bims-mepmim Biomed News
on Metabolites in pathological microenvironments and immunometabolism
Issue of 2022‒10‒23
23 papers selected by
Erika Mariana Palmieri
NIH/NCI Laboratory of Cancer ImmunoMetabolism
  1. Metabolic modeling of single bronchoalveolar macrophages reveals regulators of hyperinflammation in COVID-19.
  2. Inhibiting glutamine utilization creates a synthetic lethality for suppression of ATP citrate lyase in KRas-driven cancer cells.
  3. HIRA loss transforms FH-deficient cells.
  4. Principles and functions of metabolic compartmentalization.
  5. Tumor-produced and aging-associated oncometabolite methylmalonic acid promotes cancer-associated fibroblast activation to drive metastatic progression.
  6. Nitric oxide-driven modifications of lipoic arm inhibit α-ketoacid dehydrogenases.
  7. Metabolic Recruitment in Brain Tissue.
  8. Glucose-6-phosphate dehydrogenase exerts anti-stress effects independently of its enzymatic activity.
  9. Loss of heat shock factor initiates intracellular lipid surveillance by actin destabilization.
  10. Non-invasive classification of macrophage polarisation by 2P-FLIM and machine learning.
  11. Time-restricted feeding mitigates obesity through adipocyte thermogenesis.
  12. BCAT1 redox function maintains mitotic fidelity.
  13. Intracellular Chloride Channels Regulate Endothelial Metabolic Reprogramming in Pulmonary Arterial Hypertension.
  14. Sodium thiosulfate, a source of hydrogen sulfide, stimulates endothelial cell proliferation and neovascularization.
  15. Modulations in human neutrophil metabolome and S-glutathionylation of glycolytic pathway enzymes during the course of extracellular trap formation.
  16. Purine nucleoside phosphorylase controls nicotinamide riboside metabolism in mammalian cells.
  17. Enriched dietary saturated fatty acids induce trained immunity via ceramide production that enhances severity of endotoxemia and clearance of infection.
  18. Nitrosylation rewires metabolism.
  19. Downregulation of hepatic ceruloplasmin ameliorates NAFLD via SCO1-AMPK-LKB1 complex.
  20. Muscle atrophy phenotype gene expression during spaceflight is linked to a metabolic crosstalk in both the liver and the muscle in mice.
  21. Cross talk between glucose metabolism and immunosuppression in IFN-γ-primed mesenchymal stem cells.
  22. Association of Plasma Metabolites and Lipoproteins with Rh and ABO Blood Systems in Healthy Subjects.
  23. Relief of CoA sequestration and restoration of mitochondrial function in a mouse model of propionic acidemia.
  1. iScience. 2022 Oct 10. 105319
    Metabolic modeling of single bronchoalveolar macrophages reveals regulators of hyperinflammation in COVID-19.
    Qiuchen Zhao, Zhenyang Yu, Shengyuan Zhang, Xu-Rui Shen, Hao Yang, Yangyang Xu, Yang Liu, Lin Yang, Qing Zhang, Jiaqi Chen, Mengmeng Lu, Fei Luo, Mingming Hu, Yan Gong, Conghua Xie, Peng Zhou, Li Wang, Lishan Su, Zheng Zhang, Liang Cheng.
      SARS-CoV-2 infection induces imbalanced immune response such as hyperinflammation in patients with severe COVID-19. Here we studied the immunometabolic regulatory mechanisms for the pathogenesis of COVID-19. We depicted the metabolic landscape of immune cells, especially macrophages, from bronchoalveolar lavage fluid of COVID-19 patients at single-cell level. We found that most metabolic processes were upregulated in macrophages from lungs of mild COVID-19 patients compared to cells from heathy controls, whereas macrophages from severe COVID-19 showed downregulation of most of the core metabolic pathways including glutamate metabolism, fatty acid oxidation, citrate cycle and oxidative phosphorylation, and upregulation of a few pathways such as glycolysis. Rewiring cellular metabolism by amino acid supplementation, glycolysis inhibition or PPARγ stimulation reduces inflammation in macrophages stimulated with SARS-CoV-2. Altogether, this study demonstrates that metabolic imbalance of bronchoalveolar macrophages may contribute to hyperinflammation in patients with severe COVID-19, and provides insights into treating COVID-19 by immunometabolic modulation.
    DOI:  https://doi.org/10.1016/j.isci.2022.105319
  2. PLoS One. 2022 ;17(10): e0276579
    Inhibiting glutamine utilization creates a synthetic lethality for suppression of ATP citrate lyase in KRas-driven cancer cells.
    Ahmet Hatipoglu, Deepak Menon, Talia Levy, Maria A Frias, David A Foster.
      Metabolic reprogramming is now considered a hallmark of cancer cells. KRas-driven cancer cells use glutaminolysis to generate the tricarboxylic acid cycle intermediate α-ketoglutarate via a transamination reaction between glutamate and oxaloacetate. We reported previously that exogenously supplied unsaturated fatty acids could be used to synthesize phosphatidic acid-a lipid second messenger that activates both mammalian target of rapamycin (mTOR) complex 1 (mTORC1) and mTOR complex 2 (mTORC2). A key target of mTORC2 is Akt-a kinase that promotes survival and regulates cell metabolism. We report here that mono-unsaturated oleic acid stimulates the phosphorylation of ATP citrate lyase (ACLY) at the Akt phosphorylation site at S455 in an mTORC2 dependent manner. Inhibition of ACLY in KRas-driven cancer cells in the absence of serum resulted in loss of cell viability. We examined the impact of glutamine (Gln) deprivation in combination with inhibition of ACLY on the viability of KRas-driven cancer cells. While Gln deprivation was somewhat toxic to KRas-driven cancer cells by itself, addition of the ACLY inhibitor SB-204990 increased the loss of cell viability. However, the transaminase inhibitor aminooxyacetate was minimally toxic and the combination of SB-204990 and aminooxtacetate led to significant loss of cell viability and strong cleavage of poly-ADP ribose polymerase-indicating apoptotic cell death. This effect was not observed in MCF7 breast cancer cells that do not have a KRas mutation or in BJ-hTERT human fibroblasts which have no oncogenic mutation. These data reveal a synthetic lethality between inhibition of glutamate oxaloacetate transaminase and ACLY inhibition that is specific for KRas-driven cancer cells and the apparent metabolic reprogramming induced by activating mutations to KRas.
    DOI:  https://doi.org/10.1371/journal.pone.0276579
  3. Sci Adv. 2022 Oct 21. 8(42): eabq8297
    HIRA loss transforms FH-deficient cells.
    Lorea Valcarcel-Jimenez, Connor Rogerson, Cissy Yong, Christina Schmidt, Ming Yang, Monica Cremades-Rodelgo, Victoria Harle, Victoria Offord, Kim Wong, Ariane Mora, Alyson Speed, Veronica Caraffini, Maxine Gia Binh Tran, Eamonn R Maher, Grant D Stewart, Sakari Vanharanta, David J Adams, Christian Frezza.
      Fumarate hydratase (FH) is a mitochondrial enzyme that catalyzes the reversible hydration of fumarate to malate in the tricarboxylic acid (TCA) cycle. Germline mutations of FH lead to hereditary leiomyomatosis and renal cell carcinoma (HLRCC), a cancer syndrome characterized by a highly aggressive form of renal cancer. Although HLRCC tumors metastasize rapidly, FH-deficient mice develop premalignant cysts in the kidneys, rather than carcinomas. How Fh1-deficient cells overcome these tumor-suppressive events during transformation is unknown. Here, we perform a genome-wide CRISPR-Cas9 screen to identify genes that, when ablated, enhance the proliferation of Fh1-deficient cells. We found that the depletion of the histone cell cycle regulator (HIRA) enhances proliferation and invasion of Fh1-deficient cells in vitro and in vivo. Mechanistically, Hira loss activates MYC and its target genes, increasing nucleotide metabolism specifically in Fh1-deficient cells, independent of its histone chaperone activity. These results are instrumental for understanding mechanisms of tumorigenesis in HLRCC and the development of targeted treatments for patients.
    DOI:  https://doi.org/10.1126/sciadv.abq8297
  4. Nat Metab. 2022 Oct;4(10): 1232-1244
    Principles and functions of metabolic compartmentalization.
    Liron Bar-Peled, Nora Kory.
      Metabolism has historically been studied at the levels of whole cells, whole tissues and whole organisms. As a result, our understanding of how compartmentalization-the spatial and temporal separation of pathways and components-shapes organismal metabolism remains limited. At its essence, metabolic compartmentalization fulfils three important functions or 'pillars': establishing unique chemical environments, providing protection from reactive metabolites and enabling the regulation of metabolic pathways. However, how these pillars are established, regulated and maintained at both the cellular and systemic levels remains unclear. Here we discuss how the three pillars are established, maintained and regulated within the cell and discuss the consequences of dysregulation of metabolic compartmentalization in human disease. Organelles are increasingly emerging as 'command-and-control centres' and the increased understanding of metabolic compartmentalization is revealing new aspects of metabolic homeostasis, with this knowledge being translated into therapies for the treatment of cancer and certain neurodegenerative diseases.
    DOI:  https://doi.org/10.1038/s42255-022-00645-2
  5. Nat Commun. 2022 Oct 20. 13(1): 6239
    Tumor-produced and aging-associated oncometabolite methylmalonic acid promotes cancer-associated fibroblast activation to drive metastatic progression.
    Zhongchi Li, Vivien Low, Valbona Luga, Janet Sun, Ethan Earlie, Bobak Parang, Kripa Shobana Ganesh, Sungyun Cho, Jennifer Endress, Tanya Schild, Mengying Hu, David Lyden, Wenbing Jin, Chunjun Guo, Noah Dephoure, Lewis C Cantley, Ashley M Laughney, John Blenis.
      The systemic metabolic shifts that occur during aging and the local metabolic alterations of a tumor, its stroma and their communication cooperate to establish a unique tumor microenvironment (TME) fostering cancer progression. Here, we show that methylmalonic acid (MMA), an aging-increased oncometabolite also produced by aggressive cancer cells, activates fibroblasts in the TME, which reciprocally secrete IL-6 loaded extracellular vesicles (EVs) that drive cancer progression, drug resistance and metastasis. The cancer-associated fibroblast (CAF)-released EV cargo is modified as a result of reactive oxygen species (ROS) generation and activation of the canonical and noncanonical TGFβ signaling pathways. EV-associated IL-6 functions as a stroma-tumor messenger, activating the JAK/STAT3 and TGFβ signaling pathways in tumor cells and promoting pro-aggressive behaviors. Our findings define the role of MMA in CAF activation to drive metastatic reprogramming, unveiling potential therapeutic avenues to target MMA at the nexus of aging, the tumor microenvironment and metastasis.
    DOI:  https://doi.org/10.1038/s41467-022-33862-0
  6. Nat Chem Biol. 2022 Oct 20.
    Nitric oxide-driven modifications of lipoic arm inhibit α-ketoacid dehydrogenases.
    Gretchen L Seim, Steven V John, Nicholas L Arp, Zixiang Fang, David J Pagliarini, Jing Fan.
      Pyruvate dehydrogenase complex (PDHC) and oxoglutarate dehydrogenase complex (OGDC), which belong to the mitochondrial α-ketoacid dehydrogenase family, play crucial roles in cellular metabolism. These multi-subunit enzyme complexes use lipoic arms covalently attached to their E2 subunits to transfer an acyl group to coenzyme A (CoA). Here, we report a novel mechanism capable of substantially inhibiting PDHC and OGDC: reactive nitrogen species (RNS) can covalently modify the thiols on their lipoic arms, generating a series of adducts that block catalytic activity. S-Nitroso-CoA, a product between RNS and the E2 subunit's natural substrate, CoA, can efficiently deliver these modifications onto the lipoic arm. We found RNS-mediated inhibition of PDHC and OGDC occurs during classical macrophage activation, driving significant rewiring of cellular metabolism over time. This work provides a new mechanistic link between RNS and mitochondrial metabolism with potential relevance for numerous physiological and pathological conditions in which RNS accumulate.
    DOI:  https://doi.org/10.1038/s41589-022-01153-w
  7. Annu Rev Physiol. 2022 Oct 21.
    Metabolic Recruitment in Brain Tissue.
    L F Barros, I Ruminot, T Sotelo-Hitschfeld, R Lerchundi, I Fernández-Moncada.
      Information processing imposes urgent metabolic demands on neurons, which have negligible energy stores and restricted access to fuel. Here, we discuss metabolic recruitment, the tissue-level phenomenon whereby active neurons harvest resources from their surroundings. The primary event is the neuronal release of K+ that mirrors workload. Astrocytes sense K+ in exquisite fashion thanks to their unique coexpression of NBCe1 and α2β2 Na+[Formula: see text]K+ ATPase, and within seconds switch to Crabtree metabolism, involving GLUT1, aerobic glycolysis, transient suppression of mitochondrial respiration, and lactate export. The lactate surge serves as a secondary recruiter by inhibiting glucose consumption in distant cells. Additional recruiters are glutamate, nitric oxide, and ammonium, which signal over different spatiotemporal domains. The net outcome of these events is that more glucose, lactate, and oxygen are made available. Metabolic recruitment works alongside neurovascular coupling and various averaging strategies to support the inordinate dynamic range of individual neurons. Expected final online publication date for the Annual Review of Physiology, Volume 85 is February 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
    DOI:  https://doi.org/10.1146/annurev-physiol-021422-091035
  8. J Biol Chem. 2022 Oct 12. pii: S0021-9258(22)01030-4. [Epub ahead of print] 102587
    Glucose-6-phosphate dehydrogenase exerts anti-stress effects independently of its enzymatic activity.
    Xiaohan Jin, Xuexue Li, Lifang Li, Benfu Zhong, Yang Hong, Jing Niu, Binghui Li.
      G6PD (Glucose-6-phosphate dehydrogenase) is the rate-limiting enzyme in the oxPPP (oxidative pentose phosphate pathway) that can generate cytosolic NADPH for biosynthesis and oxidative defense. Since cytosolic NADPH can be compensatively produced by other sources, the enzymatic activity-deficiency alleles of G6PD are well tolerated in somatic cells, but the effect of null mutations is unclear. Herein, we show that G6PD knockout sensitizes cells to the stresses induced by hydrogen peroxide, superoxide, hypoxia, and the inhibition of the electron transport chain. This effect can be completely reversed by the expressions of natural mutants associated with G6PD deficiency, even without dehydrogenase activity, exactly like the wild type G6PD. Furthermore, we demonstrate that G6PD can physically interact with AMPK (AMPK-activated protein kinase) to facilitate its activity, and directly bind to NAMPT (nicotinamide phosphoribosyltransferase) to promote its activity and maintain the NAD(P)H/NAD(P)+ homeostasis. These functions are necessary to the anti-stress ability of cells but independent of the dehydrogenase activity of G6PD. In addition, the wild type G6PD and naturally inactive mutant also can similarly regulate the metabolism of glucose, glutamine, fatty acid synthesis, and glutathione, and interact with the involved enzymes. Therefore, our findings reveal the previously unidentified functions of G6PD that can act as the important physiological neutralizer of stresses independently of its enzymatic activity.
    Keywords:  G6PD; NADH homeostasis; NAMPT; oxidative stress; pentose phosphate pathway
    DOI:  https://doi.org/10.1016/j.jbc.2022.102587
  9. Cell Rep. 2022 Oct 18. pii: S2211-1247(22)01343-2. [Epub ahead of print]41(3): 111493
    Loss of heat shock factor initiates intracellular lipid surveillance by actin destabilization.
    Abigail Watterson, Sonja L B Arneaud, Naureen Wajahat, Jordan M Wall, Lexus Tatge, Shaghayegh T Beheshti, Melina Mihelakis, Nicholas Y Cheatwood, Jacob McClendon, Atossa Ghorashi, Ishmael Dehghan, Chase D Corley, Jeffrey G McDonald, Peter M Douglas.
      Cells sense stress and initiate response pathways to maintain lipid and protein homeostasis. However, the interplay between these adaptive mechanisms is unclear. Herein, we demonstrate how imbalances in cytosolic protein homeostasis affect intracellular lipid surveillance. Independent of its ancient thermo-protective properties, the heat shock factor, HSF-1, modulates lipid metabolism and age regulation through the metazoan-specific nuclear hormone receptor, NHR-49. Reduced hsf-1 expression destabilizes the Caenorhabditis elegans enteric actin network, subsequently disrupting Rab GTPase-mediated trafficking and cell-surface residency of nutrient transporters. The ensuing malabsorption limits lipid availability, thereby activating the intracellular lipid surveillance response through vesicular release and nuclear translocation of NHR-49 to both increase nutrient absorption and restore lipid homeostasis. Overall, cooperation between these regulators of cytosolic protein homeostasis and lipid surveillance ensures metabolic health and age progression through actin integrity, endocytic recycling, and lipid sensing.
    Keywords:  CP: Cell biology; NHR-49; Rab GTPase; absorption; actin cytoskeleton; geranylgeranylation; heat shock factor; lipid sensing; lipid surveillance; nuclear hormone receptor; protein homeostasis
    DOI:  https://doi.org/10.1016/j.celrep.2022.111493
  10. Elife. 2022 10 18. pii: e77373. [Epub ahead of print]11
    Non-invasive classification of macrophage polarisation by 2P-FLIM and machine learning.
    Nuno G B Neto, Sinead A O'Rourke, Mimi Zhang, Hannah K Fitzgerald, Aisling Dunne, Michael G Monaghan.
      In this study, we utilise fluorescence lifetime imaging of NAD(P)H-based cellular autofluorescence as a non-invasive modality to classify two contrasting states of human macrophages by proxy of their governing metabolic state. Macrophages derived from human blood-circulating monocytes were polarised using established protocols and metabolically challenged using small molecules to validate their responding metabolic actions in extracellular acidification and oxygen consumption. Large field-of-view images of individual polarised macrophages were obtained using fluorescence lifetime imaging microscopy (FLIM). These were challenged in real time with small-molecule perturbations of metabolism during imaging. We uncovered FLIM parameters that are pronounced under the action of carbonyl cyanide-p-trifluoromethoxyphenylhydrazone (FCCP), which strongly stratifies the phenotype of polarised human macrophages; however, this performance is impacted by donor variability when analysing the data at a single-cell level. The stratification and parameters emanating from a full field-of-view and single-cell FLIM approach serve as the basis for machine learning models. Applying a random forests model, we identify three strongly governing FLIM parameters, achieving an area under the receiver operating characteristics curve (ROC-AUC) value of 0.944 and out-of-bag (OBB) error rate of 16.67% when classifying human macrophages in a full field-of-view image. To conclude, 2P-FLIM with the integration of machine learning models is showed to be a powerful technique for analysis of both human macrophage metabolism and polarisation at full FoV and single-cell level.
    Keywords:  FLIM; cell biology; cellular metabolism; human; immunology; inflammation; machine learning; macrophages; multiphoton
    DOI:  https://doi.org/10.7554/eLife.77373
  11. Science. 2022 Oct 21. 378(6617): 276-284
    Time-restricted feeding mitigates obesity through adipocyte thermogenesis.
    Chelsea Hepler, Benjamin J Weidemann, Nathan J Waldeck, Biliana Marcheva, Jonathan Cedernaes, Anneke K Thorne, Yumiko Kobayashi, Rino Nozawa, Marsha V Newman, Peng Gao, Mengle Shao, Kathryn M Ramsey, Rana K Gupta, Joseph Bass.
      Misalignment of feeding rhythms with the light-dark cycle leads to disrupted peripheral circadian clocks and obesity. Conversely, restricting feeding to the active period mitigates metabolic syndrome through mechanisms that remain unknown. We found that genetic enhancement of adipocyte thermogenesis through ablation of the zinc finger protein 423 (ZFP423) attenuated obesity caused by consumption of a high-fat diet during the inactive (light) period by increasing futile creatine cycling in mice. Circadian control of adipocyte creatine metabolism underlies the timing of diet-induced thermogenesis, and enhancement of adipocyte circadian rhythms through overexpression of the clock activator brain and muscle Arnt-like protein-1 (BMAL1) ameliorated metabolic complications during diet-induced obesity. These findings uncover rhythmic creatine-mediated thermogenesis as an essential mechanism that drives metabolic benefits during time-restricted feeding.
    DOI:  https://doi.org/10.1126/science.abl8007
  12. Cell Rep. 2022 Oct 18. pii: S2211-1247(22)01379-1. [Epub ahead of print]41(3): 111524
    BCAT1 redox function maintains mitotic fidelity.
    Liliana Francois, Pavle Boskovic, Julian Knerr, Wei He, Gianluca Sigismondo, Carsten Schwan, Tushar H More, Magdalena Schlotter, Jeroen Krijgsveld, Karsten Hiller, Robert Grosse, Peter Lichter, Bernhard Radlwimmer.
      The metabolic enzyme branched-chain amino acid transaminase 1 (BCAT1) drives cell proliferation in aggressive cancers such as glioblastoma. Here, we show that BCAT1 localizes to mitotic structures and has a non-metabolic function as a mitotic regulator. Furthermore, BCAT1 is required for chromosome segregation in cancer and induced pluripotent stem cells and tumor growth in human cerebral organoid and mouse syngraft models. Applying gene knockout and rescue strategies, we show that the BCAT1 CXXC redox motif is crucial for controlling cysteine sulfenylation specifically in mitotic cells, promoting Aurora kinase B localization to centromeres, and securing accurate chromosome segregation. These findings offer an explanation for the well-established role of BCAT1 in promoting cancer cell proliferation. In summary, our data establish BCAT1 as a component of the mitotic apparatus that safeguards mitotic fidelity through a moonlighting redox functionality.
    Keywords:  BCAT1; CP: Cell biology; cancer; chromosome segregation; metabolism; mitosis; moonlighting function; redox; stem cells
    DOI:  https://doi.org/10.1016/j.celrep.2022.111524
  13. Am J Respir Cell Mol Biol. 2022 Oct 20.
    Intracellular Chloride Channels Regulate Endothelial Metabolic Reprogramming in Pulmonary Arterial Hypertension.
    Mai M Alzaydi, Vahitha B Abdul-Salam, Harry J Whitwell, Giusy Russomanno, Angelos Glynos, Daria Capece, Gyorgy Szabadkai, Martin R Wilkins, Beata Wojciak-Stothard.
      Mitochondrial fission and a metabolic switch from oxidative phosphorylation to glycolysis are key features of vascular pathology in pulmonary arterial hypertension (PAH) and are associated with exuberant endothelial proliferation and apoptosis. The underlying mechanisms are poorly understood. We describe the contribution of two intracellular chloride channel proteins CLIC1 and CLIC4, both highly expressed in PAH and cancer, to mitochondrial dysfunction and energy metabolism in PAH endothelium. Pathological overexpression of CLIC proteins induces mitochondrial fragmentation, inhibits mitochondrial cristae formation and induces metabolic shift towards glycolysis in human pulmonary artery endothelial cells, consistent with changes observed in patient-derived cells. Interactions of CLIC proteins with structural components of the inner mitochondrial membrane offer mechanistic insights. Endothelial CLIC4 excision and mitofusin 2 supplementation have protective effects in human PAH cells and pre-clinical PAH. This study is first to demonstrate the key role of endothelial intracellular chloride channels in the regulation of mitochondrial structure, biogenesis, and metabolic reprogramming in expression of the PAH phenotype.
    Keywords:  chloride channels; endothelial; metabolism; mitochondria; pulmonary hypertension
    DOI:  https://doi.org/10.1165/rcmb.2022-0111OC
  14. Front Cardiovasc Med. 2022 ;9 965965
    Sodium thiosulfate, a source of hydrogen sulfide, stimulates endothelial cell proliferation and neovascularization.
    Diane Macabrey, Jaroslava Joniová, Quentin Gasser, Clémence Bechelli, Alban Longchamp, Severine Urfer, Martine Lambelet, Chun-Yu Fu, Guenter Schwarz, Georges Wagnières, Sébastien Déglise, Florent Allagnat.
      Therapies to accelerate vascular repair are currently lacking. Pre-clinical studies suggest that hydrogen sulfide (H2S), an endogenous gasotransmitter, promotes angiogenesis. Here, we hypothesized that sodium thiosulfate (STS), a clinically relevant source of H2S, would stimulate angiogenesis and vascular repair. STS stimulated neovascularization in WT and LDLR receptor knockout mice following hindlimb ischemia as evidenced by increased leg perfusion assessed by laser Doppler imaging, and capillary density in the gastrocnemius muscle. STS also promoted VEGF-dependent angiogenesis in matrigel plugs in vivo and in the chorioallantoic membrane of chick embryos. In vitro, STS and NaHS stimulated human umbilical vein endothelial cell (HUVEC) migration and proliferation. Seahorse experiments further revealed that STS inhibited mitochondrial respiration and promoted glycolysis in HUVEC. The effect of STS on migration and proliferation was glycolysis-dependent. STS probably acts through metabolic reprogramming of endothelial cells toward a more proliferative glycolytic state. These findings may hold broad clinical implications for patients suffering from vascular occlusive diseases.
    Keywords:  angiogenesis; arteriogenesis; endothelial cells; hydrogen sulfide; inflammation; peripheral arterial disease; thiosulfate
    DOI:  https://doi.org/10.3389/fcvm.2022.965965
  15. Biochim Biophys Acta Mol Basis Dis. 2022 Oct 17. pii: S0925-4439(22)00252-6. [Epub ahead of print] 166581
    Modulations in human neutrophil metabolome and S-glutathionylation of glycolytic pathway enzymes during the course of extracellular trap formation.
    Deepika Awasthi, Sheela Nagarkoti, Samreen Sadaf, Hobby Aggarwal, Sonu Kumar Gupta, Tulika Chandra, Yashwant Kumar, Sachin Kumar, Madhu Dikshit.
      Neutrophil extracellular trap formation (NETosis) has been irrefutably referred to as a distinct and unique form of active cell death with the purpose to counteract invading pathogens or augmenting the inflammatory cascade. Since the discovery, consistent efforts have been made to understand the various aspects of initiation and sustenance of NETosis. In this study, using a global metabolomics approach during the phorbol 12-myristate 13-acetate (PMA) induced NETosis in human neutrophils, various metabolic pathways were found to be altered which includes intermediates related to, carbohydrate metabolism, and redox related metabolites, nucleic acid metabolism, and amino acids metabolism. Enrichment analysis of the metabolite sets highlighted the importance of the pentose phosphate pathway (PPP) and glutathione metabolism PMA-induced NETotic neutrophils. Further, analysis of the glutathyniolation status of neutrophil proteins by Matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) indicated six different glutathionylated proteins: among them, two metabolically important proteins were α-enolase and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) with MALDI score 166 and 70 respectively. Other proteins were lactoferrin, β-actin, c-myc promoter-binding protein, and uracil DNA glycosylase with MALDI scores of 96, 1,67, 104, and 68 respectively. Besides, activation of signalling proteins involved in metabolic regulation is also correlated with NETosis. Altogether, a balance between reactive oxygen species-glutathione metabolism seems to regulate the activity of glycolytic enzymes such as GAPDH and α-enolase during PMA-induced NETosis in a time-dependent manner.
    Keywords:  GAPDH; Global metabolomics; NETosis; α-Enolase
    DOI:  https://doi.org/10.1016/j.bbadis.2022.166581
  16. J Biol Chem. 2022 Oct 17. pii: S0021-9258(22)01058-4. [Epub ahead of print] 102615
    Purine nucleoside phosphorylase controls nicotinamide riboside metabolism in mammalian cells.
    Andrey Kropotov, Veronika Kulikova, Ljudmila Solovjeva, Alexander Yakimov, Kirill Nerinovski, Maria Svetlova, Julia Sudnitsyna, Alena Plusnina, Maria Antipova, Mikhail Khodorkovskiy, Marie E Migaud, Stepan Gambaryan, Mathias Ziegler, Andrey Nikiforov.
      Nicotinamide riboside (NR) is an effective precursor of nicotinamide adenine dinucleotide (NAD) in human and animal cells. NR supplementation can increase the level of NAD in various tissues and thereby improve physiological functions that are weakened or lost in experimental models of aging or various human pathologies. However, there are also reports questioning the efficacy of NR supplementation. Indeed, the mechanisms of its utilization by cells are not fully understood. Herein, we investigated the role of purine nucleoside phosphorylase (PNP) in NR metabolism in mammalian cells. Using both PNP overexpression and genetic knockout, we show that after being imported into cells by members of the equilibrative nucleoside transporter family, NR is predominantly metabolized by PNP, resulting in nicotinamide (Nam) accumulation. Intracellular cleavage of NR to Nam is prevented by the potent PNP inhibitor Immucillin H in various types of mammalian cells. In turn, suppression of PNP activity potentiates NAD synthesis from NR. Combining pharmacological inhibition of PNP with NR supplementation in mice, we demonstrate that the cleavage of the riboside to Nam is strongly diminished, maintaining high levels of NR in blood, kidney and liver. Moreover, we show that PNP inhibition stimulates Nam mononucleotide and NAD+ synthesis from NR in vivo, in particular, in the kidney. Thus, we establish PNP as a major regulator of NR metabolism in mammals and provide evidence that the health benefits of NR supplementation could be greatly enhanced by concomitant downregulation of PNP activity.
    Keywords:  NAD biosynthesis; human; metabolism; mouse; nicotinamide adenine dinucleotide (NAD); nicotinamide riboside; purine nucleoside phosphorylase
    DOI:  https://doi.org/10.1016/j.jbc.2022.102615
  17. Elife. 2022 Oct 20. pii: e76744. [Epub ahead of print]11
    Enriched dietary saturated fatty acids induce trained immunity via ceramide production that enhances severity of endotoxemia and clearance of infection.
    Amy L Seufert, James W Hickman, Ste K Traxler, Rachael M Peterson, Trent A Waugh, Sydney J Lashley, Natalia Shulzhenko, Ruth J Napier, Brooke A Napier.
      Trained immunity is an innate immune memory response that is induced by primary microbial or sterile stimuli that sensitizes monocytes and macrophages to a secondary pathogenic challenge, reprogramming the host response to infection and inflammatory disease. Nutritional components, such as dietary fatty acids, can act as inflammatory stimuli, but it is unknown if they can act as the primary stimuli in the context of innate immune memory. Here we find mice fed a diet enriched exclusively in saturated fatty acids (SFAs; ketogenic diet; KD) confer a hyper-inflammatory response to systemic lipopolysaccharide (LPS) and increased mortality, independent of diet-induced microbiome and glycemic modulation. We find KD mediates the composition of the hematopoietic stem cell (HSC) compartment, and macrophages derived from the bone marrow of mice fed KD do not have altered baseline inflammation, but enhanced responses to a secondary inflammatory challenge. Lipidomics identified enhanced free palmitic acid (PA) and PA-associated lipids in KD-fed mice serum. We found pre-treatment with physiologically relevant concentrations of PA alone reprograms macrophages to induce a hyper-inflammatory response to secondary challenge with LPS. This response was found to be dependent on the synthesis of ceramide, and reversible when treated with a ceramide synthase inhibitor. In vivo, we found systemic PA confers enhanced inflammation and mortality during an acute inflammatory response to systemic LPS, and this phenotype was not reversible for up to 7 days post-PA-exposure. While PA-treatment is harmful for endotoxemia outcome, we find PA exposure enhanced clearance of Candida albicans in Rag1-/- mice. Further, we show that oleic acid (OA), a mono-unsaturated FA that depletes intracellular ceramide, reverses the PA-induced hyper-inflammatory response shown in macrophages treated with LPS, and reduces severity and mortality of LPS endotoxin stimulation, highlighting the plasticity of SFA-dependent enhanced endotoxemia severity in vivo. These are the first data to implicate enriched dietary SFAs, and specifically PA, in the induction of long-lived innate immune memory that is detrimental during an acute inflammatory response, but beneficial for clearance of pathogens.
    Keywords:  immunology; inflammation; mouse
    DOI:  https://doi.org/10.7554/eLife.76744
  18. Nat Chem Biol. 2022 Oct 20.
    Nitrosylation rewires metabolism.
    James A Nathan.
      
    DOI:  https://doi.org/10.1038/s41589-022-01169-2
  19. Cell Rep. 2022 Oct 18. pii: S2211-1247(22)01348-1. [Epub ahead of print]41(3): 111498
    Downregulation of hepatic ceruloplasmin ameliorates NAFLD via SCO1-AMPK-LKB1 complex.
    Liping Xie, Yanmei Yuan, Simiao Xu, Sijia Lu, Jinyang Gu, Yanping Wang, Yibing Wang, Xianjing Zhang, Suzhen Chen, Jian Li, Junxi Lu, Honglin Sun, Ruixiang Hu, Hailong Piao, Wen Wang, Cunchuan Wang, Jing Wang, Na Li, Morris F White, Liu Han, Weiping Jia, Ji Miao, Junli Liu.
      Copper deficiency has emerged to be associated with various lipid metabolism diseases, including non-alcoholic fatty liver disease (NAFLD). However, the mechanisms that dictate the association between copper deficiency and metabolic diseases remain obscure. Here, we reveal that copper restoration caused by hepatic ceruloplasmin (Cp) ablation enhances lipid catabolism by promoting the assembly of copper-load SCO1-LKB1-AMPK complex. Overnutrition-mediated Cp elevation results in hepatic copper loss, whereas Cp ablation restores copper content to the normal level without eliciting detectable hepatotoxicity and ameliorates NAFLD in mice. Mechanistically, SCO1 constitutively interacts with LKB1 even in the absence of copper, and copper-loaded SCO1 directly tethers LKB1 to AMPK, thereby activating AMPK and consequently promoting mitochondrial biogenesis and fatty acid oxidation. Therefore, this study reveals a mechanism by which copper, as a signaling molecule, improves hepatic lipid catabolism, and it indicates that targeting copper-SCO1-AMPK signaling pathway ameliorates NAFLD development by modulating AMPK activity.
    Keywords:  AMPK; CP: Metabolism; NAFLD; ceruloplasmin; copper sensing; fatty acid oxidation; metabolism; mitochondrial biogenesis
    DOI:  https://doi.org/10.1016/j.celrep.2022.111498
  20. iScience. 2022 Oct 21. 25(10): 105213
    Muscle atrophy phenotype gene expression during spaceflight is linked to a metabolic crosstalk in both the liver and the muscle in mice.
    Geraldine Vitry, Rebecca Finch, Gavin Mcstay, Afshin Behesti, Sébastien Déjean, Tricia Larose, Virginia Wotring, Willian Abraham da Silveira.
      Human expansion in space is hampered by the physiological risks of spaceflight. The muscle and the liver are among the most affected tissues during spaceflight and their relationships in response to space exposure have never been studied. We compared the transcriptome response of liver and quadriceps from mice on NASA RR1 mission, after 37 days of exposure to spaceflight using GSEA, ORA, and sparse partial least square-differential analysis. We found that lipid metabolism is the most affected biological process between the two organs. A specific gene cluster expression pattern in the liver strongly correlated with glucose sparing and an energy-saving response affecting high energy demand process gene expression such as DNA repair, autophagy, and translation in the muscle. Our results show that impaired lipid metabolism gene expression in the liver and muscle atrophy gene expression are two paired events during spaceflight, for which dietary changes represent a possible countermeasure.
    Keywords:  Astronautics; Omics; Space medicine; Space sciences
    DOI:  https://doi.org/10.1016/j.isci.2022.105213
  21. Life Sci Alliance. 2022 Dec;pii: e202201493. [Epub ahead of print]5(12):
    Cross talk between glucose metabolism and immunosuppression in IFN-γ-primed mesenchymal stem cells.
    Mengwei Yao, Zhuo Chen, Xiao He, Jiaoyue Long, Xuewei Xia, Zhan Li, Yu Yang, Luoquan Ao, Wei Xing, Qizhou Lian, Huaping Liang, Xiang Xu.
      The immunosuppressive function "licensed" by IFN-γ is a vital attribute of mesenchymal stem cells (MSCs) widely used in the treatment of inflammatory diseases. However, the mechanism and impact of metabolic reprogramming on MSC immunomodulatory plasticity remain unclear. Here, we explored the mechanism by which glucose metabolism affects the immunomodulatory reprogramming of MSCs "licensed" by IFN-γ. Our data showed that glucose metabolism regulates the immunosuppressive function of human umbilical cord MSCs (hUC-MSCs) challenged by IFN-γ through the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway. Furthermore, ATP facilitated the cross talk between glucose metabolism and the JAK-STAT system, which stimulates the phosphorylation of JAK2 and STATs, as well as the expression of indoleamine 2, 3-dioxygenase and programmed cell death-1 ligand. Moreover, ATP synergistically enhanced the therapeutic efficacy of IFN-γ-primed hUC-MSCs against acute pneumonia in mice. These results indicate a novel cross talk between the immunosuppressive function, glucose metabolism, and mitochondrial oxidation and provide a novel targeting strategy to enhance the therapeutic efficacies of hUC-MSCs.
    DOI:  https://doi.org/10.26508/lsa.202201493
  22. J Proteome Res. 2022 Oct 18.
    Association of Plasma Metabolites and Lipoproteins with Rh and ABO Blood Systems in Healthy Subjects.
    Francesca Di Cesare, Leonardo Tenori, Claudio Luchinat, Edoardo Saccenti.
      This study investigated the associations between the levels of 27 plasma metabolites, 114 lipoprotein parameters, determined using nuclear magnetic resonance spectroscopy, and the ABO blood groups and the Rhesus (Rh) blood system in a cohort of n = 840 Italian healthy blood donors of both sexes. We observed good multivariate discrimination between the metabolomic and lipoproteomic profiles of subjects with positive and negative Rh. In contrast, we did not observe significant discrimination for the ABO blood group pairwise comparisons, suggesting only slight metabolic differences between these group-specific metabolic profiles. We report univariate associations (P-value < 0.05) between the subfraction HDL1 related to Apo A1, the subfraction HDL2 related to cholesterol and phospholipids, and the particle number of LDL2 related to free cholesterol, cholesterol, phospholipids, and Apo B and the ABO blood groups; we observed association of the lipid main fraction LDL4 related to free cholesterol, triglycerides, and Apo B; creatine; the particle number of LDL5; the subfraction LDL5 related to Apo B; the particle number of LDL4; and the subfraction LDL4 related to Apo B with Rh blood factors. These results suggest blood group-dependent (re)shaping of lipoprotein metabolism in healthy subjects, which may provide relevant information to explain the differential susceptibility to certain diseases observed in different blood groups.
    Keywords:  HDL; LDL; lipoproteomics; metabolomics; robust linear models
    DOI:  https://doi.org/10.1021/acs.jproteome.2c00375
  23. J Inherit Metab Dis. 2022 Oct 17.
    Relief of CoA sequestration and restoration of mitochondrial function in a mouse model of propionic acidemia.
    Chitra Subramanian, Matthew W Frank, Rajendra Tangallapally, Mi-Kyung Yun, Stephen W White, Richard E Lee, Charles O Rock, Suzanne Jackowski.
      Propionic acidemia (PA, OMIM 606054) is a devastating inborn error of metabolism arising from mutations that reduce the activity of the mitochondrial enzyme propionyl-CoA carboxylase (PCC). The defects in PCC reduce the concentrations of nonesterified coenzyme A (CoASH), thus compromising mitochondrial function and disrupting intermediary metabolism. Here, we use a hypomorphic PA mouse model to test the effectiveness of BBP-671 in correcting the metabolic imbalances in PA. BBP-671 is a high-affinity allosteric pantothenate kinase activator that counteracts feedback inhibition of the enzyme to increase the intracellular concentration of CoA. Liver CoASH and acetyl-CoA are depressed in PA mice and BBP-671 treatment normalizes the cellular concentrations of these two key cofactors. Hepatic propionyl-CoA is also reduced by BBP-671 leading to an improved intracellular C3:C2-CoA ratio. Elevated plasma C3:C2-carnitine ratio and methylcitrate, hallmark biomarkers of PA, are significantly reduced by BBP-671. The large elevations of malate and α-ketoglutarate in the urine of PA mice are biomarkers for compromised tricarboxylic acid cycle activity and BBP-671 therapy reduces the amounts of both metabolites. Furthermore, the low survival of PA mice is restored to normal by BBP-671. These data show that BBP-671 relieves CoA sequestration, improves mitochondrial function, reduces plasma PA biomarkers and extends the lifespan of PA mice, providing the preclinical foundation for the therapeutic potential of BBP-671. This article is protected by copyright. All rights reserved.
    DOI:  https://doi.org/10.1002/jimd.12570
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