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Article
| Open Access
Genome-wide characterization of circulating metabolic biomarkers
A meta-analysis of genome-wide association studies for 233 circulating metabolites from 33 cohorts reveals more than 400 loci and suggests probable causal genes, providing insights into metabolic pathways and disease aetiology.
- Minna K. Karjalainen
- , Savita Karthikeyan
- & Johannes Kettunen
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Article
| Open Access
Reverse metabolomics for the discovery of chemical structures from humans
A new discovery strategy, ‘reverse metabolomics’, facilitates high-throughput matching of mass spectrometry spectra in public untargeted metabolomics datasets, and a proof-of-concept experiment identified an association between microbial bile amidates and inflammatory bowel disease.
- Emily C. Gentry
- , Stephanie L. Collins
- & Pieter C. Dorrestein
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Article
| Open Access
Gut microbial carbohydrate metabolism contributes to insulin resistance
Faecal carbohydrates, particularly host-accessible monosaccharides, are increased in individuals with insulin resistance and are associated with microbial carbohydrate metabolisms and host inflammatory cytokines.
- Tadashi Takeuchi
- , Tetsuya Kubota
- & Hiroshi Ohno
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Metabolic programs of T cell tissue residency empower tumour immunity
A study describes the metabolic adaptations supporting differentiation, survival and function of tissue-resident memory CD8+ T cells and how to leverage them to enhance immunity against pathogens and tumours.
- Miguel Reina-Campos
- , Maximilian Heeg
- & Ananda W. Goldrath
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Article
| Open Access
Mitochondrial integrated stress response controls lung epithelial cell fate
This study highlights the role of mitochondrial complex I-dependent NAD+ regeneration in directing lung epithelial cell fate during postnatal alveolar development by preventing pathological integrated stress response induction.
- SeungHye Han
- , Minho Lee
- & Navdeep S. Chandel
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Article
| Open Access
Uridine-derived ribose fuels glucose-restricted pancreatic cancer
A metabolite screen of pancreatic cells shows that pancreatic cancer cells metabolize uridine-derived ribose via UPP1, supporting redox balance, survival and proliferation.
- Zeribe C. Nwosu
- , Matthew H. Ward
- & Costas A. Lyssiotis
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Article
| Open Access
Profiling the human intestinal environment under physiological conditions
Variations in microbial composition, phage induction, antimicrobial resistance genes and bile acid profiles are identified by using an ingestible device for site-specific sampling along the intestines.
- Dari Shalon
- , Rebecca Neal Culver
- & Kerwyn Casey Huang
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Ornithine aminotransferase supports polyamine synthesis in pancreatic cancer
Pancreatic ductal adenocarcinoma cells show a specific dependency on ornithine aminotransferase-mediated ornithine synthesis from glutamine, providing an opportunity to develop targeted therapies with minimal toxicity for this cancer.
- Min-Sik Lee
- , Courtney Dennis
- & Nada Y. Kalaany
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Macrophage fumarate hydratase restrains mtRNA-mediated interferon production
Inhibition of the tricarboxylic acid cycle enzyme fumarate hydratase leads to deregulation of cytokine production in macrophages, which has implications in human diseases such as systemic lupus erythematosus.
- Alexander Hooftman
- , Christian G. Peace
- & Luke A. J. O’Neill
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Article
| Open Access
Fumarate induces vesicular release of mtDNA to drive innate immunity
Fumarate metabolism regulates the innate immune response through a mechanism in which high levels of fumarate result in the generation of mitochondrial-derived vesicles and the release of mitochondrial DNA into the cytosol, which activates inflammatory pathways.
- Vincent Zecchini
- , Vincent Paupe
- & Christian Frezza
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Slow TCA flux and ATP production in primary solid tumours but not metastases
As solid tumours develop, cancer cells shed energetically expensive tissue-specific functions, enabling uncontrolled growth despite a limited ability to produce ATP.
- Caroline R. Bartman
- , Daniel R. Weilandt
- & Joshua D. Rabinowitz
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Article
| Open Access
Insulin-regulated serine and lipid metabolism drive peripheral neuropathy
Serine deficiency can increase small fibre neuropathy in wild-type mice and serine replacement in diabetic mice alleviates diabetic neuropathy, directly linking amino acid metabolism to peripheral nerve disorders.
- Michal K. Handzlik
- , Jivani M. Gengatharan
- & Christian M. Metallo
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Article |
LACC1 bridges NOS2 and polyamine metabolism in inflammatory macrophages
Findings suggest that l-ornithine could serve as a novel nutraceutical to ameliorate LACC1-associated immunological dysfunctions.
- Zheng Wei
- , Joonseok Oh
- & Jason M. Crawford
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Article
| Open Access
PI3K drives the de novo synthesis of coenzyme A from vitamin B5
The PI3K–PANK4 axis regulates coenzyme A synthesis, the abundance of acetyl-CoA, and CoA-dependent processes such as lipid metabolism, and these regulatory mechanisms coordinate cellular CoA supplies with the demands of hormone and growth-factor-driven or oncogene-driven metabolism and growth.
- Christian C. Dibble
- , Samuel A. Barritt
- & Alex Toker
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C. elegans as a model for inter-individual variation in metabolism
Using differences among strains as a model for inter-individual variation, this paper identifies a conserved metabolicadaptation in C. elegans that compensates for genetic variation.
- Bennett W. Fox
- , Olga Ponomarova
- & Albertha J. M. Walhout
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An exercise-inducible metabolite that suppresses feeding and obesity
A newly identified exercise-induced signalling metabolite—an amidated conjugate of lactate and phenylalanine—can reduce food intake and improve blood glucose homeostasis.
- Veronica L. Li
- , Yang He
- & Jonathan Z. Long
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A non-canonical tricarboxylic acid cycle underlies cellular identity
A non-canonical tricarboxylic acid cycle is required for changes in cell state.
- Paige K. Arnold
- , Benjamin T. Jackson
- & Lydia W. S. Finley
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Article
| Open Access
B cell-derived GABA elicits IL-10+ macrophages to limit anti-tumour immunity
A paper in Nature demonstrates that B cell-derived GABA promotes monocyte differentiation into anti-inflammatory macrophages able to limit anti-tumour T cell cytotoxicity.
- Baihao Zhang
- , Alexis Vogelzang
- & Sidonia Fagarasan
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SLC25A39 is necessary for mitochondrial glutathione import in mammalian cells
SLC25A39 and its paralogue SLC25A40 have redundant roles in the import of glutathione into mitochondria of mammalian cells.
- Ying Wang
- , Frederick S. Yen
- & Kıvanç Birsoy
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Low glycaemic diets alter lipid metabolism to influence tumour growth
Lien et al. show that low glycemic diets can reduce tumour growth by deregulating lipid metabolism.
- Evan C. Lien
- , Anna M. Westermark
- & Matthew G. Vander Heiden
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The polar oxy-metabolome reveals the 4-hydroxymandelate CoQ10 synthesis pathway
18O2 labelling is used to identify metabolites in human cells that incorporate gaseous oxygen, including 4-hydroxymandelate, an intermediate in the synthesis of the coenzyme Q10 head group.
- Robert S. Banh
- , Esther S. Kim
- & Michael E. Pacold
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Article |
Dietary fructose improves intestinal cell survival and nutrient absorption
A high-fructose diet in mice improves the survival of intestinal epithelial cells, which leads to an increase in gut surface area, enhanced absorption of lipids and the promotion of tumour growth and obesity.
- Samuel R. Taylor
- , Shakti Ramsamooj
- & Marcus D. Goncalves
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A metabolomics pipeline for the mechanistic interrogation of the gut microbiome
A microbiome-focused metabolomics pipeline and interactive metabolomics profile explorer are a powerful tool for the characterization of gut-resident microorganisms and the interactions between microorganisms and their host.
- Shuo Han
- , Will Van Treuren
- & Justin L. Sonnenburg
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MFSD12 mediates the import of cysteine into melanosomes and lysosomes
A rapid labelling and immunopurification-based method is used to isolate melanosomes and profile their labile metabolites, revealing that MFSD12 has a key role in cysteine import into melanosomes and lysosomes.
- Charles H. Adelmann
- , Anna K. Traunbauer
- & David M. Sabatini
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A reference map of potential determinants for the human serum metabolome
The levels of 1,251 metabolites are measured in 475 phenotyped individuals, and machine-learning algorithms reveal that diet and the microbiome are the determinants with the strongest predictive power for the levels of these metabolites.
- Noam Bar
- , Tal Korem
- & Eran Segal
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A universal trade-off between growth and lag in fluctuating environments
A model of sequential flux bottlenecks explains a universal trade-off between steady-state growth and physiological adaptation time in bacteria exposed to fluctuating growth conditions.
- Markus Basan
- , Tomoya Honda
- & Uwe Sauer
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Mitochondrial ubiquinol oxidation is necessary for tumour growth
Oxidation of ubiquinol by the mitochondrial electron transfer chain drives tumour growth by maintaining the function of the oxidative Krebs cycle and de novo pyrimidine synthesis.
- Inmaculada Martínez-Reyes
- , Luzivette Robles Cardona
- & Navdeep S. Chandel
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Hepatic NADH reductive stress underlies common variation in metabolic traits
The authors identify an increased hepatic NADH/NAD+ ratio as an underlying metabolic parameter that is shaped by human genetic variation and contributes causally to key metabolic traits and diseases.
- Russell P. Goodman
- , Andrew L. Markhard
- & Vamsi K. Mootha
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Dietary fructose feeds hepatic lipogenesis via microbiota-derived acetate
A genetic mouse model is used to reveal a two-pronged mechanism of fructose-induced de novo lipogenesis in the liver, in which fructose catabolism in hepatocytes provides a signal to promote lipogenesis, whereas fructose metabolism by the gut microbiota provides acetate as a substrate to feed lipogenesis.
- Steven Zhao
- , Cholsoon Jang
- & Kathryn E. Wellen
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Global chemical effects of the microbiome include new bile-acid conjugations
Metabolomics data from germ-free and specific-pathogen-free mice reveal effects of the microbiome on host chemistry, identifying conjugations of bile acids that are also enriched in patients with inflammatory bowel disease or cystic fibrosis.
- Robert A. Quinn
- , Alexey V. Melnik
- & Pieter C. Dorrestein
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Lipid signalling drives proteolytic rewiring of mitochondria by YME1L
Under conditions such as hypoxia or starvation, an mTORC1-lipid signalling pathway initiates mitochondrial proteolysis by YME1L.
- Thomas MacVicar
- , Yohsuke Ohba
- & Thomas Langer
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BCAA catabolism in brown fat controls energy homeostasis through SLC25A44
The solute carrier transporter protein SLC25A44 regulates uptake of branched-chain amino acids in mitochondria of brown adipose tissue in which they are utilized for thermogenesis.
- Takeshi Yoneshiro
- , Qiang Wang
- & Shingo Kajimura
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Letter |
Lysine harvesting is an antioxidant strategy and triggers underground polyamine metabolism
The harvest of large quantities of lysine by yeast and other microbes triggers a reprogramming of redox metabolism, in which NADPH is channelled into glutathione metabolism to reduce levels of reactive oxygen species and increase tolerance to oxidative stress.
- Viridiana Olin-Sandoval
- , Jason Shu Lim Yu
- & Markus Ralser
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Letter |
Squalene accumulation in cholesterol auxotrophic lymphomas prevents oxidative cell death
The authors find that loss of squalene monooxygenase expression alters the lipid metabolism of cancer cells, which confers protection from ferroptotic cell death and thus promotes tumour growth.
- Javier Garcia-Bermudez
- , Lou Baudrier
- & Kıvanç Birsoy
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Letter |
Mitochondrial complex III is essential for suppressive function of regulatory T cells
Specific ablation of mitochondrial complex III subunits in Treg cells in mice results in inflammatory disease, altered Treg gene expression and defective Treg function, indicating a key functional role for mitochondrial complex III in Treg cells.
- Samuel E. Weinberg
- , Benjamin D. Singer
- & Navdeep S. Chandel
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Letter |
Metabolic reprogramming by the S-nitroso-CoA reductase system protects against kidney injury
AKR1A1-regulated protein S-nitrosylation protects against kidney injury through PKM2-mediated metabolic reprogramming.
- Hua-Lin Zhou
- , Rongli Zhang
- & Jonathan S. Stamler
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Letter |
Accumulation of succinate controls activation of adipose tissue thermogenesis
A comparative metabolomics approach is used to identify succinate as a key activator of thermogenesis in brown adipose tissue.
- Evanna L. Mills
- , Kerry A. Pierce
- & Edward T. Chouchani
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Letter |
A naturally occurring antiviral ribonucleotide encoded by the human genome
Viperin inhibits the replication of various viruses by catalysing the conversion of CTP to ddhCTP, which is a unique nucleotide that functions as replication-chain terminator of RNA-dependent RNA polymerases.
- Anthony S. Gizzi
- , Tyler L. Grove
- & Steven C. Almo
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Letter |
Electrophilic properties of itaconate and derivatives regulate the IκBζ–ATF3 inflammatory axis
The immunoregulatory metabolite itaconate and its dimethyl derivative induce electrophilic stress and react with glutathione to induce both Nrf2-dependent and Nrf2-independent responses, resulting in AF3-mediated inhibition of the inflammation-related protein IκBζ.
- Monika Bambouskova
- , Laurent Gorvel
- & Maxim N. Artyomov
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Letter |
Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1
WebTreatment of lipopolysaccharide-activated macrophages with the cell-permeable itaconate derivative 4-octyl itaconate activates the anti-inflammatory transcription factor Nrf2 by alkylating key cysteine residues on the KEAP1 protein.
- Evanna L. Mills
- , Dylan G. Ryan
- & Luke A. O’Neill
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Letter |
NFS1 undergoes positive selection in lung tumours and protects cells from ferroptosis
Cancers growing in high-oxygen environments, such as lung adenocarcinomas, select for the iron–sulfur cluster synthesizing enzyme NFS1 to support malignant proliferation and to protect from oxidative damage.
- Samantha W. Alvarez
- , Vladislav O. Sviderskiy
- & Richard Possemato
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Letter |
A gut bacterial pathway metabolizes aromatic amino acids into nine circulating metabolites
A pathway for the production of aromatic amino acid metabolites in Clostridium sporogenes is described; modulation of serum levels of these metabolites in gnotobiotic mice affects intestinal permeability and systemic immunity.
- Dylan Dodd
- , Matthew H. Spitzer
- & Justin L. Sonnenburg
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Letter |
BCAT1 restricts αKG levels in AML stem cells leading to IDHmut-like DNA hypermethylation
The mechanistic basis for the role of the metabolic enzyme BCAA transaminase 1 (BCAT1) in acute myeloid leukaemias.
- Simon Raffel
- , Mattia Falcone
- & Andreas Trumpp
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Letter |
Interplay between metabolic identities in the intestinal crypt supports stem cell function
The glycolytic activity of Paneth cells provides lactate, which is required by self-renewing intestinal stem cells for oxidative metabolism to activate p38 MAP kinase, ensuring regeneration of a mature crypt.
- Maria J. Rodríguez-Colman
- , Matthias Schewe
- & Boudewijn M. T. Burgering
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Article |
Thermophilic archaea activate butane via alkyl-coenzyme M formation
Anaerobic archaea enriched in thermophilic microbial consortia completely degrade butane by modifying mechanisms which were hitherto thought to be specific to methane metabolism.
- Rafael Laso-Pérez
- , Gunter Wegener
- & Florin Musat
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Letter |
Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS
A metabolomics study on the ischaemic heart identifies succinate as a metabolite that drives the production of reactive oxygen species and contributes to ischaemia-reperfusion injury; pharmacological inhibition of succinate accumulation ameliorates ischaemia-reperfusion injury in a mouse model of heart attack and a rat model of stroke.
- Edward T. Chouchani
- , Victoria R. Pell
- & Michael P. Murphy
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Letter |
Quantitative flux analysis reveals folate-dependent NADPH production
A metabolomics quantification of NADPH production and consumption fluxes in proliferating mammalian cells reveals that, in addition to canonical pathways such as the oxidative pentose phosphate pathway, NADPH can also be produced by a folate metabolism pathway, a discovery providing new insights into the metabolism of cell growth.
- Jing Fan
- , Jiangbin Ye
- & Joshua D. Rabinowitz
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Letter |
Pyrimidine homeostasis is accomplished by directed overflow metabolism
Here, the authors identify a previously unknown regulatory strategy used by Escherichia coli to control end-product levels of the pyrimidine biosynthetic pathway: this involves feedback regulation of the near-terminal pathway enzyme UMP kinase, with accumulation of UMP prevented by its degradation to uridine through UmpH, a phosphatase with a previously unknown function.
- Marshall Louis Reaves
- , Brian D. Young
- & Joshua D. Rabinowitz
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Letter |
Succinate is an inflammatory signal that induces IL-1β through HIF-1α
Succinate is identified as a metabolite in innate immune signalling, which leads to enhanced interleukin-1β production during inflammation.
- G. M. Tannahill
- , A. M. Curtis
- & L. A. J. O’Neill
Metabolic rewiring promotes anti-inflammatory effects of glucocorticoids