bims-mepmim Biomed News
on Metabolites in pathological microenvironments and immunometabolism
Issue of 2023–08–13
sixteen papers selected by
Erika Mariana Palmieri, NIH/NCI Laboratory of Cancer ImmunoMetabolism
  1. The miR-23-27-24 clusters drive lipid-associated macrophage proliferation in obese adipose tissue.
  2. Aberrant metabolite trafficking and fuel sensitivity in human pluripotent stem cell-derived islets.
  3. Pseudomonas aeruginosa hijacks the murine nitric oxide metabolic pathway to evade killing by neutrophils in the lung.
  4. Genetic ablation of ketohexokinase C isoform impairs pancreatic cancer development.
  5. Humanized mouse liver reveals endothelial control of essential hepatic metabolic functions.
  6. Fibrosis induced by resident macrophages has divergent roles in pancreas inflammatory injury and PDAC.
  7. Mitochondrial integrated stress response controls lung epithelial cell fate.
  8. Mechanisms and physiological function of daily haemoglobin oxidation rhythms in red blood cells.
  9. TNIK is a conserved regulator of glucose and lipid metabolism in obesity.
  10. High resolution cryo-EM and crystallographic snapshots of the actinobacterial two-in-one 2-oxoglutarate dehydrogenase.
  11. STING-IRG1 inhibits liver metastasis of colorectal cancer by regulating the polarization of tumor-associated macrophages.
  12. Mitochondrial metabolites predict adverse cardiovascular events in individuals with diabetes.
  13. Protocol for establishing a coculture with fibroblasts and colorectal cancer organoids.
  14. ACOT1 deficiency attenuates high-fat diet induced fat mass gain by increasing energy expenditure.
  15. A MYC-controlled redox switch protects B lymphoma cells from EGR1-dependent apoptosis.
  16. Malonyl-CoA is a conserved endogenous ATP-competitive mTORC1 inhibitor.
  1. Cell Rep. 2023 Aug 03. pii: S2211-1247(23)00939-7. [Epub ahead of print]42(8): 112928
    The miR-23-27-24 clusters drive lipid-associated macrophage proliferation in obese adipose tissue.
    Neil T Sprenkle, Nathan C Winn, Kaitlyn E Bunn, Yang Zhao, Deborah J Park, Brenna G Giese, John J Karijolich, K Mark Ansel, C Henrique Serezani, Alyssa H Hasty, Heather H Pua.
      Identifying molecular circuits that control adipose tissue macrophage (ATM) function is necessary to understand how ATMs contribute to tissue homeostasis and obesity-induced insulin resistance. In this study, we find that mice with a myeloid-specific knockout of the miR-23-27-24 clusters of microRNAs (miRNAs) gain less weight on a high-fat diet but exhibit worsened glucose and insulin tolerance. Analysis of ATMs from these mice shows selectively reduced numbers and proliferation of a recently reported subset of lipid-associated CD9+Trem2+ ATMs (lipid-associated macrophages [LAMs]). Leveraging the role of miRNAs to control networks of genes, we use RNA sequencing (RNA-seq), functional screens, and biochemical assays to identify candidate target transcripts that regulate proliferation-associated signaling. We determine that miR-23 directly targets the mRNA of Eif4ebp2, a gene that restricts protein synthesis and proliferation in macrophages. Altogether, our study demonstrates that control of proliferation of a protective subset of LAMs by noncoding RNAs contributes to protection against diet-induced obesity metabolic dysfunction.
    Keywords:  CP: Immunology; CP: Metabolism; Trem2; adipose tissue macrophage; diabetes; miR-23; miR-24; miR-27; microRNA; obesity
    DOI:  https://doi.org/10.1016/j.celrep.2023.112928
  2. Cell Rep. 2023 Aug 08. pii: S2211-1247(23)00981-6. [Epub ahead of print]42(8): 112970
    Aberrant metabolite trafficking and fuel sensitivity in human pluripotent stem cell-derived islets.
    Tom Barsby, Eliisa Vähäkangas, Jarkko Ustinov, Hossam Montaser, Hazem Ibrahim, Väinö Lithovius, Emilia Kuuluvainen, Vikash Chandra, Jonna Saarimäki-Vire, Pekka Katajisto, Ville Hietakangas, Timo Otonkoski.
      Pancreatic islets regulate blood glucose homeostasis through the controlled release of insulin; however, current metabolic models of glucose-sensitive insulin secretion are incomplete. A comprehensive understanding of islet metabolism is integral to studies of endocrine cell development as well as diabetic islet dysfunction. Human pluripotent stem cell-derived islets (SC-islets) are a developmentally relevant model of human islet function that have great potential in providing a cure for type 1 diabetes. Using multiple 13C-labeled metabolic fuels, we demonstrate that SC-islets show numerous divergent patterns of metabolite trafficking in proposed insulin release pathways compared with primary human islets but are still reliant on mitochondrial aerobic metabolism to derive function. Furthermore, reductive tricarboxylic acid cycle activity and glycolytic metabolite cycling occur in SC-islets, suggesting that non-canonical coupling factors are also present. In aggregate, we show that many facets of SC-islet metabolism overlap with those of primary islets, albeit with a retained immature signature.
    Keywords:  Beta cells; CP: Metabolism; diabetes; insulin; islets; metabolism; stem cells
    DOI:  https://doi.org/10.1016/j.celrep.2023.112970
  3. Cell Rep. 2023 Aug 09. pii: S2211-1247(23)00984-1. [Epub ahead of print]42(8): 112973
    Pseudomonas aeruginosa hijacks the murine nitric oxide metabolic pathway to evade killing by neutrophils in the lung.
    Yoshinari Nakatsuka, Masanori Matsumoto, Naohiro Inohara, Gabriel Núñez.
      Neutrophils play a critical role in the eradication of Pseudomonas aeruginosa, a major pathogen causing lung infection. However, the mechanisms used by the pathogen to evade neutrophil-mediated killing remain poorly understood. Using a high-density transposon screen, we find that P. aeruginosa colonization in the lung is promoted by pathogen nitrite reductase nirD. nirD is required for ammonia production from nitrite, a metabolite derived from nitrogen oxide (NO) generated by inducible NO synthetase (iNOS) in phagocytes. P. aeruginosa deficient in nirD exhibit reduced survival in wild-type neutrophils but not in iNOS-deficient neutrophils. Mechanistically, nirD enhances P. aeruginosa survival in neutrophils by inhibiting the localization of the pathogen in late phagosomes. P. aeruginosa deficient in nirD show impaired lung colonization after infection in wild-type mice but not in mice with selective iNos deficiency in neutrophils. Thus, P. aeruginosa uses neutrophil iNOS-mediated NO production to limit neutrophil pathogen killing and to promote its colonization in the lung.
    Keywords:  CP: Immunology; CP: Microbiology; Pseudomonas aeruginosa; ammonium; iNos; immune evasion; lung infection; neutrophils; nirD; nitric oxide; nitrite reductase
    DOI:  https://doi.org/10.1016/j.celrep.2023.112973
  4. iScience. 2023 Aug 18. 26(8): 107368
    Genetic ablation of ketohexokinase C isoform impairs pancreatic cancer development.
    Ilaria Guccini, Guanghui Tang, Trang Thuy To, Laura Di Rito, Solange Le Blanc, Oliver Strobel, Mariantonietta D'Ambrosio, Emiliano Pasquini, Marco Bolis, Pamuditha Silva, Hasan Ali Kabakci, Svenja Godbersen, Andrea Alimonti, Gerald Schwank, Markus Stoffel.
      Although dietary fructose is associated with an elevated risk for pancreatic cancer, the underlying mechanisms remain elusive. Here, we report that ketohexokinase (KHK), the rate-limiting enzyme of fructose metabolism, is a driver of PDAC development. We demonstrate that fructose triggers KHK and induces fructolytic gene expression in mouse and human PDAC. Genetic inactivation of KhkC enhances the survival of KPC-driven PDAC even in the absence of high fructose diet. Furthermore, it decreases the viability, migratory capability, and growth of KPC cells in a cell autonomous manner. Mechanistically, we demonstrate that genetic ablation of KHKC strongly impairs the activation of KRAS-MAPK pathway and of rpS6, a downstream target of mTORC signaling. Moreover, overexpression of KHKC in KPC cells enhances the downstream KRAS pathway and cell viability. Our data provide new insights into the role of KHK in PDAC progression and imply that inhibiting KHK could have profound implications for pancreatic cancer therapy.
    Keywords:  Biochemistry; Biological sciences; Cancer systems biology; Natural sciences; Systems biology
    DOI:  https://doi.org/10.1016/j.isci.2023.107368
  5. Cell. 2023 Aug 01. pii: S0092-8674(23)00795-X. [Epub ahead of print]
    Humanized mouse liver reveals endothelial control of essential hepatic metabolic functions.
    AlcHepNet
      Hepatocytes, the major metabolic hub of the body, execute functions that are human-specific, altered in human disease, and currently thought to be regulated through endocrine and cell-autonomous mechanisms. Here, we show that key metabolic functions of human hepatocytes are controlled by non-parenchymal cells (NPCs) in their microenvironment. We developed mice bearing human hepatic tissue composed of human hepatocytes and NPCs, including human immune, endothelial, and stellate cells. Humanized livers reproduce human liver architecture, perform vital human-specific metabolic/homeostatic processes, and model human pathologies, including fibrosis and non-alcoholic fatty liver disease (NAFLD). Leveraging species mismatch and lipidomics, we demonstrate that human NPCs control metabolic functions of human hepatocytes in a paracrine manner. Mechanistically, we uncover a species-specific interaction whereby WNT2 secreted by sinusoidal endothelial cells controls cholesterol uptake and bile acid conjugation in hepatocytes through receptor FZD5. These results reveal the essential microenvironmental regulation of hepatic metabolism and its human-specific aspects.
    Keywords:  FZD5; WNT2; bile acid conjugation; cholesterol; fibrosis; humanized liver; lipidomics; liver sinusoidal endothelial cells; non-alcoholic fatty liver disease; stellate cells
    DOI:  https://doi.org/10.1016/j.cell.2023.07.017
  6. Nat Immunol. 2023 Aug 10.
    Fibrosis induced by resident macrophages has divergent roles in pancreas inflammatory injury and PDAC.
    John M Baer, Chong Zuo, Liang-I Kang, Angela Alarcon de la Lastra, Nicholas C Borcherding, Brett L Knolhoff, Savannah J Bogner, Yu Zhu, Liping Yang, Jennifer Laurent, Mark A Lewis, Nan Zhang, Ki-Wook Kim, Ryan C Fields, Wayne M Yokoyama, Jason C Mills, Li Ding, Gwendalyn J Randolph, David G DeNardo.
      Tissue-resident macrophages (TRMs) are long-lived cells that maintain locally and can be phenotypically distinct from monocyte-derived macrophages. Whether TRMs and monocyte-derived macrophages have district roles under differing pathologies is not understood. Here, we showed that a substantial portion of the macrophages that accumulated during pancreatitis and pancreatic cancer in mice had expanded from TRMs. Pancreas TRMs had an extracellular matrix remodeling phenotype that was important for maintaining tissue homeostasis during inflammation. Loss of TRMs led to exacerbation of severe pancreatitis and death, due to impaired acinar cell survival and recovery. During pancreatitis, TRMs elicited protective effects by triggering the accumulation and activation of fibroblasts, which was necessary for initiating fibrosis as a wound healing response. The same TRM-driven fibrosis, however, drove pancreas cancer pathogenesis and progression. Together, these findings indicate that TRMs play divergent roles in the pathogenesis of pancreatitis and cancer through regulation of stromagenesis.
    DOI:  https://doi.org/10.1038/s41590-023-01579-x
  7. Nature. 2023 Aug 09.
    Mitochondrial integrated stress response controls lung epithelial cell fate.
    SeungHye Han, Minho Lee, Youngjin Shin, Regina Giovanni, Ram P Chakrabarty, Mariana M Herrerias, Laura A Dada, Annette S Flozak, Paul A Reyfman, Basil Khuder, Colleen R Reczek, Lin Gao, José Lopéz-Barneo, Cara J Gottardi, G R Scott Budinger, Navdeep S Chandel.
      Alveolar epithelial type 1 (AT1) cells are necessary to transfer oxygen and carbon dioxide between the blood and air. Alveolar epithelial type 2 (AT2) cells serve as a partially committed stem cell population, producing AT1 cells during postnatal alveolar development and repair after influenza A and SARS-CoV-2 pneumonia1-6. Little is known about the metabolic regulation of the fate of lung epithelial cells. Here we report that deleting the mitochondrial electron transport chain complex I subunit Ndufs2 in lung epithelial cells during mouse gestation led to death during postnatal alveolar development. Affected mice displayed hypertrophic cells with AT2 and AT1 cell features, known as transitional cells. Mammalian mitochondrial complex I, comprising 45 subunits, regenerates NAD+ and pumps protons. Conditional expression of yeast NADH dehydrogenase (NDI1) protein that regenerates NAD+ without proton pumping7,8 was sufficient to correct abnormal alveolar development and avert lethality. Single-cell RNA sequencing revealed enrichment of integrated stress response (ISR) genes in transitional cells. Administering an ISR inhibitor9,10 or NAD+ precursor reduced ISR gene signatures in epithelial cells and partially rescued lethality in the absence of mitochondrial complex I function. Notably, lung epithelial-specific loss of mitochondrial electron transport chain complex II subunit Sdhd, which maintains NAD+ regeneration, did not trigger high ISR activation or lethality. These findings highlight an unanticipated requirement for mitochondrial complex I-dependent NAD+ regeneration in directing cell fate during postnatal alveolar development by preventing pathological ISR induction.
    DOI:  https://doi.org/10.1038/s41586-023-06423-8
  8. EMBO J. 2023 Aug 09. e114164
    Mechanisms and physiological function of daily haemoglobin oxidation rhythms in red blood cells.
    Andrew D Beale, Edward A Hayter, Priya Crosby, Utham K Valekunja, Rachel S Edgar, Johanna E Chesham, Elizabeth S Maywood, Fatima H Labeed, Akhilesh B Reddy, Kenneth P Wright, Kathryn S Lilley, David A Bechtold, Michael H Hastings, John S O'Neill.
      Cellular circadian rhythms confer temporal organisation upon physiology that is fundamental to human health. Rhythms are present in red blood cells (RBCs), the most abundant cell type in the body, but their physiological function is poorly understood. Here, we present a novel biochemical assay for haemoglobin (Hb) oxidation status which relies on a redox-sensitive covalent haem-Hb linkage that forms during SDS-mediated cell lysis. Formation of this linkage is lowest when ferrous Hb is oxidised, in the form of ferric metHb. Daily haemoglobin oxidation rhythms are observed in mouse and human RBCs cultured in vitro, or taken from humans in vivo, and are unaffected by mutations that affect circadian rhythms in nucleated cells. These rhythms correlate with daily rhythms in core body temperature, with temperature lowest when metHb levels are highest. Raising metHb levels with dietary sodium nitrite can further decrease daytime core body temperature in mice via nitric oxide (NO) signalling. These results extend our molecular understanding of RBC circadian rhythms and suggest they contribute to the regulation of body temperature.
    Keywords:  body temperature; circadian rhythms; erythrocyte; haemoglobin; redox
    DOI:  https://doi.org/10.15252/embj.2023114164
  9. Sci Adv. 2023 Aug 09. 9(32): eadf7119
    TNIK is a conserved regulator of glucose and lipid metabolism in obesity.
    T C Phung Pham, Lucile Dollet, Mona S Ali, Steffen H Raun, Lisbeth L V Møller, Abbas Jafari, Nicholas Ditzel, Nicoline R Andersen, Andreas M Fritzen, Zachary Gerhart-Hines, Bente Kiens, Anu Suomalainen, Stephen J Simpson, Morten Salling Olsen, Arnd Kieser, Peter Schjerling, Anni I Nieminen, Erik A Richter, Essi Havula, Lykke Sylow.
      Obesity and type 2 diabetes (T2D) are growing health challenges with unmet treatment needs. Traf2- and NCK-interacting protein kinase (TNIK) is a recently identified obesity- and T2D-associated gene with unknown functions. We show that TNIK governs lipid and glucose homeostasis in Drosophila and mice. Loss of the Drosophila ortholog of TNIK, misshapen, altered the metabolite profiles and impaired de novo lipogenesis in high sugar-fed larvae. Tnik knockout mice exhibited hyperlocomotor activity and were protected against diet-induced fat expansion, insulin resistance, and hepatic steatosis. The improved lipid profile of Tnik knockout mice was accompanied by enhanced skeletal muscle and adipose tissue insulin-stimulated glucose uptake and glucose and lipid handling. Using the T2D Knowledge Portal and the UK Biobank, we observed associations of TNIK variants with blood glucose, HbA1c, body mass index, body fat percentage, and feeding behavior. These results define an untapped paradigm of TNIK-controlled glucose and lipid metabolism.
    DOI:  https://doi.org/10.1126/sciadv.adf7119
  10. Nat Commun. 2023 Aug 10. 14(1): 4851
    High resolution cryo-EM and crystallographic snapshots of the actinobacterial two-in-one 2-oxoglutarate dehydrogenase.
    Lu Yang, Tristan Wagner, Ariel Mechaly, Alexandra Boyko, Eduardo M Bruch, Daniela Megrian, Francesca Gubellini, Pedro M Alzari, Marco Bellinzoni.
      Actinobacteria possess unique ways to regulate the oxoglutarate metabolic node. Contrary to most organisms in which three enzymes compose the 2-oxoglutarate dehydrogenase complex (ODH), actinobacteria rely on a two-in-one protein (OdhA) in which both the oxidative decarboxylation and succinyl transferase steps are carried out by the same polypeptide. Here we describe high-resolution cryo-EM and crystallographic snapshots of representative enzymes from Mycobacterium smegmatis and Corynebacterium glutamicum, showing that OdhA is an 800-kDa homohexamer that assembles into a three-blade propeller shape. The obligate trimeric and dimeric states of the acyltransferase and dehydrogenase domains, respectively, are critical for maintaining the overall assembly, where both domains interact via subtle readjustments of their interfaces. Complexes obtained with substrate analogues, reaction products and allosteric regulators illustrate how these domains operate. Furthermore, we provide additional insights into the phosphorylation-dependent regulation of this enzymatic machinery by the signalling protein OdhI.
    DOI:  https://doi.org/10.1038/s41467-023-40253-6
  11. iScience. 2023 Aug 18. 26(8): 107376
    STING-IRG1 inhibits liver metastasis of colorectal cancer by regulating the polarization of tumor-associated macrophages.
    Yixuan Liu, Qi Sun, Chengfei Zhang, Min Ding, Cheng Wang, Qian Zheng, Zhijie Ma, Haojun Xu, Guoren Zhou, Xiaoming Wang, Zhangjun Cheng, Hongping Xia.
      The liver is the main site of colorectal cancer (CRC) metastasis. Tumor-associated macrophages (TAMs) play a key role in tumor metastasis. Therefore, modulating the function of tumor-associated macrophages is a potential therapeutic strategy to control tumor metastasis. We found in vivo experiments that the activation of STING inhibited CRC liver metastasis in model mice and affected the macrophage phenotype in the tumor microenvironment. Mechanistically, STING affects TAM polarization and regulates macrophage function through IRG1. And STING activates IRG1 to promote the nuclear translocation of TFEB, affecting the ability of macrophages to suppress tumor metastasis.Therefore, this study highlights the critical role of the STING-IRG1 axis on TAM reprogramming and its role in the process of tumor liver metastasis, which may provide a promising therapeutic strategy for CRC liver metastasis.
    Keywords:  Biological sciences; Immunity; cancer; molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2023.107376
  12. JCI Insight. 2023 Aug 08. pii: e168563. [Epub ahead of print]
    Mitochondrial metabolites predict adverse cardiovascular events in individuals with diabetes.
    Jessica A Regan, Robert J Mentz, Maggie Nguyen, Jennifer B Green, Lauren K Truby, Olga Ilkayeva, Christopher Newgard, John B Buse, Harald Sourij, C David Sjöström, Naveed Sattar, Robert W McGarrah, Yinggan Zheng, Darren K McGuire, Eberhard Standl, Paul Armstrong, Eric Peterson, Adrian Hernandez, Rury R Holman, Svati H Shah.
      Metabolic mechanisms underlying the heterogeneity of major adverse cardiovascular events (MACE) risk in individuals with type 2 diabetes mellitus (T2D) remain unclear. We hypothesized that circulating metabolites reflecting mitochondrial dysfunction predict incident MACE in T2D. Targeted mass-spectrometry profiling of 60 metabolites was performed on baseline plasma from TECOS (discovery) and EXSCEL (validation) trial biomarker substudy cohorts. A principal components analysis metabolite factor comprised of medium-chain acylcarnitines was associated with MACE in TECOS and validated in EXSCEL, with higher levels associated with higher MACE risk. Meta-analysis showed that long-chain acylcarnitines and dicarboxylacylcarnitines were also associated with MACE. Metabolites remained associated with MACE in multivariate models and favorably changed with exenatide therapy. A third cohort (CATHGEN) with T2D assessed whether these metabolites improved discriminative capability multivariate for MACE; nine metabolites (medium- and long-chain acylcarnitines and one dicarboxylacylcarnitine) were associated with time-to-MACE in CATHGEN. Addition of these metabolites to clinical models minimally improved the discriminative capability for MACE but did significantly down reclassify risk. Thus, metabolites reporting on dysregulated mitochondrial fatty acid oxidation are higher in individuals with T2D who experience subsequent MACE. These biomarkers may improve CV risk prediction models, be therapy responsive, and highlight emerging risk mechanisms.
    Keywords:  Cardiology; Cardiovascular disease; Diabetes; Metabolism; Mitochondria
    DOI:  https://doi.org/10.1172/jci.insight.168563
  13. STAR Protoc. 2023 Aug 03. pii: S2666-1667(23)00448-3. [Epub ahead of print]4(3): 102481
    Protocol for establishing a coculture with fibroblasts and colorectal cancer organoids.
    Svenja Wallisch, Sylvia Karin Neef, Lukas Denzinger, Dina Mönch, Jana Koch, Julia Marzi, Thomas Mürdter, Nicole Janssen.
      The tumor microenvironment is essential for mediating drug resistance and tumor progression. Here, we present a coculture system, which enables drug testing of colorectal cancer organoids and fibroblasts without additional matrix components such as Matrigel or basement membrane extracts. First, we describe steps to use a readout for high-throughput drug testing using a luminescence-based viability assay. Second, we detail a readout that uses flow cytometry to distinguish toxic effects on either colorectal cancer organoids or fibroblasts.
    Keywords:  Cancer; Cell Biology; Cell Culture; Organoids
    DOI:  https://doi.org/10.1016/j.xpro.2023.102481
  14. JCI Insight. 2023 Aug 10. pii: e160987. [Epub ahead of print]
    ACOT1 deficiency attenuates high-fat diet induced fat mass gain by increasing energy expenditure.
    Timothy D Heden, Mallory P Franklin, Christina Dailey, Mara T Mashek, Chen Chen, Douglas G Mashek.
      Acyl-CoA thioesterase 1 (ACOT1) catalyzes the hydrolysis of long-chain acyl-CoAs to free fatty acids and coenzyme A and is typically upregulated in obesity. Whether targeting ACOT1 in the setting of high-fat diet induced obesity would be metabolically beneficial is not known. Here we report that male and female ACOT1KO mice are partially protected from high-fat diet induced obesity, an effect associated with increased energy expenditure without alterations in physical activity or food intake. In males, ACOT1 deficiency increased mitochondrial uncoupling protein-2 (UCP2) protein abundance, while reducing 4-hydroxynonenal (4-HNE), a marker of oxidative stress, in white adipose tissue and liver of high-fat fed mice. Moreover, concurrent knockdown of UCP2 with ACOT1 in hepatocytes prevented increases in oxygen consumption observed with ACOT1 knockdown during high lipid loading, suggesting that UCP2-induced uncoupling may increase energy expenditure to attenuate weight gain. Together, these data indicate that targeting ACOT1 may be effective for obesity prevention during caloric excess by increasing energy expenditure.
    Keywords:  Fatty acid oxidation; Metabolism; Obesity; Uncoupling proteins
    DOI:  https://doi.org/10.1172/jci.insight.160987
  15. Cell Rep. 2023 Aug 09. pii: S2211-1247(23)00972-5. [Epub ahead of print]42(8): 112961
    A MYC-controlled redox switch protects B lymphoma cells from EGR1-dependent apoptosis.
    Haidong Yao, Xue Chen, Ting Wang, Muhammad Kashif, Xi Qiao, Elin Tüksammel, Lars-Gunnar Larsson, Sam Okret, Volkan I Sayin, Hong Qian, Martin O Bergo.
      Refractory and relapsed B cell lymphomas are often driven by the difficult-to-target oncogene MYC. Here, we report that high MYC expression stimulates proliferation and protects B lymphoma cells from apoptosis under normal oxidative stress levels and that compounds including N-acetylcysteine (NAC) and vitamin C (VitC) induce apoptosis by reducing oxidative stress. NAC and VitC injections effectively reduce tumor growth in lymphoma cells with high MYC expression but not in those with low MYC expression. MYC knockdown confers tumor resistance to NAC and VitC, while MYC activation renders B cells sensitive to these compounds. Mechanistically, NAC and VitC stimulate MYC binding to EGR1 through Cys117 of MYC, shifting its transcriptional output from cell cycle to apoptosis gene expression. These results identify a redox-controlled mechanism for MYC's role in maintaining proliferation and preventing apoptosis, offering a potential therapeutic rationale for evaluating NAC or VitC in patients with MYC-driven B cell lymphoma.
    Keywords:  B cell; CP: Cancer; MYC; apoptosis; lymphoma; vitamin C
    DOI:  https://doi.org/10.1016/j.celrep.2023.112961
  16. Nat Cell Biol. 2023 Aug 10.
    Malonyl-CoA is a conserved endogenous ATP-competitive mTORC1 inhibitor.
    Raffaele Nicastro, Laura Brohée, Josephine Alba, Julian Nüchel, Gianluca Figlia, Stefanie Kipschull, Peter Gollwitzer, Jesus Romero-Pozuelo, Stephanie A Fernandes, Andreas Lamprakis, Stefano Vanni, Aurelio A Teleman, Claudio De Virgilio, Constantinos Demetriades.
      Cell growth is regulated by the mammalian/mechanistic target of rapamycin complex 1 (mTORC1), which functions both as a nutrient sensor and a master controller of virtually all biosynthetic pathways. This ensures that cells are metabolically active only when conditions are optimal for growth. Notably, although mTORC1 is known to regulate fatty acid biosynthesis, how and whether the cellular lipid biosynthetic capacity signals back to fine-tune mTORC1 activity remains poorly understood. Here we show that mTORC1 senses the capacity of a cell to synthesise fatty acids by detecting the levels of malonyl-CoA, an intermediate of this biosynthetic pathway. We find that, in both yeast and mammalian cells, this regulation is direct, with malonyl-CoA binding to the mTOR catalytic pocket and acting as a specific ATP-competitive inhibitor. When fatty acid synthase (FASN) is downregulated/inhibited, elevated malonyl-CoA levels are channelled to proximal mTOR molecules that form direct protein-protein interactions with acetyl-CoA carboxylase 1 (ACC1) and FASN. Our findings represent a conserved and unique homeostatic mechanism whereby impaired fatty acid biogenesis leads to reduced mTORC1 activity to coordinately link this metabolic pathway to the overall cellular biosynthetic output. Moreover, they reveal the existence of a physiological metabolite that directly inhibits the activity of a signalling kinase in mammalian cells by competing with ATP for binding.
    DOI:  https://doi.org/10.1038/s41556-023-01198-6
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