulates feeding behaviour and addiction-like ethanol preference. In summary, this study proposes that bacteriophages in the gut microbiome contribute to regulating food addiction by modulating tryptophan and tyrosine metabolism. Castells-Nobau et al. provide insight into how bacteriophages in the gut microbiome contribute to regulating food addiction by modulating tryptophan and tyrosine metabolism in the host.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"6 11","pages":"2157-2186"},"PeriodicalIF":18.9,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142697060","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}
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