bims-mepmim Biomed News
on Metabolites in pathological microenvironments and immunometabolism
Issue of 2022–05–29
fifty-nine papers selected by
Erika Mariana Palmieri, NIH/NCI Laboratory of Cancer ImmunoMetabolism
  1. Nicotinamide reprograms adipose cellular metabolism and increases mitochondrial biogenesis to ameliorate obesity.
  2. Increased Ammonium Toxicity in Response to Exogenous Glutamine in Metastatic Breast Cancer Cells.
  3. Cholesterol accumulation induced by acetylated LDL exposure modifies the enzymatic activities of the TCA cycle without impairing the respiratory chain functionality in macrophages.
  4. Fatty Acid Metabolism and T Cells in Multiple Sclerosis.
  5. Isolation of human and mouse myeloid-derived suppressor cells for metabolic analysis.
  6. PARK7/DJ-1 promotes pyruvate dehydrogenase activity and maintains Treg homeostasis during ageing.
  7. A Spectroscopic Technique to Simultaneously Characterize Fatty Acid Uptake, Mitochondrial Activity, Vascularity, and Oxygen Saturation for Longitudinal Studies In Vivo.
  8. Crosstalk between IL-15Rα+ tumor-associated macrophages and breast cancer cells reduces CD8+ T cell recruitment.
  9. Effect of Thrombin on the Metabolism and Function of Murine Macrophages.
  10. p16INK4A dependent senescence in the bone marrow niche drives age-related metabolic changes of hematopoietic progenitors.
  11. Leveraging STING, Batf3 Dendritic Cells, CXCR3 Ligands, and Other Components Related to Innate Immunity to Induce A "Hot" Tumor Microenvironment That Is Responsive to Immunotherapy.
  12. 13C-Isotope-Assisted Assessment of Metabolic Quenching During Sample Collection from Suspension Cell Cultures.
  13. Targeted LC-MS/MS-based metabolomics and lipidomics on limited hematopoietic stem cell numbers.
  14. MPST sulfurtransferase maintains mitochondrial protein import and cellular bioenergetics to attenuate obesity.
  15. Integrative analysis of mitochondrial metabolic dynamics in reprogramming human fibroblast cells.
  16. N6 -methyladenosine-RNA methylation promotes expression of solute carrier family 7 member 11, an uptake transporter of cystine for lipid reactive oxygen species scavenger glutathione synthesis, leading to hepatoblastoma ferroptosis resistance.
  17. Metabolic Reprogramming of Innate Immune Cells as a Possible Source of New Therapeutic Approaches in Autoimmunity.
  18. Extracellular mitochondria drive CD8 T cell dysfunction in trauma by upregulating CD39.
  19. Multiomics reveals persistence of obesity-associated immune cell phenotypes in adipose tissue during weight loss and weight regain in mice.
  20. Integrated Multiomics, Bioinformatics, and Computational Modeling Approaches to Central Metabolism in Organs.
  21. Unraveling the Rewired Metabolism in Lung Cancer Using Quantitative NMR Metabolomics.
  22. Pyruvate Upregulates Hepatic FGF21 Expression by Activating PDE and Inhibiting cAMP-Epac-CREB Signaling Pathway.
  23. SARS-CoV-2 Causes Lung Inflammation through Metabolic Reprogramming and RAGE.
  24. Oxy210, a Semi-Synthetic Oxysterol, Exerts Anti-Inflammatory Effects in Macrophages via Inhibition of Toll-like Receptor (TLR) 4 and TLR2 Signaling and Modulation of Macrophage Polarization.
  25. Methionine Deprivation Reveals the Pivotal Roles of Cell Cycle Progression in Ferroptosis That Is Induced by Cysteine Starvation.
  26. Sex-Specific Metabolic Effects of Dietary Folate Withdrawal in Wild-Type and Aldh1l1 Knockout Mice.
  27. Fibroblasts Drive Metabolic Reprogramming in Pacemaker Cardiomyocytes.
  28. Deletion of ACLY Disrupts Histone Acetylation and IL-10 Secretion in Trophoblasts, Which Inhibits M2 Polarization of Macrophages: A Possible Role in Recurrent Spontaneous Abortion.
  29. Unexpected Role of MPO-Oxidized LDLs in Atherosclerosis: In between Inflammation and Its Resolution.
  30. CD133 increases oxidative glucose metabolism of HT29 cancer cells by mitochondrial uncoupling and its inhibition enhances reactive oxygen species-inducing therapy.
  31. Blockade LAT1 Mediates Methionine Metabolism to Overcome Oxaliplatin Resistance under Hypoxia in Renal Cell Carcinoma.
  32. Multiple metabolic pathways fuel the truncated tricarboxylic acid cycle of the prostate to sustain constant citrate production and secretion.
  33. Dysfunction of the energy sensor NFE2L1 triggers uncontrollable AMPK signaling and glucose metabolism reprogramming.
  34. Robustness of the Krebs Cycle under Physiological Conditions and in Cancer: New Clues for Evaluating Metabolism-Modifying Drug Therapies.
  35. The ART of tumor immune escape.
  36. Ferroptosis at the crossroads of tumor-host interactions, metastasis, and therapy response.
  37. Circadian rhythm of lipid metabolism.
  38. Non-oxidative pentose phosphate pathway controls regulatory T cell function by integrating metabolism and epigenetics.
  39. Nicotinamide Mononucleotide Administration Amends Protein Acetylome of Aged Mouse Liver.
  40. NADH-independent enzymatic assay to quantify extracellular and intracellular L-lactate levels.
  41. Targeting of the Peritumoral Adipose Tissue Microenvironment as an Innovative Antitumor Therapeutic Strategy.
  42. O-GlcNAc modification of leucyl-tRNA synthetase 1 integrates leucine and glucose availability to regulate mTORC1 and the metabolic fate of leucine.
  43. Lysosomal lipid switch sensitises to nutrient deprivation and mTOR targeting in pancreatic cancer.
  44. Persistent CAD activity in memory CD8+ T cells supports rRNA synthesis and ribosomal biogenesis required at rechallenge.
  45. Mitochondrial damage-associated molecular patterns trigger arginase-dependent lymphocyte immunoregulation.
  46. UDP-glucose 6-dehydrogenase lessens sorafenib sensitivity via modulating unfolded protein response.
  47. Probing the Role of Cysteine Thiyl Radicals in Biology: Eminently Dangerous, Difficult to Scavenge.
  48. Lipid metabolism dysfunction induced by age-dependent DNA methylation accelerates aging.
  49. FOXO Dictates Initiation of B Cell Development and Myeloid Restriction in Common Lymphoid Progenitors.
  50. The bone marrow niche regulates redox and energy balance in MLL::AF9 leukemia stem cells.
  51. Fine tuning Acetyl-CoA Carboxylase 1 activity through localization: Functional genomics reveal a role for the lysine acetyltransferase NuA4 and sphingolipid metabolism in regulating Acc1 activity and localization.
  52. KIF11 manipulates SREBP2-dependent mevalonate cross talk to promote tumor progression in pancreatic ductal adenocarcinoma.
  53. Role of Erythrocytes in Nitric Oxide Metabolism and Paracrine Regulation of Endothelial Function.
  54. N‑acetyl cysteine prevents ambient fine particulate matter‑potentiated atherosclerosis via inhibition of reactive oxygen species‑induced oxidized low density lipoprotein elevation and decreased circulating endothelial progenitor cell.
  55. c-JUN inhibits mTORC2 and glucose uptake to promote self-renewal and obesity.
  56. Metabolic Shades of S-D-Lactoylglutathione.
  57. The Reversible Carnitine Palmitoyltransferase 1 Inhibitor (Teglicar) Ameliorates the Neurodegenerative Phenotype in a Drosophila Huntington's Disease Model by Acting on the Expression of Carnitine-Related Genes.
  58. Metabolomes of Lewis lung carcinoma metastases and normal lung tissue from mice fed different diets.
  59. Tiffany Porta Siegel (Ed.): MALDI mass spectrometry imaging: from fundamentals to spatial omics.
  1. J Nutr Biochem. 2022 May 21. pii: S0955-2863(22)00127-9. [Epub ahead of print] 109056
    Nicotinamide reprograms adipose cellular metabolism and increases mitochondrial biogenesis to ameliorate obesity.
    Chengting Luo, Changmei Yang, Xueying Wang, Yuling Chen, Xiaohui Liu, Haiteng Deng.
      Obesity poses a global health challenge and is a major risk factor for diabetes mellitus, cardiovascular diseases, hypertension, stroke and certain kinds of cancers. Although the effects of nicotinamide (NAM) on liver metabolism and diseases were well documented, its effects on adipose tissue are yet to be characterized. Herein, we found that NAM supplementation significantly reduced fat mass and improved glucose tolerance in obese mice. Proteomic analysis revealed that NAM supplementation upregulates mitochondrial proteins while qPCR showed that PPARα and PGC1α were both upregulated in adipose tissues, proposing that NAM increased mitochondrial biogenesis in adipose tissue. Indeed, NAM treatment increased proteins related to mitochondrial functions including OXPHOS, fatty acid oxidation, and TCA cycle. Furthermore, isotope-tracing assisted metabolic profiling revealed that NAM activated NAMPT and increased cellular NAD+ level by 30%. Unexpectedly, we found that NAM also increased glucose derived amino acids to enhance glutathione synthesis for maintaining cellular redox homeostasis. Taken together, our results demonstrated that NAM reprogramed cellular metabolism, enhanced adipose mitochondrial functions to ameliorate symptoms associated with obesity.
    Keywords:  glutathione; mitochondrial biogenesis; nicotinamide; nicotinamide adenine dinucleotide (NAD+); obesity
    DOI:  https://doi.org/10.1016/j.jnutbio.2022.109056
  2. Metabolites. 2022 May 23. pii: 469. [Epub ahead of print]12(5):
    Increased Ammonium Toxicity in Response to Exogenous Glutamine in Metastatic Breast Cancer Cells.
    Violet A Kiesel, Madeline P Sheeley, Shawn S Donkin, Michael K Wendt, Stephen D Hursting, Dorothy Teegarden.
      Several cancers, including breast cancers, show dependence on glutamine metabolism. The purpose of the present study was to determine the mechanistic basis and impact of differential glutamine metabolism in nonmetastatic and metastatic murine mammary cancer cells. Universally labeled 13C5-glutamine metabolic tracing, qRT-PCR, measures of reductive-oxidative balance, and exogenous ammonium chloride treatment were used to assess glutamine reprogramming. Results show that 4 mM media concentration of glutamine, compared with 2 mM, reduced viability only in metastatic cells, and that this decrease in viability was accompanied by increased incorporation of glutamine-derived carbon into the tricarboxylic acid (TCA) cycle. While increased glutamine metabolism in metastatic cells occurred in tandem with a decrease in the reduced/oxidized glutathione ratio, treatment with the antioxidant molecule N-acetylcysteine did not rescue cell viability. However, the viability of metastatic cells was more sensitive to ammonium chloride treatment compared with nonmetastatic cells, suggesting a role of metabolic reprogramming in averting nitrogen cytotoxicity in nonmetastatic cells. Overall, these results demonstrate the ability of nonmetastatic cancer cells to reprogram glutamine metabolism and that this ability may be lost in metastatic cells.
    Keywords:  ammonium toxicity; breast cancer; glutamine metabolism; metabolic reprogramming; metastasis
    DOI:  https://doi.org/10.3390/metabo12050469
  3. Biochimie. 2022 May 23. pii: S0300-9084(22)00133-X. [Epub ahead of print]
    Cholesterol accumulation induced by acetylated LDL exposure modifies the enzymatic activities of the TCA cycle without impairing the respiratory chain functionality in macrophages.
    Pierre-Hadrien Becker, Edouard Le Guillou, Mathilde Duque, Amélie Blondel, Camille Gons, Hajar Ben Souna, Apolline Imbard, Natalie Fournier, Pauline Gaignard, Patrice Thérond.
      The unregulated uptake of modified low-density lipoproteins (LDL) by macrophages leads to foam cell formation, promoting atherosclerotic plaque progression. The cholesterol efflux capacity of macrophages by the ATP-Binding Cassette transporters depends on the ATP mitochondrial production. Therefore, the mitochondrial function maintenance is crucial in limiting foam cell formation. Thus, we aimed to investigate the mechanisms involved in the mitochondrial dysfunction that may occur in cholesterol-laden macrophages. We incubated THP-1 macrophages with acetylated LDL (acLDL) to obtain cholesterol-laden cells or with mildly oxidized LDL (oxLDL) to generate cholesterol- and oxidized lipids-laden cells. Cellular cholesterol content was measured in each condition. Mitochondrial function was evaluated by measurement of several markers of energetic metabolism, oxidative phosphorylation, oxidative stress, mitochondrial biogenesis and dynamics. OxLDL-exposed macrophages exhibited a significantly reduced mitochondrial respiration and complexes I and III activities, associated to an oxidative stress state and a reduced mitochondrial DNA copy number. Meanwhile, acLDL-exposed macrophages featured an efficient oxidative phosphorylation despite the decreased activities of aconitase, isocitrate dehydrogenase and α-ketoglutarate dehydrogenase. Our study revealed that mitochondrial function was differently impacted according to the nature of modified LDL. Exposure to cholesterol and oxidized lipids carried by oxLDL leads to a mitochondrial dysfunction in macrophages, affecting the mitochondrial respiratory chain functional capacity, whereas the cellular cholesterol enrichment induced by acLDL exposure results in a tricarboxylic acid cycle shunt while maintaining mitochondrial energetic production, reflecting a metabolic adaptation to cholesterol intake. These new mechanistic insights are of direct relevance to the understanding of the mitochondrial dysfunction in foam cells.
    Keywords:  Atherosclerosis; Cholesterol; Foam cells; Low-density lipoprotein; Macrophage; Mitochondrion; Oxidative stress; Respiratory chain
    DOI:  https://doi.org/10.1016/j.biochi.2022.05.011
  4. Front Immunol. 2022 ;13 869197
    Fatty Acid Metabolism and T Cells in Multiple Sclerosis.
    Saige L Pompura, David A Hafler, Margarita Dominguez-Villar.
      Cellular metabolic remodeling is intrinsically linked to the development, activation, differentiation, function, and survival of T cells. T cells transition from a catabolic, naïve state to an anabolic effector state upon T cell activation. Subsequently, specialization of T cells into T helper (Th) subsets, including regulatory T cells (Treg), requires fine-tuning of metabolic programs that better support and optimize T cell functions for that particular environment. Increasingly, studies have shown that changes in nutrient availability at both the cellular and organismal level during disease states can alter T cell function, highlighting the importance of better characterizing metabolic-immune axes in both physiological and disease settings. In support of these data, a growing body of evidence is emerging that shows specific lipid species are capable of altering the inflammatory functional phenotypes of T cells. In this review we summarize the metabolic programs shown to support naïve and effector T cells, and those driving Th subsets. We then discuss changes to lipid profiles in patients with multiple sclerosis, and focus on how the presence of specific lipid species can alter cellular metabolism and function of T cells.
    Keywords:  T cell; T regulatory (Treg) cell; fatty acids; immunometabolism; multiple sclerosis
    DOI:  https://doi.org/10.3389/fimmu.2022.869197
  5. STAR Protoc. 2022 Jun 17. 3(2): 101389
    Isolation of human and mouse myeloid-derived suppressor cells for metabolic analysis.
    Jee Eun Choi, Cameron R MacDonald, Nishant Gandhi, Gokul Das, Elizabeth A Repasky, Hemn Mohammadpour.
      Metabolic reprogramming is associated with myeloid-derived suppressor cell (MDSC) immunosuppressive function. Here, we outline the process for acquiring MDSCs from human and murine sources for subsequent analysis of fatty acid oxidation, oxidative phosphorylation, and glycolysis using the Seahorse XFe 96 Analyzer. Murine MDSCs can be isolated directly from tumor-bearing mice or derived through IL-6 and GM-CSF culture of bone marrow cells from non-tumor-bearing mice. To generate human MDSCs, peripheral blood mononuclear cells (PBMCs) can be cultured with IL-6 and GM-CSF. For complete details on the use and execution of this protocol, please refer to Mohammadpour et al. (2021).
    Keywords:  Cancer; Cell Biology; Cell isolation; Cell-based Assays; Immunology; Metabolism; Model Organisms
    DOI:  https://doi.org/10.1016/j.xpro.2022.101389
  6. Nat Metab. 2022 May 26.
    PARK7/DJ-1 promotes pyruvate dehydrogenase activity and maintains Treg homeostasis during ageing.
    Egle Danileviciute, Ni Zeng, Christophe M Capelle, Nicole Paczia, Mark A Gillespie, Henry Kurniawan, Mohaned Benzarti, Myriam P Merz, Djalil Coowar, Sabrina Fritah, Daniela Maria Vogt Weisenhorn, Gemma Gomez Giro, Melanie Grusdat, Alexandre Baron, Coralie Guerin, Davide G Franchina, Cathy Léonard, Olivia Domingues, Sylvie Delhalle, Wolfgang Wurst, Jonathan D Turner, Jens Christian Schwamborn, Johannes Meiser, Rejko Krüger, Jeff Ranish, Dirk Brenner, Carole L Linster, Rudi Balling, Markus Ollert, Feng Q Hefeng.
      Pyruvate dehydrogenase (PDH) is the gatekeeper enzyme of the tricarboxylic acid (TCA) cycle. Here we show that the deglycase DJ-1 (encoded by PARK7, a key familial Parkinson's disease gene) is a pacemaker regulating PDH activity in CD4+ regulatory T cells (Treg cells). DJ-1 binds to PDHE1-β (PDHB), inhibiting phosphorylation of PDHE1-α (PDHA), thus promoting PDH activity and oxidative phosphorylation (OXPHOS). Park7 (Dj-1) deletion impairs Treg survival starting in young mice and reduces Treg homeostatic proliferation and cellularity only in aged mice. This leads to increased severity in aged mice during the remission of experimental autoimmune encephalomyelitis (EAE). Dj-1 deletion also compromises differentiation of inducible Treg cells especially in aged mice, and the impairment occurs via regulation of PDHB. These findings provide unforeseen insight into the complicated regulatory machinery of the PDH complex. As Treg homeostasis is dysregulated in many complex diseases, the DJ-1-PDHB axis represents a potential target to maintain or re-establish Treg homeostasis.
    DOI:  https://doi.org/10.1038/s42255-022-00576-y
  7. Metabolites. 2022 Apr 19. pii: 369. [Epub ahead of print]12(5):
    A Spectroscopic Technique to Simultaneously Characterize Fatty Acid Uptake, Mitochondrial Activity, Vascularity, and Oxygen Saturation for Longitudinal Studies In Vivo.
    Riley J Deutsch, Victoria W D'Agostino, Enakshi D Sunassee, Michelle Kwan, Megan C Madonna, Gregory Palmer, Brian T Crouch, Nimmi Ramanujam.
      Aggressive breast cancer has been shown to shift its metabolism towards increased lipid catabolism as the primary carbon source for oxidative phosphorylation. In this study, we present a technique to longitudinally monitor lipid metabolism and oxidative phosphorylation in pre-clinical tumor models to investigate the metabolic changes with mammary tissue development and characterize metabolic differences between primary murine breast cancer and normal mammary tissue. We used optical spectroscopy to measure the signal of two simultaneously injected exogenous fluorescent metabolic reporters: TMRE (oxidative phosphorylation surrogate) and Bodipy FL C16 (lipid catabolism surrogate). We leverage an inverse Monte Carlo algorithm to correct for aberrations resulting from tissue optical properties and to extract vascular endpoints relevant to oxidative metabolism, specifically oxygen saturation (SO2) and hemoglobin concentration ([Hb]). We extensively validated our optical method to demonstrate that our two fluorescent metabolic endpoints can be measured without chemical or optical crosstalk and that dual measurements of both fluorophores in vivo faithfully recapitulate the measurements of each fluorophore independently. We then applied our method to track the metabolism of growing 4T1 and 67NR breast tumors and aging mammary tissue, all highly metabolic tissue types. Our results show the changes in metabolism as a function of mammary age and tumor growth, and these changes can be best distinguished through the combination of endpoints measured with our system. Clustering analysis incorporating both Bodipy FL C16 and TMRE endpoints combined with either SO2 or [Hb] proved to be the most effective in minimizing intra-group variance and maximizing inter-group differences. Our platform can be extended to applications in which long-term metabolic flexibility is important to study, for example in tumor regression, recurrence following dormancy, and responses to cancer treatment.
    Keywords:  fatty acid uptake; mitochondrial metabolism; murine tumor lines; optical spectroscopy; tumor metabolism; tumor vascular environment
    DOI:  https://doi.org/10.3390/metabo12050369
  8. Cancer Commun (Lond). 2022 May 25.
    Crosstalk between IL-15Rα+ tumor-associated macrophages and breast cancer cells reduces CD8+ T cell recruitment.
    Wenlong Zhang, Qing Zhang, Nanfei Yang, Qian Shi, Huifang Su, Tingsheng Lin, Zhonglei He, Wenxin Wang, Hongqian Guo, Pingping Shen.
       BACKGROUND: Interleukin-15 (IL-15) is a promising immunotherapeutic agent owing to its powerful immune-activating effects. However, the clinical benefits of these treatments are limited. Crosstalk between tumor cells and immune cells plays an important role in immune escape and immunotherapy drug resistance. Herein, this study aimed to obtain in-depth understanding of crosstalk in the tumor microenvironment for providing potential therapeutic strategies to prevent tumor progression.
    METHODS: T-cell killing assays and co-culture models were developed to determine the role of crosstalk between macrophages and tumor cells in breast cancer resistant to IL-15. Western blotting, histological analysis, CRISPR-Cas9 knockout, multi-parameter flow cytometry, and tumor cell-macrophage co-injection mouse models were developed to examine the mechanism by which IL-15Rα+ tumor-associated macrophages (TAMs) regulate breast cancer cell resistance to IL-15.
    RESULTS: We found that macrophages contributed to the resistance of tumor cells to IL-15, and tumor cells induced macrophages to express high levels of the α subunit of the IL-15 receptor (IL-15Rα). Further investigation showed that IL-15Rα+ TAMs reduced the protein levels of chemokine CX3C chemokine ligand 1 (CX3CL1) in tumor cells to inhibit the recruitment of CD8+ T cells by releasing the IL-15/IL-15Rα complex (IL-15Rc). Administration of an IL-15Rc blocking peptide markedly suppressed breast tumor growth and overcame the resistance of cancer cells to anti- programmed cell death protein 1 (PD-1) antibody immunotherapy. Interestingly, Granulocyte-macrophage colony-stimulating factor (GMCSF) induced γ chain (γc) expression to promote tumor cell-macrophage crosstalk, which facilitated tumor resistance to IL-15. Additionally, we observed that the non-transcriptional regulatory function of hypoxia inducible factor-1alpha (HIF-1α) was essential for IL-15Rc to regulate CX3CL1 expression in tumor cells.
    CONCLUSIONS: The IL-15Rc-HIF-1α-CX3CL1 signaling pathway serves as a crosstalk between macrophages and tumor cells in the tumor microenvironment of breast cancer. Targeting this pathway may provide a potential therapeutic strategy for enhancing the efficacy of cancer immunotherapy.
    Keywords:  CD8+ T-cell; IL-15Rα; breast cancer; crosstalk; immunotherapy; tumor microenvironment; tumor-associated macrophages
    DOI:  https://doi.org/10.1002/cac2.12311
  9. Cells. 2022 May 23. pii: 1718. [Epub ahead of print]11(10):
    Effect of Thrombin on the Metabolism and Function of Murine Macrophages.
    Ürün Ukan, Fredy Delgado Lagos, Sebastian Kempf, Stefan Günther, Mauro Siragusa, Beate Fisslthaler, Ingrid Fleming.
      Macrophages are plastic and heterogeneous immune cells that adapt pro- or anti-inflammatory phenotypes upon exposure to different stimuli. Even though there has been evidence supporting a crosstalk between coagulation and innate immunity, the way in which protein components of the hemostasis pathway influence macrophages remains unclear. We investigated the effect of thrombin on macrophage polarization. On the basis of gene expression and cytokine secretion, our results suggest that polarization with thrombin induces an anti-inflammatory, M2-like phenotype. In functional studies, thrombin polarization promoted oxLDL phagocytosis by macrophages, and conditioned medium from the same cells increased endothelial cell proliferation. There were, however, clear differences between the classical M2a polarization and the effects of thrombin on gene expression. Finally, the deletion and inactivation of secreted modular Ca2+-binding protein 1 (SMOC1) attenuated phagocytosis by thrombin-stimulated macrophages, a phenomenon revered by the addition of recombinant SMOC1. Manipulation of SMOC1 levels also had a pronounced impact on the expression of TGF-β-signaling-related genes. Taken together, our results show that thrombin induces an anti-inflammatory macrophage phenotype with similarities as well as differences to the classical alternatively activated M2 polarization states, highlighting the importance of tissue levels of SMOC1 in modifying thrombin-induced macrophage polarization.
    Keywords:  SMOC1; macrophage polarization; thrombin
    DOI:  https://doi.org/10.3390/cells11101718
  10. Blood Adv. 2022 May 27. pii: bloodadvances.2022007033. [Epub ahead of print]
    p16INK4A dependent senescence in the bone marrow niche drives age-related metabolic changes of hematopoietic progenitors.
    Charlotte Hellmich, Edyta Wojtowicz, Jamie A Moore, Jayna J Mistry, Aisha Jibril, Benjamin B Johnson, James Gw Smith, Naiara Beraza, Kristian M Bowles, Stuart A Rushworth.
      Rapid and effective leucocyte response to infection is a fundamental function of the bone marrow (BM). However, with increasing age this response becomes impaired, resulting in an increased burden of infectious diseases. Here, we investigate how aging changes the metabolism and function of hematopoietic progenitor cells (HPCs) and the impact of the bone marrow niche on this phenotype. We found that, in response to LPS induced stress, HPC mitochondrial function is impaired and there is a failure to upregulate the TCA cycle in progenitor populations in aged animals compared to young animals. Furthermore, aged mesenchymal stromal cells (MSC) of the BM niche, but not HPCs, exhibit a senescent phenotype and selective depletion of senescent cells from the BM niche, as well as treatment with the senolytic drug ABT-263, improves mitochondrial function of HPCs when stressed with LPS. In summary, age related HPC metabolic dysfunction occurs indirectly as a 'bystander phenomenon' in the aging BM niche and can be restored by targeting senescent MSCs.
    DOI:  https://doi.org/10.1182/bloodadvances.2022007033
  11. Cancers (Basel). 2022 May 16. pii: 2458. [Epub ahead of print]14(10):
    Leveraging STING, Batf3 Dendritic Cells, CXCR3 Ligands, and Other Components Related to Innate Immunity to Induce A "Hot" Tumor Microenvironment That Is Responsive to Immunotherapy.
    Robin Reschke, Daniel J Olson.
      In a T-cell-inflamed phenotype, tumor eradication works best and is potentiated by immunotherapy such as checkpoint blockade. However, a majority of patients die despite receiving immunotherapy. One reason is insufficient T cell priming and infiltration in the tumor. Nature provides us with innate immune mechanisms in T-cell-inflamed tumors that we can adopt for more personalized immunotherapy strategies. Tumor sensing through innate signaling pathways and efficient antigen-presenting possess a significant role in bridging innate and adaptive immunity and generating a T-cell-inflamed tumor. One approach to strengthen these innate immune mechanisms is to deliver innate immune factors such as STING or activated DCs into the tumor microenvironment, in particular in patients resistant to checkpoint blockade. The low number of DCs in the tumor bed could potentially be increased with the growth factor FMS-like tyrosine kinase 3 ligand (Flt3L). CD103+ DCs are integral for three phases of anti-tumor immunity: priming, recruiting, and re-invigoration of effector T cells. Re-activation of dysfunctional T cells is achieved via co-stimulatory molecules such as the 4-1BB ligand. The presence of myeloid-cell-derived CXCL9 and CXCL10 in the tumor microenvironment can predict response to immunotherapy. We outline recent preclinical and clinical approaches to deliver these crucial components bridging innate and adaptive immunity into the tumor microenvironment.
    Keywords:  chemokines; dendritic cells; tumor microenvironment
    DOI:  https://doi.org/10.3390/cancers14102458
  12. Anal Chem. 2022 May 25.
    13C-Isotope-Assisted Assessment of Metabolic Quenching During Sample Collection from Suspension Cell Cultures.
    Bo Wang, Jamey D Young.
      Metabolomics and fluxomics are core approaches to directly profile and interrogate cellular metabolism in response to various genetic or environmental perturbations. In order to accurately measure the abundance and isotope enrichment of intracellular metabolites, cell culture samples must be rapidly harvested and cold quenched to preserve the in vivo metabolic state of the cells at the time of sample collection. When dealing with suspension cultures, this process is complicated by the need to separate the liquid culture media from cellular biomass prior to metabolite extraction. Here, we examine the efficacy of several commonly used metabolic quenching methods, using the model cyanobacterium Synechocystis sp. PCC 6803 as an example. Multiple 13C-labeled compounds, including 13C-bicarbonate, 13C-glucose, and 13C-glutamine, were used as tracers during the sample collection and the cold-quenching process to assess the extent of metabolic turnover after cells were harvested from culture flasks. We show that the combination of rapid filtration followed by 100% cold (-80 °C) methanol quenching exhibits the highest quenching efficiency, while mixing cell samples with a partially frozen 30% methanol slurry (-24 °C) followed by centrifugation is slightly less effective at quenching metabolism but enables less laborious sample processing. By contrast, rapidly mixing the cells with a saline ice slurry (∼0 °C) is less effective, as indicated by high isotope-labeling rates after sample harvest, while mixing the cells with 60% cold methanol (-65 °C) prior to centrifugation causes significant metabolite loss. This study demonstrates a rigorous, quantitative, and broadly applicable method for assessing the metabolic quenching efficacy of protocols used for sample collection in metabolomics and fluxomics studies.
    DOI:  https://doi.org/10.1021/acs.analchem.1c05338
  13. STAR Protoc. 2022 Jun 17. 3(2): 101408
    Targeted LC-MS/MS-based metabolomics and lipidomics on limited hematopoietic stem cell numbers.
    Katharina Schönberger, Michael Mitterer, Joerg M Buescher, Nina Cabezas-Wallscheid.
      Metabolism is important for the regulation of hematopoietic stem cells (HSCs) and drives cellular fate. Due to the scarcity of HSCs, it has been technically challenging to perform metabolome analyses gaining insight into HSC metabolic regulatory networks. Here, we present two targeted liquid chromatography-mass spectrometry approaches that enable the detection of metabolites after fluorescence-activated cell sorting when sample amounts are limited. One protocol covers signaling lipids and retinoids, while the second detects tricarboxylic acid cycle metabolites and amino acids. For complete details on the use and execution of this protocol, please refer to Schönberger et al. (2022).
    Keywords:  Mass Spectrometry; Metabolomics; Stem Cells
    DOI:  https://doi.org/10.1016/j.xpro.2022.101408
  14. J Exp Med. 2022 Jul 04. pii: e20211894. [Epub ahead of print]219(7):
    MPST sulfurtransferase maintains mitochondrial protein import and cellular bioenergetics to attenuate obesity.
    Antonia Katsouda, Dimitrios Valakos, Vasilios S Dionellis, Sofia-Iris Bibli, Ioannis Akoumianakis, Sevasti Karaliota, Karim Zuhra, Ingrid Fleming, Noriyuki Nagahara, Sophia Havaki, Vassilis G Gorgoulis, Dimitris Thanos, Charalambos Antoniades, Csaba Szabo, Andreas Papapetropoulos.
      Given the clinical, economic, and societal impact of obesity, unraveling the mechanisms of adipose tissue expansion remains of fundamental significance. We previously showed that white adipose tissue (WAT) levels of 3-mercaptopyruvate sulfurtransferase (MPST), a mitochondrial cysteine-catabolizing enzyme that yields pyruvate and sulfide species, are downregulated in obesity. Here, we report that Mpst deletion results in fat accumulation in mice fed a high-fat diet (HFD) through transcriptional and metabolic maladaptation. Mpst-deficient mice on HFD exhibit increased body weight and inguinal WAT mass, reduced metabolic rate, and impaired glucose/insulin tolerance. At the molecular level, Mpst ablation activates HIF1α, downregulates subunits of the translocase of outer/inner membrane (TIM/TOM) complex, and impairs mitochondrial protein import. MPST deficiency suppresses the TCA cycle, oxidative phosphorylation, and fatty acid oxidation, enhancing lipid accumulation. Sulfide donor administration to obese mice reverses the HFD-induced changes. These findings reveal the significance of MPST for white adipose tissue biology and metabolic health and identify a potential new therapeutic target for obesity.
    DOI:  https://doi.org/10.1084/jem.20211894
  15. STAR Protoc. 2022 Jun 17. 3(2): 101401
    Integrative analysis of mitochondrial metabolic dynamics in reprogramming human fibroblast cells.
    Young Cha, Pierre Leblanc, Yean Ju Hong, Kwang-Soo Kim.
      Mitochondrial dynamics play critical roles in both tissue homeostasis and somatic cell reprogramming. Here, we provide integrated guidance for assessing mitochondrial function and dynamics while reprogramming human fibroblasts via an integrated analysis approach. This protocol includes instructions for mitochondrial metabolic analysis in real time and flow cytometry-based assessment of mitochondrial mass and membrane potential. We also describe a protocol for quantification of mitochondrial network and key metabolites. For complete details on the use and execution of this protocol, please refer to Cha et al. (2021).
    Keywords:  Cell Biology; Cell culture; Cell-based Assays; Flow Cytometry/Mass Cytometry; Metabolism; Microscopy; Stem Cells
    DOI:  https://doi.org/10.1016/j.xpro.2022.101401
  16. Clin Transl Med. 2022 May;12(5): e889
    N6 -methyladenosine-RNA methylation promotes expression of solute carrier family 7 member 11, an uptake transporter of cystine for lipid reactive oxygen species scavenger glutathione synthesis, leading to hepatoblastoma ferroptosis resistance.
    Ronald A Hill, Yong-Yu Liu.
      
    Keywords:  METTL3; RNA methylation; SLC7A11 transporter; cystine; ferroptosis; hepatoblastoma
    DOI:  https://doi.org/10.1002/ctm2.889
  17. Cells. 2022 May 17. pii: 1663. [Epub ahead of print]11(10):
    Metabolic Reprogramming of Innate Immune Cells as a Possible Source of New Therapeutic Approaches in Autoimmunity.
    Leila Mohammadnezhad, Mojtaba Shekarkar Azgomi, Marco Pio La Manna, Guido Sireci, Chiara Rizzo, Giusto Davide Badami, Bartolo Tamburini, Francesco Dieli, Giuliana Guggino, Nadia Caccamo.
      Immune cells undergo different metabolic pathways or immunometabolisms to interact with various antigens. Immunometabolism links immunological and metabolic processes and is critical for innate and adaptive immunity. Although metabolic reprogramming is necessary for cell differentiation and proliferation, it may mediate the imbalance of immune homeostasis, leading to the pathogenesis and development of some diseases, such as autoimmune diseases. Here, we discuss the effects of metabolic changes in autoimmune diseases, exerted by the leading actors of innate immunity, and their role in autoimmunity pathogenesis, suggesting many immunotherapeutic approaches.
    Keywords:  HIF-1α; autoimmunity; chronic inflammatory disease; glycolysis; immune response; innate immunity; metabolic pathways; oxidative phosphorylation; therapy
    DOI:  https://doi.org/10.3390/cells11101663
  18. Thorax. 2022 May 25. pii: thoraxjnl-2021-218047. [Epub ahead of print]
    Extracellular mitochondria drive CD8 T cell dysfunction in trauma by upregulating CD39.
    Shilpa Tiwari-Heckler, Ghee Rye Lee, James Harbison, Carola Ledderose, Eva Csizmadia, David Melton, Quanzhi Zhang, Wolfgang Junger, Guanqing Chen, Carl J Hauser, Leo E Otterbein, Maria Serena Longhi, Simon Christopher Robson.
       RATIONALE: The increased mortality and morbidity seen in critically injured patients appears associated with systemic inflammatory response syndrome (SIRS) and immune dysfunction, which ultimately predisposes to infection. Mitochondria released by injury could generate danger molecules, for example, ATP, which in turn would be rapidly scavenged by ectonucleotidases, expressed on regulatory immune cells.
    OBJECTIVE: To determine the association between circulating mitochondria, purinergic signalling and immune dysfunction after trauma.
    METHODS: We tested the impact of hepatocyte-derived free mitochondria on blood-derived and lung-derived CD8 T cells in vitro and in experimental mouse models in vivo. In parallel, immune phenotypic analyses were conducted on blood-derived CD8 T cells obtained from trauma patients.
    RESULTS: Isolated intact mitochondria are functional and generate ATP ex vivo. Extracellular mitochondria perturb CD8+ T cells in co-culture, inducing select features of immune exhaustion in vitro. These effects are modulated by scavenging ATP, modelled by addition of apyrase in vitro. Injection of intact mitochondria into recipient mice markedly upregulates the ectonucleotidase CD39, and other immune checkpoint markers in circulating CD8+ T cells. We note that mice injected with mitochondria, prior to instilling bacteria into the lung, exhibit more severe lung injury, characterised by elevated neutrophil influx and by changes in CD8+ T cell cytotoxic capacity. Importantly, the development of SIRS in injured humans, is likewise associated with disordered purinergic signalling and CD8 T cell dysfunction.
    CONCLUSION: These studies in experimental models and in a cohort of trauma patients reveal important associations between extracellular mitochondria, aberrant purinergic signalling and immune dysfunction. These pathogenic factors with immune exhaustion are linked to SIRS and could be targeted therapeutically.
    Keywords:  Bacterial Infection; Critical Care; Emergency Medicine; Pneumonia
    DOI:  https://doi.org/10.1136/thoraxjnl-2021-218047
  19. Nat Commun. 2022 May 26. 13(1): 2950
    Multiomics reveals persistence of obesity-associated immune cell phenotypes in adipose tissue during weight loss and weight regain in mice.
    Matthew A Cottam, Heather L Caslin, Nathan C Winn, Alyssa H Hasty.
      Within adipose tissue (AT), immune cells and parenchymal cells closely interact creating a complex microenvironment. In obesity, immune cell derived inflammation contributes to insulin resistance and glucose intolerance. Diet-induced weight loss improves glucose tolerance; however, weight regain further exacerbates the impairment in glucose homeostasis observed with obesity. To interrogate the immunometabolic adaptations that occur in AT during murine weight loss and weight regain, we utilized cellular indexing of transcriptomes and epitopes by sequencing (CITEseq) in male mice. Obesity-induced imprinting of AT immune cells persisted through weight-loss and progressively worsened with weight regain, ultimately leading to impaired recovery of type 2 regulatory cells, activation of antigen presenting cells, T cell exhaustion, and enhanced lipid handling in macrophages in weight cycled mice. This work provides critical groundwork for understanding the immunological causes of weight cycling-accelerated metabolic disease. For further discovery, we provide an open-access web portal of diet-induced AT immune cell imprinting: https://hastylab.shinyapps.io/MAIseq .
    DOI:  https://doi.org/10.1038/s41467-022-30646-4
  20. Methods Mol Biol. 2022 ;2399 151-170
    Integrated Multiomics, Bioinformatics, and Computational Modeling Approaches to Central Metabolism in Organs.
    Sonia Cortassa, Pierre Villon, Steven J Sollott, Miguel A Aon.
      Data-driven research led by computational systems biology methods, encompassing bioinformatics of multiomics datasets and mathematical modeling, are critical for discovery. Herein, we describe a multiomics (metabolomics-fluxomics) approach as applied to heart function in diabetes. The methodology presented has general applicability and enables the quantification of the fluxome or set of metabolic fluxes from cytoplasmic and mitochondrial compartments in central catabolic pathways of glucose and fatty acids. Additionally, we present, for the first time, a general method to reduce the dimension of detailed kinetic, and in general stoichiometric models of metabolic networks at the steady state, to facilitate their optimization and avoid numerical problems. Representative results illustrate the powerful mechanistic insights that can be gained from this integrative and quantitative methodology.
    Keywords:  Diabetes; Fluxomics; Glucose and fatty acids catabolism; Heart; Kinetic modeling; Metabolomics
    DOI:  https://doi.org/10.1007/978-1-0716-1831-8_7
  21. Int J Mol Sci. 2022 May 17. pii: 5602. [Epub ahead of print]23(10):
    Unraveling the Rewired Metabolism in Lung Cancer Using Quantitative NMR Metabolomics.
    Karolien Vanhove, Elien Derveaux, Liesbet Mesotten, Michiel Thomeer, Maarten Criel, Hanne Mariën, Peter Adriaensens.
      Lung cancer cells are well documented to rewire their metabolism and energy production networks to enable proliferation and survival in a nutrient-poor and hypoxic environment. Although metabolite profiling of blood plasma and tissue is still emerging in omics approaches, several techniques have shown potential in cancer diagnosis. In this paper, the authors describe the alterations in the metabolic phenotype of lung cancer patients. In addition, we focus on the metabolic cooperation between tumor cells and healthy tissue. Furthermore, the authors discuss how metabolomics could improve the management of lung cancer patients.
    Keywords:  NMR (nuclear magnetic resonance); lung cancer; metabolism
    DOI:  https://doi.org/10.3390/ijms23105602
  22. Int J Mol Sci. 2022 May 14. pii: 5490. [Epub ahead of print]23(10):
    Pyruvate Upregulates Hepatic FGF21 Expression by Activating PDE and Inhibiting cAMP-Epac-CREB Signaling Pathway.
    Yan-Yan Zhao, Li-Jun Zhang, Xiang-Yan Liang, Xiao-Chun Zhang, Jin-Rui Chang, Man Shi, Huan Liu, Ying Zhou, Zhuo Sun, Yu-Feng Zhao.
      Fibroblast growth factor 21 (FGF21) functions as a polypeptide hormone to regulate glucose and lipid metabolism, and its expression is regulated by cellular metabolic stress. Pyruvate is an important intermediate metabolite that acts as a key hub for cellular fuel metabolism. However, the effect of pyruvate on hepatic FGF21 expression and secretion remains unknown. Herein, we examined the gene expression and protein levels of FGF21 in human hepatoma HepG2 cells and mouse AML12 hepatocytes in vitro, as well as in mice in vivo. In HepG2 and AML12 cells, pyruvate at concentrations above 0.1 mM significantly increased FGF21 expression and secretion. The increase in cellular cAMP levels by adenylyl cyclase activation, phosphodiesterase (PDE) inhibition and 8-Bromo-cAMP administration significantly restrained pyruvate-stimulated FGF21 expression. Pyruvate significantly increased PDE activities, reduced cAMP levels and decreased CREB phosphorylation. The inhibition of exchange protein directed activated by cAMP (Epac) and cAMP response element binding protein (CREB) upregulated FGF21 expression, upon which pyruvate no longer increased FGF21 expression. The increase in plasma pyruvate levels in mice induced by the intraperitoneal injection of pyruvate significantly increased FGF21 gene expression and PDE activity with a reduction in cAMP levels and CREB phosphorylation in the mouse liver compared with the control. In conclusion, pyruvate activates PDEs to reduce cAMP and then inhibits the cAMP-Epac-CREB signaling pathway to upregulate FGF21 expression in hepatocytes.
    Keywords:  CREB; FGF21; PDE; cAMP; hepatocytes; pyruvate
    DOI:  https://doi.org/10.3390/ijms23105490
  23. Viruses. 2022 May 06. pii: 983. [Epub ahead of print]14(5):
    SARS-CoV-2 Causes Lung Inflammation through Metabolic Reprogramming and RAGE.
    Charles N S Allen, Maryline Santerre, Sterling P Arjona, Lea J Ghaleb, Muna Herzi, Megan D Llewellyn, Natalia Shcherbik, Bassel E Sawaya.
      Clinical studies indicate that patients infected with SARS-CoV-2 develop hyperinflammation, which correlates with increased mortality. The SARS-CoV-2/COVID-19-dependent inflammation is thought to occur via increased cytokine production and hyperactivity of RAGE in several cell types, a phenomenon observed for other disorders and diseases. Metabolic reprogramming has been shown to contribute to inflammation and is considered a hallmark of cancer, neurodegenerative diseases, and viral infections. Malfunctioning glycolysis, which normally aims to convert glucose into pyruvate, leads to the accumulation of advanced glycation end products (AGEs). Being aberrantly generated, AGEs then bind to their receptor, RAGE, and activate several pro-inflammatory genes, such as IL-1b and IL-6, thus, increasing hypoxia and inducing senescence. Using the lung epithelial cell (BEAS-2B) line, we demonstrated that SARS-CoV-2 proteins reprogram the cellular metabolism and increase pyruvate kinase muscle isoform 2 (PKM2). This deregulation promotes the accumulation of AGEs and senescence induction. We showed the ability of the PKM2 stabilizer, Tepp-46, to reverse the observed glycolysis changes/alterations and restore this essential metabolic process.
    Keywords:  RAGE; SARS-CoV-2; Tepp-46; glycolysis; inflammation; metabolic reprogramming; mitochondria
    DOI:  https://doi.org/10.3390/v14050983
  24. Int J Mol Sci. 2022 May 13. pii: 5478. [Epub ahead of print]23(10):
    Oxy210, a Semi-Synthetic Oxysterol, Exerts Anti-Inflammatory Effects in Macrophages via Inhibition of Toll-like Receptor (TLR) 4 and TLR2 Signaling and Modulation of Macrophage Polarization.
    Feng Wang, Frank Stappenbeck, Liu-Ya Tang, Ying E Zhang, Simon T Hui, Aldons J Lusis, Farhad Parhami.
      Inflammatory responses by the innate and adaptive immune systems protect against infections and are essential to health and survival. Many diseases including atherosclerosis, osteoarthritis, rheumatoid arthritis, psoriasis, and obesity involve persistent chronic inflammation. Currently available anti-inflammatory agents, including non-steroidal anti-inflammatory drugs, steroids, and biologics, are often unsafe for chronic use due to adverse effects. The development of effective non-toxic anti-inflammatory agents for chronic use remains an important research arena. We previously reported that oral administration of Oxy210, a semi-synthetic oxysterol, ameliorates non-alcoholic steatohepatitis (NASH) induced by a high-fat diet in APOE*3-Leiden.CETP humanized mouse model of NASH and inhibits expression of hepatic and circulating levels of inflammatory cytokines. Here, we show that Oxy210 also inhibits diet-induced white adipose tissue inflammation in APOE*3-Leiden.CETP mice, evidenced by the inhibition of adipose tissue expression of IL-6, MCP-1, and CD68 macrophage marker. Oxy210 and related analogs exhibit anti-inflammatory effects in macrophages treated with lipopolysaccharide in vitro, mediated through inhibition of toll-like receptor 4 (TLR4), TLR2, and AP-1 signaling, independent of cyclooxygenase enzymes or steroid receptors. The anti-inflammatory effects of Oxy210 are correlated with the inhibition of macrophage polarization. We propose that Oxy210 and its structural analogs may be attractive candidates for future therapeutic development for targeting inflammatory diseases.
    Keywords:  Oxy210; anti-inflammatory agents; inflammation; macrophage polarization; oxysterol therapeutics; oxysterols; toll-like receptors (TLRs); white adipose tissue
    DOI:  https://doi.org/10.3390/ijms23105478
  25. Cells. 2022 May 10. pii: 1603. [Epub ahead of print]11(10):
    Methionine Deprivation Reveals the Pivotal Roles of Cell Cycle Progression in Ferroptosis That Is Induced by Cysteine Starvation.
    Takujiro Homma, Sho Kobayashi, Junichi Fujii.
      Ferroptosis, a type of iron-dependent necrotic cell death, is triggered by the accumulation of excessive lipid peroxides in cells. Glutathione (GSH), a tripeptide redox molecule that contains a cysteine (Cys) unit in the center, plays a pivotal role in protection against ferroptosis. When the transsulfuration pathway is activated, the sulfur atom of methionine (Met) is utilized to generate Cys, which can then suppress Cys-starvation-induced ferroptosis. In the current study, we cultured HeLa cells in Met- and/or cystine (an oxidized Cys dimer)- deprived medium and investigated the roles of Met in ferroptosis execution. The results indicate that, in the absence of cystine or Met, ferroptosis or cell cycle arrest, respectively, occurred. Contrary to our expectations, however, the simultaneous deprivation of both Met and cystine failed to induce ferroptosis, although the intracellular levels of Cys and GSH were maintained at low levels. Supplementation with S-adenosylmethionine (SAM), a methyl group donor that is produced during the metabolism of Met, caused the cell cycle progression to resume and lipid peroxidation and the subsequent induction of ferroptosis was also restored under conditions of Met/cystine double deprivation. DNA methylation appeared to be involved in the resumption in the SAM-mediated cell cycle because its downstream metabolite S-adenosylhomocysteine failed to cause either cell cycle progression or ferroptosis to be induced. Taken together, our results suggest that elevated lipid peroxidation products that are produced during cell cycle progression are involved in the execution of ferroptosis under conditions of Cys starvation.
    Keywords:  cell cycle; cysteine; ferroptosis; glutathione; methionine
    DOI:  https://doi.org/10.3390/cells11101603
  26. Metabolites. 2022 May 18. pii: 454. [Epub ahead of print]12(5):
    Sex-Specific Metabolic Effects of Dietary Folate Withdrawal in Wild-Type and Aldh1l1 Knockout Mice.
    Jaspreet Sharma, Blake R Rushing, Madeline S Hall, Kristi L Helke, Susan L McRitchie, Natalia I Krupenko, Susan J Sumner, Sergey A Krupenko.
      ALDH1L1 (10-formyltetrahydrofolate dehydrogenase), an enzyme of folate metabolism, is highly expressed in the liver. It regulates the overall flux of folate-bound one-carbon groups by converting 10-formyltetrahydrofolate to tetrahydrofolate and CO2 in a NADP+-dependent reaction. Our previous study revealed that Aldh1l1 knockout (KO) mice have an altered liver metabotype with metabolic symptoms of folate deficiency when fed a standard chow diet containing 2 ppm folic acid. Here we performed untargeted metabolomic analysis of liver and plasma of KO and wild-type (WT) male and female mice fed for 16 weeks either standard or folate-deficient diet. OPLS-DA, a supervised multivariate technique that was applied to 6595 and 10,678 features for the liver and plasma datasets, respectively, indicated that genotype and diet, alone or in combination, gave distinct metabolic profiles in both types of biospecimens. A more detailed analysis of affected metabolic pathways based on most confidently identified metabolites in the liver and plasma (OL1 and OL2a ontology level) indicated that the dietary folate restriction itself does not fully recapitulate the metabolic effect of the KO. Of note, dietary folate withdrawal enhanced the metabolic perturbations linked to the ALDH1L1 loss only for a subset of metabolites. Importantly, both the ALDH1L1 loss and dietary folate deficiency produced sex-specific metabolic effects.
    Keywords:  Aldh1l1 knockout; dietary folate restriction; folate metabolism; liver; plasma; untargeted metabolomics
    DOI:  https://doi.org/10.3390/metabo12050454
  27. Circ Res. 2022 May 25. 101161CIRCRESAHA121320301
    Fibroblasts Drive Metabolic Reprogramming in Pacemaker Cardiomyocytes.
    Pei-Chun Chou, Chih-Min Liu, Ching-Hui Weng, Kai-Chien Yang, Mei-Ling Cheng, Yuh-Charn Lin, Ruey-Bing Yang, Bai-Chuang Shyu, Song-Kun Shyue, Jin-Dian Liu, Shih-Pin Chen, Michael Hsiao, Yu-Feng Hu.
       BACKGROUND: The sinoatrial node (SAN) is characterized by the microenvironment of pacemaker cardiomyocytes (PCs) encased with fibroblasts. An altered microenvironment leads to rhythm failure. Operable cell or tissue models are either generally lacking or difficult to handle. The biological process behind the milieu of SANs to evoke pacemaker rhythm is unknown. We explored how fibroblasts interact with PCs and regulate metabolic reprogramming and rhythmic activity in the SAN.
    METHODS: Tbx18 (T-box transcription factor 18)-induced PCs and fibroblasts were used for cocultures and engineered tissues, which were used as the in vitro models to explore how fibroblasts regulate the functional integrity of SANs. RNA-sequencing, metabolomics, and cellular and molecular techniques were applied to characterize the molecular signals underlying metabolic reprogramming and identify its critical regulators. These pathways were further validated in vivo in rodents and induced human pluripotent stem cell-derived cardiomyocytes.
    RESULTS: We observed that rhythmicity in Tbx18-induced PCs was regulated by aerobic glycolysis. Fibroblasts critically activated metabolic reprogramming and aerobic glycolysis within PCs, and, therefore, regulated pacemaker activity in PCs. The metabolic reprogramming was attributed to the exclusive induction of Aldoc (aldolase c) within PCs after fibroblast-PC integration. Fibroblasts activated the integrin-dependent mitogen-activated protein kinase-E2F1 signal through cell-cell contact and turned on Aldoc expression in PCs. Interruption of fibroblast-PC interaction or Aldoc knockdown nullified electrical activity. Engineered Tbx18-PC tissue sheets were generated to recapitulate the microenvironment within SANs. Aldoc-driven rhythmic machinery could be replicated within tissue sheets. Similar machinery was faithfully validated in de novo PCs of adult mice and rats, and in human PCs derived from induced pluripotent stem cells.
    CONCLUSIONS: Fibroblasts drive Aldoc-mediated metabolic reprogramming and rhythmic regulation in SANs. This work details the cellular machinery behind the complex milieu of vertebrate SANs and opens a new direction for future therapy.
    Keywords:  fibroblasts; glycolysis; integrins; metabolomics; vertebrates
    DOI:  https://doi.org/10.1161/CIRCRESAHA.121.320301
  28. Oxid Med Cell Longev. 2022 ;2022 5216786
    Deletion of ACLY Disrupts Histone Acetylation and IL-10 Secretion in Trophoblasts, Which Inhibits M2 Polarization of Macrophages: A Possible Role in Recurrent Spontaneous Abortion.
    Xin Chen, Qian Lin Song, Ze Hong Li, Rui Ji, Jia Yu Wang, Chang Ge, Zhuo Ni Xiao, Duan Ying Guo, Jing Yang.
      Changes to macrophage polarization affect the local microenvironment of the placenta, resulting in pathological pregnancy diseases such as recurrent spontaneous abortion (RSA). Macrophages are in close contact with trophoblasts during placental development, and trophoblast-derived cytokines are important regulators of macrophage polarization and function. Histone acetylation can affect the expression and secretion of cytokines, and ATP citrate lyase (ACLY) is an important factor that regulates histone acetylation. The aim of this study was to investigate the effect of ACLY expression differences in trophoblast on macrophage polarization and its mechanism. Our data demonstrate that ACLY level in placental villi of patients with RSA is decreased, which may lead to the inhibition of histone acetylation in trophoblasts, thereby reducing the secretion of IL-10. Reduced IL-10 secretion activates endoplasmic reticulum stress in macrophages, thus inhibiting their M2 polarization.
    DOI:  https://doi.org/10.1155/2022/5216786
  29. Antioxidants (Basel). 2022 Apr 28. pii: 874. [Epub ahead of print]11(5):
    Unexpected Role of MPO-Oxidized LDLs in Atherosclerosis: In between Inflammation and Its Resolution.
    Cecilia Tangeten, Karim Zouaoui Boudjeltia, Cedric Delporte, Pierre Van Antwerpen, Keziah Korpak.
      Inflammation and its resolution are the result of the balance between pro-inflammatory and pro-resolving factors, such as specialized pro-resolving mediators (SPMs). This balance is crucial for plaque evolution in atherosclerosis, a chronic inflammatory disease. Myeloperoxidase (MPO) has been related to oxidative stress and atherosclerosis, and MPO-oxidized low-density lipoproteins (Mox-LDLs) have specific characteristics and effects. They participate in foam cell formation and cause specific reactions when interacting with macrophages and endothelial cells. They also increase the production of intracellular reactive oxygen species (ROS) in macrophages and the resulting antioxidant response. Mox-LDLs also drive macrophage polarization. Mox-LDLs are known to be pro-inflammatory particles. However, in the presence of Mox-LDLs, endothelial cells produce resolvin D1 (RvD1), a SPM. SPMs are involved in the resolution of inflammation by stimulating efferocytosis and by reducing the adhesion and recruitment of neutrophils and monocytes. RvD1 also induces the synthesis of other SPMs. In vitro, Mox-LDLs have a dual effect by promoting RvD1 release and inducing a more anti-inflammatory phenotype macrophage, thereby having a mixed effect on inflammation. In this review, we discuss the interrelationship between MPO, Mox-LDLs, and resolvins, highlighting a new perception of the role of Mox-LDLs in atherosclerosis.
    Keywords:  atherosclerosis; inflammation; myeloperoxidase; myeloperoxidase oxidized low-density lipoprotein; resolvin D1; specialized pro-resolving mediators
    DOI:  https://doi.org/10.3390/antiox11050874
  30. Nucl Med Commun. 2022 May 30.
    CD133 increases oxidative glucose metabolism of HT29 cancer cells by mitochondrial uncoupling and its inhibition enhances reactive oxygen species-inducing therapy.
    Jin Hee Lee, Eun Ji Lee, Jin Won Park, Mina Kim, Kyung-Ho Jung, Young Seok Cho, Kyung-Han Lee.
       OBJECTIVE: A better understanding of the metabolic phenotype of stem-like cancer cells could provide targets to help overcome chemoresistance. In this study, we hypothesized that colon cancer cells with the stem cell feature of CD133 expression have increased proton leakage that influences glucose metabolism and offers protection against reactive oxygen species (ROS)-inducing treatment.
    METHODS AND RESULTS: In HT29 colon cancer cells, 18F-fluorodeoxyglucose (FDG) uptake was increased by CD133 selection and decreased by CD133 silencing. In CD133(+) cells, greater 18F-FDG uptake was accompanied by increased oxygen consumption rate (OCR) and reduced mitochondrial membrane potential and mitochondrial ROS, indicating increased proton leakage. The uncoupling protein inhibitor genipin reversed the increased 18F-FDG uptake and greater OCR of CD133(+) cells. The ROS-inducing drug, piperlongumine, suppressed CD133(-) cell survival by stimulating mitochondrial ROS generation but was unable to influence CD133(+) cells when used alone. However, cotreatment of CD133(+) cells with genipin and piperlongumine efficiently stimulated mitochondrial ROS for an enhanced antitumor effect with substantially reduced CD133 expression.
    CONCLUSION: These results demonstrate that mitochondrial uncoupling is a metabolic feature of CD133(+) colon cancer cells that provides protection against piperlongumine therapy by suppressing mitochondrial ROS generation. Hence, combining genipin with ROS-inducing treatment may be an effective strategy to reverse the metabolic feature and eliminate stem-like colon cancer cells.
    DOI:  https://doi.org/10.1097/MNM.0000000000001587
  31. Cancers (Basel). 2022 May 22. pii: 2551. [Epub ahead of print]14(10):
    Blockade LAT1 Mediates Methionine Metabolism to Overcome Oxaliplatin Resistance under Hypoxia in Renal Cell Carcinoma.
    Qingwen Xu, Yuxi Liu, Wen Sun, Tiantian Song, Xintong Jiang, Kui Zeng, Su Zeng, Lu Chen, Lushan Yu.
      Hypoxic microenvironment and metabolic dysregulation of tumor impairs the therapeutic efficacy of chemotherapeutic drugs, resulting in drug resistance and tumor metastasis, which has always been a challenge for the treatment of solid tumors, including renal cell carcinoma (RCC). Herein, starting from the evaluation of methionine metabolism in RCC cells, we demonstrated that the increased methionine accumulation in RCC cells was mediated by L-type amino acid transporter 1 (LAT1) under hypoxia. Glutathione (GSH), as a methionine metabolite, would attenuate the therapeutic efficacy of oxaliplatin through chemical chelation. Reducing methionine uptake by LAT1 inhibitor JPH203 significantly enhanced the sensitivity of RCC cells to oxaliplatin by reducing GSH production in vitro and in vivo. Therefore, we proposed an effective and stable therapeutic strategy based on the combination of oxaliplatin and LAT1 inhibitor, which is expected to solve the resistance of RCC to platinum-based drugs under hypoxia to a certain extent, providing a meaningful insight into the development of new therapeutic strategies and RCC treatment.
    Keywords:  LAT1; drug combination; hypoxia; methionine metabolism; renal cell carcinoma
    DOI:  https://doi.org/10.3390/cancers14102551
  32. Mol Metab. 2022 May 19. pii: S2212-8778(22)00085-0. [Epub ahead of print] 101516
    Multiple metabolic pathways fuel the truncated tricarboxylic acid cycle of the prostate to sustain constant citrate production and secretion.
    Lilianne Frégeau-Proulx, Aurélie Lacouture, Line Berthiaume, Cindy Weidmann, Mario Harvey, Kevin Gonthier, Jean-François Pelletier, Bertrand Neveu, Cynthia Jobin, Dominic Bastien, Alain Bergeron, Yves Fradet, Louis Lacombe, Isabelle Laverdière, Chantal Atallah, Frédéric Pouliot, Étienne Audet-Walsh.
       OBJECTIVE: The prostate is metabolically unique: it produces high levels of citrate for secretion via a truncated tricarboxylic acid (TCA) cycle to maintain male fertility. In prostate cancer (PCa), this phenotype is reprogrammed, making it an interesting therapeutic target. However, how the truncated prostate TCA cycle works is still not completely understood.
    METHODS: We optimized targeted metabolomics in mouse and human organoid models in ex vivo primary culture. We then used stable isotope tracer analyses to identify the pathways that fuel citrate synthesis.
    RESULTS: First, mouse and human organoids were shown to recapitulate the unique citrate-secretory program of the prostate, thus representing a novel model that reproduces this unusual metabolic profile. Using stable isotope tracer analysis, several key nutrients were shown to allow the completion of the prostate TCA cycle, revealing a much more complex metabolic profile than originally anticipated. Indeed, along with the known pathway of aspartate replenishing oxaloacetate, glutamine was shown to fuel citrate synthesis through both glutaminolysis and reductive carboxylation in a GLS1-dependent manner. In human organoids, aspartate entered the TCA cycle at the malate entry point, upstream of oxaloacetate. Our results demonstrate that the citrate-secretory phenotype of prostate organoids is supported by the known aspartate-oxaloacetate-citrate pathway, but also by at least three additional pathways: glutaminolysis, reductive carboxylation, and aspartate-malate conversion.
    CONCLUSIONS: Our results add a significant new dimension to the prostate citrate-secretory phenotype, with at least four distinct pathways being involved in citrate synthesis. Better understanding this distinctive citrate metabolic program will have applications in both male fertility as well as in the development of novel targeted anti-metabolic therapies for PCa.
    Keywords:  TCA cycle; androgen; fertility; organoids; prostate cancer
    DOI:  https://doi.org/10.1016/j.molmet.2022.101516
  33. Cell Death Dis. 2022 May 25. 13(5): 501
    Dysfunction of the energy sensor NFE2L1 triggers uncontrollable AMPK signaling and glucose metabolism reprogramming.
    Lu Qiu, Qiufang Yang, Wenshan Zhao, Yadi Xing, Peng Li, Xiaowen Zhou, Haoming Ning, Ranran Shi, Shanshan Gou, Yalan Chen, Wenjie Zhai, Yahong Wu, Guodong Li, Zhenzhen Chen, Yonggang Ren, Yanfeng Gao, Yiguo Zhang, Yuanming Qi.
      The antioxidant transcription factor NFE2L1 (also called Nrf1) acts as a core regulator of redox signaling and metabolism homeostasis, and thus, its dysfunction results in multiple systemic metabolic diseases. However, the molecular mechanism(s) by which NFE2L1 regulates glycose and lipid metabolism remains elusive. Here, we found that loss of NFE2L1 in human HepG2 cells led to a lethal phenotype upon glucose deprivation and NFE2L1 deficiency could affect the uptake of glucose. Further experiments revealed that glycosylation of NFE2L1 enabled it to sense the energy state. These results indicated that NFE2L1 can serve as a dual sensor and regulator of glucose homeostasis. The transcriptome, metabolome, and seahorse data further revealed that disruption of NFE2L1 could reprogram glucose metabolism to aggravate the Warburg effect in NFE2L1-silenced hepatoma cells, concomitant with mitochondrial damage. Co-expression and Co-immunoprecipitation experiments demonstrated that NFE2L1 could directly interact and inhibit AMPK. Collectively, NFE2L1 functioned as an energy sensor and negatively regulated AMPK signaling through directly interacting with AMPK. The novel NFE2L1/AMPK signaling pathway delineate the mechanism underlying of NFE2L1-related metabolic diseases and highlight the crosstalk between redox homeostasis and metabolism homeostasis.
    DOI:  https://doi.org/10.1038/s41419-022-04917-3
  34. Biomedicines. 2022 May 22. pii: 1199. [Epub ahead of print]10(5):
    Robustness of the Krebs Cycle under Physiological Conditions and in Cancer: New Clues for Evaluating Metabolism-Modifying Drug Therapies.
    Rafael Franco, Joan Serrano-Marín.
      The Krebs cycle in cells that contain mitochondria is necessary for both energy production and anabolic processes. In given cell/condition, the Krebs cycle is dynamic but remains at a steady state. In this article, we first aimed at comparing the properties of a closed cycle versus the same metabolism in a linear array. The main finding is that, unlike a linear metabolism, the closed cycle can reach a steady state (SS) regardless of the nature and magnitude of the disturbance. When the cycle is modeled with input and output reactions, the "open" cycle is robust and reaches a steady state but with exceptions that lead to sustained accumulation of intermediate metabolites, i.e., conditions at which no SS can be achieved. The modeling of the cycle in cancer, trying to obtain marked reductions in flux, shows that these reductions are limited and therefore the Warburg effect is moderate at most. In general, our results of modeling the cycle in different conditions and looking for the achievement, or not, of SS, suggest that the cycle may have a regulation, not yet discovered, to go from an open cycle to a closed one. Said regulation could allow for reaching the steady state, thus avoiding the unwanted effects derived from the aberrant accumulation of metabolites in the mitochondria. The information in this paper might be useful to evaluate metabolism-modifying medicines.
    Keywords:  anaplerotic reactions; broken Krebs cycle; carcinoma; citric acid cycle; mitophagy
    DOI:  https://doi.org/10.3390/biomedicines10051199
  35. Oncoimmunology. 2022 ;11(1): 2076310
    The ART of tumor immune escape.
    Erik Wennerberg, Sumit Mukherjee, Ricardo M Sainz, Brendon M Stiles.
      We recently identified the adenosine-5'-diphosphate (ADP)-ribosyltransferase-1 (ART1) as a novel immune checkpoint expressed by cancer cells. ART1 utilizes free nicotinamide adenine dinucleotide (NAD+) in the tumor microenvironment (TME) to mono-ADP-ribosylate (MARylate) the P2X7 receptor (P2X7R) on CD8 T cells, resulting in NAD-induced cell death (NICD) and tumor immune resistance. This process is blocked by therapeutic antibody targeting of ART1.
    Keywords:  CD38; CD8 T cells; NAD-induced cell death; P2X7 receptor; immune escape; lung cancer; mono-ADP-ribosylation
    DOI:  https://doi.org/10.1080/2162402X.2022.2076310
  36. Am J Physiol Cell Physiol. 2022 May 25.
    Ferroptosis at the crossroads of tumor-host interactions, metastasis, and therapy response.
    Yinan Yao, Yuxin Shi, Zizhe Gao, Yutong Sun, Fan Yao, Li Ma.
      Ferroptosis is a form of regulated cell death characterized by the accumulation of lipid peroxides in an iron-dependent manner. Ferroptotic cell death is modulated by many metabolic pathways, such as pathways governing the metabolism of sugars, lipids, amino acids, and iron, as well as mitochondrial activity and redox homeostasis. Tumor metastasis and therapy resistance are the main obstacles to curing cancers. Because tumor cells usually exhibit higher iron dependence than normal cells, they may be more susceptible to ferroptosis despite being resistant to other forms of cell death. Moreover, recent evidence has suggested that ferroptosis is involved in tumor-host interactions, modulates the tumor microenvironment, and serves as an anti-metastatic mechanism. Thus, inducing ferroptosis in tumor cells has the potential to improve cancer treatment. Here, we review ferroptosis-regulating mechanisms and the roles of ferroptosis in malignant progression, including the tumor-host interactions, metastasis, and cancer therapy response.
    Keywords:  Ferroptosis; Metastasis; Therapy response; Tumor-host interactions
    DOI:  https://doi.org/10.1152/ajpcell.00148.2022
  37. Biochem Soc Trans. 2022 May 23. pii: BST20210508. [Epub ahead of print]
    Circadian rhythm of lipid metabolism.
    Flore Sinturel, Weronika Spaleniak, Charna Dibner.
      Lipids comprise a diverse group of metabolites that are indispensable as energy storage molecules, cellular membrane components and mediators of inter- and intra-cellular signaling processes. Lipid homeostasis plays a crucial role in maintaining metabolic health in mammals including human beings. A growing body of evidence suggests that the circadian clock system ensures temporal orchestration of lipid homeostasis, and that perturbation of such diurnal regulation leads to the development of metabolic disorders comprising obesity and type 2 diabetes. In view of the emerging role of circadian regulation in maintaining lipid homeostasis, in this review, we summarize the current knowledge on lipid metabolic pathways controlled by the mammalian circadian system. Furthermore, we review the emerging connection between the development of human metabolic diseases and changes in lipid metabolites that belong to major classes of lipids. Finally, we highlight the mechanisms underlying circadian organization of lipid metabolic rhythms upon the physiological situation, and the consequences of circadian clock dysfunction for dysregulation of lipid metabolism.
    Keywords:  T2D; circadian clock; lipid metabolism; lipidomics; metabolic disorders
    DOI:  https://doi.org/10.1042/BST20210508
  38. Nat Metab. 2022 May 23.
    Non-oxidative pentose phosphate pathway controls regulatory T cell function by integrating metabolism and epigenetics.
    Qi Liu, Fangming Zhu, Xinnan Liu, Ying Lu, Ke Yao, Na Tian, Lingfeng Tong, David A Figge, Xiuwen Wang, Yichao Han, Yakui Li, Yemin Zhu, Lei Hu, Yingning Ji, Nannan Xu, Dan Li, Xiaochuan Gu, Rui Liang, Guifang Gan, Lifang Wu, Ping Zhang, Tianle Xu, Hui Hu, Zeping Hu, Huji Xu, Dan Ye, Hui Yang, Bin Li, Xuemei Tong.
      Regulatory T (Treg) cells are critical for maintaining immune homeostasis and preventing autoimmunity. Here, we show that the non-oxidative pentose phosphate pathway (PPP) regulates Treg function to prevent autoimmunity. Deletion of transketolase (TKT), an indispensable enzyme of non-oxidative PPP, in Treg cells causes a fatal autoimmune disease in mice, with impaired Treg suppressive capability despite regular Treg numbers and normal Foxp3 expression levels. Mechanistically, reduced glycolysis and enhanced oxidative stress induced by TKT deficiency triggers excessive fatty acid and amino acid catabolism, resulting in uncontrolled oxidative phosphorylation and impaired mitochondrial fitness. Reduced α-KG levels as a result of reductive TCA cycle activity leads to DNA hypermethylation, thereby limiting functional gene expression and suppressive activity of TKT-deficient Treg cells. We also find that TKT levels are frequently downregulated in Treg cells of people with autoimmune disorders. Our study identifies the non-oxidative PPP as an integrator of metabolic and epigenetic processes that control Treg function.
    DOI:  https://doi.org/10.1038/s42255-022-00575-z
  39. Cells. 2022 May 16. pii: 1654. [Epub ahead of print]11(10):
    Nicotinamide Mononucleotide Administration Amends Protein Acetylome of Aged Mouse Liver.
    Chengting Luo, Wenxi Ding, Songbiao Zhu, Yuling Chen, Xiaohui Liu, Haiteng Deng.
      It is known that the activities of nicotine adenine dinucleotide (NAD+)-dependent deacetylase decline in the aging mouse liver, and nicotinamide mononucleotide (NMN)-mediated activation of deacetylase has been shown to increase healthspans. However, age-induced changes of the acetylomic landscape and effects of NMN treatment on protein acetylation have not been reported. Here, we performed immunoprecipitation coupled with label-free quantitative LC-MS/MS (IPMS) to identify the acetylome and investigate the effects of aging and NMN on liver protein acetylation. In total, 7773 acetylated peptides assigned to 1997 proteins were commonly identified from young and aged livers treated with vehicle or NMN. The major biological processes associated with proteins exhibiting increased acetylation from aged livers were oxidation-reduction and metabolic processes. Proteins with decreased acetylation from aged livers mostly participated in transport and translation processes. Furthermore, NMN treatment inhibited the aging-related increase of acetylation on proteins regulating fatty acid β oxidation, the tricarboxylic acid (TCA) cycle and valine degradation. In particular, NAD (P) transhydrogenase (NNT) was markedly hyperacetylated at K70 in aged livers, and NMN treatment decreased acetylation intensity without altering protein levels. Acetylation at cytochrome 3a25 (Cyp3a25) at K141 was also greatly increased in aged livers, and NMN treatment totally arrested this increase. Our extensive identification and analysis provide novel insight and potential targets to combat aging and aging-related functional decline.
    Keywords:  NAD (P) transhydrogenase; TCA cycle; acetylome; aging; fatty acid β oxidation; nicotinamide mononucleotide
    DOI:  https://doi.org/10.3390/cells11101654
  40. STAR Protoc. 2022 Jun 17. 3(2): 101403
    NADH-independent enzymatic assay to quantify extracellular and intracellular L-lactate levels.
    Cyrielle L Bouchez, Thomas Daubon, Arnaud Mourier.
      Lactate is a central metabolite in energy metabolism and is also involved in cell signaling and epigenetic regulations. Here, we describe an NADH-independent enzymatic assay allowing rapid, selective, and sensitive quantification of L-lactate down to the pmol range. We detail lactate extraction from intracellular and extracellular fractions, followed by total protein amount determination and enzymatic assay. This approach allows quantification of intracellular and extracellular L-lactate levels, validated by treating adherent and non-adherent cells with inhibitors of lactate transporters (MCT).
    Keywords:  Cell Biology; Cell culture; Metabolism; Protein Biochemistry
    DOI:  https://doi.org/10.1016/j.xpro.2022.101403
  41. Biomolecules. 2022 May 14. pii: 702. [Epub ahead of print]12(5):
    Targeting of the Peritumoral Adipose Tissue Microenvironment as an Innovative Antitumor Therapeutic Strategy.
    Melania Lo Iacono, Chiara Modica, Gaetana Porcelli, Ornella Roberta Brancato, Giampaolo Muratore, Paola Bianca, Miriam Gaggianesi, Alice Turdo, Veronica Veschi, Matilde Todaro, Simone Di Franco, Giorgio Stassi.
      The tumor microenvironment (TME) plays a key role in promoting and sustaining cancer growth. Adipose tissue (AT), due to its anatomical distribution, is a prevalent component of TME, and contributes to cancer development and progression. Cancer-associated adipocytes (CAAs), reprogrammed by cancer stem cells (CSCs), drive cancer progression by releasing metabolites and inflammatory adipokines. In this review, we highlight the mechanisms underlying the bidirectional crosstalk among CAAs, CSCs, and stromal cells. Moreover, we focus on the recent advances in the therapeutic targeting of adipocyte-released factors as an innovative strategy to counteract cancer progression.
    Keywords:  adipokines; adipose tissue; cancer stem cells; exosomes; target therapy; tumor microenvironment
    DOI:  https://doi.org/10.3390/biom12050702
  42. Nat Commun. 2022 May 25. 13(1): 2904
    O-GlcNAc modification of leucyl-tRNA synthetase 1 integrates leucine and glucose availability to regulate mTORC1 and the metabolic fate of leucine.
    Kibum Kim, Hee Chan Yoo, Byung Gyu Kim, Sulhee Kim, Yulseung Sung, Ina Yoon, Ya Chun Yu, Seung Joon Park, Jong Hyun Kim, Kyungjae Myung, Kwang Yeon Hwang, Sunghoon Kim, Jung Min Han.
      All living organisms have the ability to sense nutrient levels to coordinate cellular metabolism. Despite the importance of nutrient-sensing pathways that detect the levels of amino acids and glucose, how the availability of these two types of nutrients is integrated is unclear. Here, we show that glucose availability regulates the central nutrient effector mTORC1 through intracellular leucine sensor leucyl-tRNA synthetase 1 (LARS1). Glucose starvation results in O-GlcNAcylation of LARS1 on residue S1042. This modification inhibits the interaction of LARS1 with RagD GTPase and reduces the affinity of LARS1 for leucine by promoting phosphorylation of its leucine-binding site by the autophagy-activating kinase ULK1, decreasing mTORC1 activity. The lack of LARS1 O-GlcNAcylation constitutively activates mTORC1, supporting its ability to sense leucine, and deregulates protein synthesis and leucine catabolism under glucose starvation. This work demonstrates that LARS1 integrates leucine and glucose availability to regulate mTORC1 and the metabolic fate of leucine.
    DOI:  https://doi.org/10.1038/s41467-022-30696-8
  43. Gut. 2022 May 27. pii: gutjnl-2021-325117. [Epub ahead of print]
    Lysosomal lipid switch sensitises to nutrient deprivation and mTOR targeting in pancreatic cancer.
    Maria Chiara De Santis, Luca Gozzelino, Jean Piero Margaria, Andrea Costamagna, Edoardo Ratto, Federico Gulluni, Enza Di Gregorio, Erica Mina, Nicla Lorito, Marina Bacci, Rossano Lattanzio, Gianluca Sala, Paola Cappello, Francesco Novelli, Elisa Giovannetti, Caterina Vicentini, Silvia Andreani, Pietro Delfino, Vincenzo Corbo, Aldo Scarpa, Paolo Ettore Porporato, Andrea Morandi, Emilio Hirsch, Miriam Martini.
       OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with limited therapeutic options. However, metabolic adaptation to the harsh PDAC environment can expose liabilities useful for therapy. Targeting the key metabolic regulator mechanistic target of rapamycin complex 1 (mTORC1) and its downstream pathway shows efficacy only in subsets of patients but gene modifiers maximising response remain to be identified.
    DESIGN: Three independent cohorts of PDAC patients were studied to correlate PI3K-C2γ protein abundance with disease outcome. Mechanisms were then studied in mouse (KPC mice) and cellular models of PDAC, in presence or absence of PI3K-C2γ (WT or KO). PI3K-C2γ-dependent metabolic rewiring and its impact on mTORC1 regulation were assessed in conditions of limiting glutamine availability. Finally, effects of a combination therapy targeting mTORC1 and glutamine metabolism were studied in WT and KO PDAC cells and preclinical models.
    RESULTS: PI3K-C2γ expression was reduced in about 30% of PDAC cases and was associated with an aggressive phenotype. Similarly, loss of PI3K-C2γ in KPC mice enhanced tumour development and progression. The increased aggressiveness of tumours lacking PI3K-C2γ correlated with hyperactivation of mTORC1 pathway and glutamine metabolism rewiring to support lipid synthesis. PI3K-C2γ-KO tumours failed to adapt to metabolic stress induced by glutamine depletion, resulting in cell death.
    CONCLUSION: Loss of PI3K-C2γ prevents mTOR inactivation and triggers tumour vulnerability to RAD001 (mTOR inhibitor) and BPTES/CB-839 (glutaminase inhibitors). Therefore, these results might open the way to personalised treatments in PDAC with PI3K-C2γ loss.
    Keywords:  AMINO ACIDS; CELL BIOLOGY; LIPID METABOLISM; PANCREATIC CANCER; SIGNAL TRANSDUCTION
    DOI:  https://doi.org/10.1136/gutjnl-2021-325117
  44. Sci Immunol. 2022 May 27. 7(71): eabh4271
    Persistent CAD activity in memory CD8+ T cells supports rRNA synthesis and ribosomal biogenesis required at rechallenge.
    Michael D Claiborne, Srona Sengupta, Liang Zhao, Matthew L Arwood, Im-Meng Sun, Jiayu Wen, Elizabeth A Thompson, Marisa Mitchell-Flack, Marikki Laiho, Jonathan D Powell.
      Memory CD8+ T cells are characterized by their ability to persist long after the initial antigen encounter and their capacity to generate a rapid recall response. Recent studies have identified a role for metabolic reprogramming and mitochondrial function in promoting the longevity of memory T cells. However, detailed mechanisms involved in promoting their rapid recall response are incompletely understood. Here, we identify a role for the initial and continued activation of the trifunctional rate-limiting enzyme of the de novo pyrimidine synthesis pathway CAD (carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase) as critical in promoting the rapid recall response of previously activated CD8+ T cells. We found that CAD was rapidly phosphorylated upon naïve T cell activation in an mTORC1-dependent manner, yet remained phosphorylated long after initial activation. Previously activated CD8+ T cells displayed continued de novo pyrimidine synthesis in the absence of mitogenic signals, and interfering with this pathway diminished the speed and magnitude of cytokine production upon rechallenge. Inhibition of CAD did not affect cytokine transcript levels but diminished available pre-rRNA (ribosomal RNA), the polycistronic rRNA precursor whose synthesis is the rate-limiting step in ribosomal biogenesis. CAD inhibition additionally decreased levels of detectable ribosomal proteins in previously activated CD8+ T cells. Conversely, overexpression of CAD improved both the cytokine response and proliferation of memory T cells. Overall, our studies reveal a critical role for CAD-induced pyrimidine synthesis and ribosomal biogenesis in promoting the rapid recall response characteristic of memory T cells.
    DOI:  https://doi.org/10.1126/sciimmunol.abh4271
  45. Cell Rep. 2022 May 24. pii: S2211-1247(22)00620-9. [Epub ahead of print]39(8): 110847
    Mitochondrial damage-associated molecular patterns trigger arginase-dependent lymphocyte immunoregulation.
    Lauren P Westhaver, Sarah Nersesian, Adam Nelson, Leah K MacLean, Emily B Carter, Derek Rowter, Jun Wang, Boris L Gala-Lopez, Andrew W Stadnyk, Brent Johnston, Jeanette E Boudreau.
      Tissue damage leads to loss of cellular and mitochondrial membrane integrity and release of damage-associated molecular patterns, including those of mitochondrial origin (mitoDAMPs). Here, we describe the lymphocyte response to mitoDAMPs. Using primary cells from mice and human donors, we demonstrate that natural killer (NK) cells and T cells adopt regulatory phenotypes and functions in response to mitoDAMPs. NK cell-mediated cytotoxicity, interferon gamma (IFN-γ) production, T cell proliferation, and in vivo anti-viral T cell activation are all interrupted in the presence of mitoDAMPs or mitoDAMP-rich irradiated cells in in vitro and in vivo assays. Mass spectrometry analysis of mitoDAMPs demonstrates that arginase and products of its enzymatic activity are prevalent in mitoDAMP preparations. Functional validation by arginase inhibition and/or arginine add-back shows that arginine depletion is responsible for the alteration in immunologic polarity. We conclude that lymphocyte responses to mitoDAMPs reflect a highly conserved mechanism that regulates inflammation in response to tissue injury.
    Keywords:  CP: Immunology; NK cell; arginase; arginine metabolism; damage-associated molecular patterns (DAMPs); immunoregulation; lymphocytes; mass spectrometry; mitochondria; natural killer cell; tissue damage
    DOI:  https://doi.org/10.1016/j.celrep.2022.110847
  46. Biochem Biophys Res Commun. 2022 May 14. pii: S0006-291X(22)00746-X. [Epub ahead of print]613 207-213
    UDP-glucose 6-dehydrogenase lessens sorafenib sensitivity via modulating unfolded protein response.
    Bao Guo, Xiaoyan Xu, Miaomiao Shao, Xu Yang, Gaofei He, Kangwei Qi, Jianxin Gu, Lan Wang.
      As the first-generation targeted therapy, sorafenib remains an effective single-drug treatment for advanced hepatocellular carcinoma (HCC). Unfortunately, the existence of resistance restricts the long-term benefit of patients. UDP-glucose 6-dehydrogenase (UGDH) is the key enzyme of glucuronic acid metabolism which was largely reported in mediating drug systemic elimination. In this study, we explore its critical role in regulating sorafenib sensitivity. Here we find sorafenib exposure could activate glucuronic acid metabolism, accompanied with the elevated expression of UGDH. Interference with the route by silencing UGDH could boost HCC cells sensitivity to sorafenib. Meanwhile, the analysis of HCC patients with sorafenib treatment displayed that low UGDH expression predicted superior prognosis. Further screening assay suggested that unfolded protein response (UPR) involves in UGDH silencing-mediated apoptosis. Xenograft model confirmed that combined UGDH intervention could significantly improve sorafenib efficacy. Our results reveal the impact of sorafenib exposure on glucuronic acid metabolism reprogramming and provide UGDH as a promising target to improve sorafenib efficacy.
    Keywords:  Drug sensitivity; Glucuronic acid metabolism; UGDH; UPR
    DOI:  https://doi.org/10.1016/j.bbrc.2022.05.048
  47. Antioxidants (Basel). 2022 Apr 29. pii: 885. [Epub ahead of print]11(5):
    Probing the Role of Cysteine Thiyl Radicals in Biology: Eminently Dangerous, Difficult to Scavenge.
    Bernd Moosmann, Parvana Hajieva.
      Thiyl radicals are exceptionally interesting reactive sulfur species (RSS), but rather rarely considered in a biological or medical context. We here review the reactivity of protein thiyl radicals in aqueous and lipid phases and provide an overview of their most relevant reaction partners in biological systems. We deduce that polyunsaturated fatty acids (PUFAs) are their preferred reaction substrates in lipid phases, whereas protein side chains arguably prevail in aqueous phases. In both cellular compartments, a single, dominating thiyl radical-specific antioxidant does not seem to exist. This conclusion is rationalized by the high reaction rate constants of thiyl radicals with several highly concentrated substrates in the cell, precluding effective interception by antioxidants, especially in lipid bilayers. The intractable reactivity of thiyl radicals may account for a series of long-standing, but still startling biochemical observations surrounding the amino acid cysteine: (i) its global underrepresentation on protein surfaces, (ii) its selective avoidance in aerobic lipid bilayers, especially the inner mitochondrial membrane, (iii) the inverse correlation between cysteine usage and longevity in animals, (iv) the mitochondrial synthesis and translational incorporation of cysteine persulfide, and potentially (v) the ex post introduction of selenocysteine into the genetic code.
    Keywords:  aging; chain-transfer agent; cysteine persulfide; glutathione; lipid peroxidation; longevity; peroxyl radical; selenocysteine
    DOI:  https://doi.org/10.3390/antiox11050885
  48. Signal Transduct Target Ther. 2022 May 25. 7(1): 162
    Lipid metabolism dysfunction induced by age-dependent DNA methylation accelerates aging.
    Xin Li, Jiaqiang Wang, LeYun Wang, Yuanxu Gao, Guihai Feng, Gen Li, Jun Zou, Meixin Yu, Yu Fei Li, Chao Liu, Xue Wei Yuan, Ling Zhao, Hong Ouyang, Jian-Kang Zhu, Wei Li, Qi Zhou, Kang Zhang.
      Epigenetic alterations and metabolic dysfunction are two hallmarks of aging. However, the mechanism of how their interaction regulates aging, particularly in mammals, remains largely unknown. Here we show ELOVL fatty acid elongase 2 (Elovl2), a gene whose epigenetic alterations are most highly correlated with age prediction, contributes to aging by regulating lipid metabolism. We applied artificial intelligence to predict the protein structure of ELOVL2 and the interaction with its substrate. Impaired Elovl2 function disturbs lipid synthesis with increased endoplasmic reticulum stress and mitochondrial dysfunction, leading to key aging phenotypes at both cellular and physiological level. Furthermore, restoration of mitochondrial activity can rescue age-related macular degeneration (AMD) phenotypes induced by Elovl2 deficiency in human retinal pigmental epithelial (RPE) cells; this indicates a conservative mechanism in both human and mouse. Taken together, we revealed an epigenetic-metabolism axis contributing to aging and illustrate the power of an AI-based approach in structure-function studies.
    DOI:  https://doi.org/10.1038/s41392-022-00964-6
  49. Front Immunol. 2022 ;13 880668
    FOXO Dictates Initiation of B Cell Development and Myeloid Restriction in Common Lymphoid Progenitors.
    Lucía Peña-Pérez, Shabnam Kharazi, Nicolai Frengen, Aleksandra Krstic, Thibault Bouderlique, Julia Hauenstein, Minghui He, Ece Somuncular, Xiaoze Li Wang, Carin Dahlberg, Charlotte Gustafsson, Ann-Sofie Johansson, Julian Walfridsson, Nadir Kadri, Petter Woll, Marcin Kierczak, Hong Qian, Lisa Westerberg, Sidinh Luc, Robert Månsson.
      The development of B cells relies on an intricate network of transcription factors critical for developmental progression and lineage commitment. In the B cell developmental trajectory, a temporal switch from predominant Foxo3 to Foxo1 expression occurs at the CLP stage. Utilizing VAV-iCre mediated conditional deletion, we found that the loss of FOXO3 impaired B cell development from LMPP down to B cell precursors, while the loss of FOXO1 impaired B cell commitment and resulted in a complete developmental block at the CD25 negative proB cell stage. Strikingly, the combined loss of FOXO1 and FOXO3 resulted in the failure to restrict the myeloid potential of CLPs and the complete loss of the B cell lineage. This is underpinned by the failure to enforce the early B-lineage gene regulatory circuitry upon a predominantly pre-established open chromatin landscape. Altogether, this demonstrates that FOXO3 and FOXO1 cooperatively govern early lineage restriction and initiation of B-lineage commitment in CLPs.
    Keywords:  B cell; FOXO (forkhead box protein O); gene regulation; lineage commitment/specification; myeloid restriction
    DOI:  https://doi.org/10.3389/fimmu.2022.880668
  50. Leukemia. 2022 May 26.
    The bone marrow niche regulates redox and energy balance in MLL::AF9 leukemia stem cells.
    Ana C Viñado, Isabel A Calvo, Itziar Cenzano, Danel Olaverri, Miguel Cocera, Patxi San Martin-Uriz, Juan P Romero, Amaia Vilas-Zornoza, Laura Vera, Nuria Gomez-Cebrian, Leonor Puchades-Carrasco, Livia E Lisi-Vega, Iñigo Apaolaza, Pablo Valera, Elisabeth Guruceaga, Froilan Granero-Molto, Purificacion Ripalda-Cemborain, Tamara J Luck, Lars Bullinger, Francisco J Planes, José J Rifon, Simón Méndez-Ferrer, Rushdia Z Yusuf, Ana Pardo-Saganta, Felipe Prosper, Borja Saez.
      Eradicating leukemia requires a deep understanding of the interaction between leukemic cells and their protective microenvironment. The CXCL12/CXCR4 axis has been postulated as a critical pathway dictating leukemia stem cell (LSC) chemoresistance in AML due to its role in controlling cellular egress from the marrow. Nevertheless, the cellular source of CXCL12 in the acute myeloid leukemia (AML) microenvironment and the mechanism by which CXCL12 exerts its protective role in vivo remain unresolved. Here, we show that CXCL12 produced by Prx1+ mesenchymal cells but not by mature osteolineage cells provide the necessary cues for the maintenance of LSCs in the marrow of an MLL::AF9-induced AML model. Prx1+ cells promote survival of LSCs by modulating energy metabolism and the REDOX balance in LSCs. Deletion of Cxcl12 leads to the accumulation of reactive oxygen species and DNA damage in LSCs, impairing their ability to perpetuate leukemia in transplantation experiments, a defect that can be attenuated by antioxidant therapy. Importantly, our data suggest that this phenomenon appears to be conserved in human patients. Hence, we have identified Prx1+ mesenchymal cells as an integral part of the complex niche-AML metabolic intertwining, pointing towards CXCL12/CXCR4 as a target to eradicate parenchymal LSCs in AML.
    DOI:  https://doi.org/10.1038/s41375-022-01601-5
  51. Genetics. 2022 May 24. pii: iyac086. [Epub ahead of print]
    Fine tuning Acetyl-CoA Carboxylase 1 activity through localization: Functional genomics reveal a role for the lysine acetyltransferase NuA4 and sphingolipid metabolism in regulating Acc1 activity and localization.
    Trang Pham, Elizabeth Walden, Sylvain Huard, John Pezacki, Morgan D Fullerton, Kristin Baetz.
      Acetyl-CoA Carboxylase 1 (Acc1) catalyzes the conversion of acetyl-CoA to malonyl-CoA, the committed step of de novo fatty acid synthesis. As a master-regulator of lipid synthesis, Acc1 has been proposed to be a therapeutic target for numerous metabolic diseases. We have shown that Acc1 activity is reduced in the absence of the lysine acetyltransferase NuA4 in Saccharomyces cerevisiae. This change in Acc1 activity is correlated with a change in localization. In wild-type cells Acc1 is localized throughout the cytoplasm in small punctate and rod-like structures. However, in NuA4 mutants, Acc1 localization becomes diffuse. To uncover mechanisms regulating Acc1 localization we performed a microscopy screen to identify other deletion mutants that impact Acc1 localization and then measured Acc1 activity in these mutants through chemical genetics and biochemical assays. Three phenotypes were identified. Mutants with hyper-active Acc1 form one or two rod-like structures centrally within the cytoplasm, mutants with mid-low Acc1 activity displayed diffuse Acc1, while the mutants with the lowest Acc1 activity (hypomorphs) formed thick rod-like Acc1 structures at the periphery of the cell. All the Acc1 hypomorphic mutants were implicated in sphingolipid metabolism or very-long chain fatty acid elongation and in common, their deletion causes an accumulation of palmitoyl-CoA. Through exogenous lipid treatments, enzyme inhibitors and genetics, we determined that increasing palmitoyl-CoA levels inhibits Acc1 activity and remodels Acc1 localization. Together this study suggests yeast cells have developed a dynamic feed-back mechanism in which downstream products of Acc1 can fine-tune the rate of fatty acid synthesis.
    Keywords:   Saccharomyces cerevisiae ; Acc1; Fatty acids; Lysine acetylation; NuA4; Protein aggregation; Protein localization
    DOI:  https://doi.org/10.1093/genetics/iyac086
  52. Cancer Med. 2022 May 26.
    KIF11 manipulates SREBP2-dependent mevalonate cross talk to promote tumor progression in pancreatic ductal adenocarcinoma.
    Xiang Gu, Qunshan Zhu, Guangyu Tian, Wenbo Song, Tao Wang, Ali Wang, Xiaojun Chen, Songbing Qin.
      Cholesterol metabolism is highly correlated with risks of pancreatic ductal adenocarcinoma (PDAC). Nevertheless, the underlying mechanisms of activation of cholesterol biogenesis remain inconclusive. KIF11 is a key component of the bipolar spindle and expresses highly in various malignancies. However, its functional role in PDAC tumorigenesis is still unclear. This study aims to elucidate the oncogenic functions of KIF11 in stimulating cholesterol metabolism, thereby driving PDAC progression. We utilized bioinformatics analysis to identify that KIF11 expressed highly in tumor samples versus paired normal tissues and high KIF11 correlated with high clinical stages of patients. Patients with high KIF11 had worse survival outcomes relative to those with low KIF11. Gene set enrichment analysis (GSEA) revealed that KIF11 correlated intensively with the mevalonate (MVA) metabolic pathway. Positive associations were observed between KIF11 and MVA-signature (HMGCR, FDFT1, SQLE, and MSMO1). KIF11 could elevate the free cholesterol content of PDAC cells and targeting MVA inhibited the in vitro growth of KIF11-overexpressing cells. Mechanistically, we found KIF11 could interact with SREBP2, the master regulator of MVA. High KIF11 could increase SREBP2 proteins, but not alter their mRNA levels. KIF11 could attenuate the ubiquitination-mediated degradation of SREBP2, thereby enhancing its stability and accumulation. Accordingly, KIF11 stimulated the expressions of MVA-signature and free cholesterol contents depending on SREBP2. In addition, KIF11 depended on SREBP2 to promote cell growth, migration, stemness, and colony formation abilities. The subcutaneous xenograft models indicated that targeting MVA biogenesis (atorvastatin) is effective to restrict the in vivo growth of KIF11high PDAC. Taken together, our study identified that KIF11 could activate the MVA cross talk to drive PDAC progression and inhibiting the KIF11/MVA axis provided a therapeutic vulnerability in the treatment of PDAC.
    Keywords:  KIF11; PDAC; SREBP2; mevalonate metabolism; ubiquitination
    DOI:  https://doi.org/10.1002/cam4.4683
  53. Antioxidants (Basel). 2022 May 11. pii: 943. [Epub ahead of print]11(5):
    Role of Erythrocytes in Nitric Oxide Metabolism and Paracrine Regulation of Endothelial Function.
    Damian Gajecki, Jakub Gawryś, Ewa Szahidewicz-Krupska, Adrian Doroszko.
      Emerging studies provide new data shedding some light on the complex and pivotal role of red blood cells (RBCs) in nitric oxide (NO) metabolism and paracrine regulation of endothelial function. NO is involved in the regulation of vasodilatation, platelet aggregation, inflammation, hypoxic adaptation, and oxidative stress. Even though tremendous knowledge about NO metabolism has been collected, the exact RBCs' status still requires evaluation. This paper summarizes the actual knowledge regarding the role of erythrocytes as a mobile depot of amino acids necessary for NO biotransformation. Moreover, the complex regulation of RBCs' translocases is presented with a particular focus on cationic amino acid transporters (CATs) responsible for the NO substrates and derivatives transport. The main part demonstrates the intraerythrocytic metabolism of L-arginine with its regulation by reactive oxygen species and arginase activity. Additionally, the process of nitrite and nitrate turnover was demonstrated to be another stable source of NO, with its reduction by xanthine oxidoreductase or hemoglobin. Additional function of hemoglobin in NO synthesis and its subsequent stabilization in steady intermediates is also discussed. Furthermore, RBCs regulate the vascular tone by releasing ATP, inducing smooth muscle cell relaxation, and decreasing platelet aggregation. Erythrocytes and intraerythrocytic NO metabolism are also responsible for the maintenance of normotension. Hence, RBCs became a promising new therapeutic target in restoring NO homeostasis in cardiovascular disorders.
    Keywords:  endothelium; hemoglobin; nitrates; nitric oxide; nitrites; nitrosylation; red blood cells
    DOI:  https://doi.org/10.3390/antiox11050943
  54. Mol Med Rep. 2022 Jul;pii: 236. [Epub ahead of print]26(1):
    N‑acetyl cysteine prevents ambient fine particulate matter‑potentiated atherosclerosis via inhibition of reactive oxygen species‑induced oxidized low density lipoprotein elevation and decreased circulating endothelial progenitor cell.
    Yixin Xu, Haoran Bu, Yufan Jiang, Xiaoqing Zhuo, Ke Hu, Zhihua Si, Yong Chen, Qiwei Liu, Xianwei Gong, Haihui Sun, Qingyi Zhu, Lianqun Cui, Xiaochun Ma, Yuqi Cui.
      Ambient fine particulate matter (PM) serves an important role in the development of cardiovascular disease, including atherosclerosis. Antioxidant N‑acetyl cysteine (NAC) has protective effects in the cardiovascular system. However, it is unknown if NAC prevents PM‑potentiated atherosclerosis in hyperlipidemia. Low‑density lipoprotein (LDL) receptor knockout mice were pretreated with 1 mg/ml NAC in drinking water for 1 week and continued to receive NAC, high‑fat diet and intranasal instillation of PM for 1 week or 6 months. Blood plasma was collected for lipid profile, oxidized (ox‑)LDL, blood reactive oxygen species (ROS) and inflammatory cytokine (TNF‑α, IL‑1β and IL‑6) measurement. Blood cells were harvested for endothelial progenitor cell (EPC) population and intracellular ROS analysis. Murine aorta was isolated for atherosclerotic plaque ratio calculation. NAC treatment maintained circulating EPC level and significantly decreased blood ox‑LDL and ROS, inflammatory cytokines, mononuclear and EPC intracellular ROS levels as well as aortic plaque ratio. NAC prevented PM‑potentiated atherosclerosis by inhibiting plasma ROS‑induced ox‑LDL elevation, mononuclear cell and EPC intracellular ROS‑induced circulating EPC reduction and inflammatory cytokine production.
    Keywords:  N‑acetyl cysteine; air pollution; endothelial progenitor cells; hyperlipidemia; inflammation; oxidized low density lipoprotein; particulate matter; reactive oxygen species
    DOI:  https://doi.org/10.3892/mmr.2022.12752
  55. iScience. 2022 Jun 17. 25(6): 104325
    c-JUN inhibits mTORC2 and glucose uptake to promote self-renewal and obesity.
    Raphael Serna, Ambika Ramrakhiani, Juan Carlos Hernandez, Chia-Lin Chen, Chad Nakagawa, Tatsuya Machida, Ratna B Ray, Xiaohang Zhan, Stanley M Tahara, Keigo Machida.
      Metabolic syndrome is associated with obesity, insulin resistance, and the risk of cancer. We tested whether oncogenic transcription factor c-JUN metabolically reprogrammed cells to induce obesity and cancer by reduction of glucose uptake, with promotion of the stemness phenotype leading to malignant transformation. Liquid alcohol, high-cholesterol, fat diet (HCFD), and isocaloric dextrin were fed to wild-type or experimental mice for 12 months to promote hepatocellular carcinoma (HCC). We demonstrated 40% of mice developed liver tumors after chronic HCFD feeding. Disruption of liver-specific c-Jun reduced tumor incidence 4-fold and improved insulin sensitivity. Overexpression of c-JUN downregulated RICTOR transcription, leading to inhibition of the mTORC2/AKT and glycolysis pathways. c-JUN inhibited GLUT1, 2, and 3 transactivation to suppress glucose uptake. Silencing of RICTOR or c-JUN overexpression promoted self-renewal ability. Taken together, c-JUN inhibited mTORC2 via RICTOR downregulation and inhibited glucose uptake via downregulation of glucose intake, leading to self-renewal and obesity.
    Keywords:  Biological sciences; Cancer; Cell biology; Diabetology; Endocrinology; Molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2022.104325
  56. Antioxidants (Basel). 2022 May 20. pii: 1005. [Epub ahead of print]11(5):
    Metabolic Shades of S-D-Lactoylglutathione.
    Miklós Péter Kalapos, Cinzia Antognelli, Lidia de Bari.
      S-D-lactoylglutathione (SDL) is an intermediate of the glutathione-dependent metabolism of methylglyoxal (MGO) by glyoxalases. MGO is an electrophilic compound that is inevitably produced in conjunction with glucose breakdown and is essentially metabolized via the glyoxalase route. In the last decades, MGO metabolism and its cytotoxic effects have been under active investigation, while almost nothing is known about SDL. This article seeks to fill the gap by presenting an overview of the chemistry, biochemistry, physiological role and clinical importance of SDL. The effects of intracellular SDL are investigated in three main directions: as a substrate for post-translational protein modifications, as a reservoir for mitochondrial reduced glutathione and as an energy currency. In essence, all three approaches point to one direction, namely, a metabolism-related regulatory role, enhancing the cellular defense against insults. It is also suggested that an increased plasma concentration of SDL or its metabolites may possibly serve as marker molecules in hemolytic states, particularly when the cause of hemolysis is a disturbance of the pay-off phase of the glycolytic chain. Finally, SDL could also represent a useful marker in such metabolic disorders as diabetes mellitus or ketotic states, in which its formation is expected to be enhanced. Despite the lack of clear-cut evidence underlying the clinical and experimental findings, the investigation of SDL metabolism is a promising field of research.
    Keywords:  N-lact(o)ylation; S-D-lactoylglutathione; S-glutathionylation; cytoskeleton; glyoxalases; methylglyoxal
    DOI:  https://doi.org/10.3390/antiox11051005
  57. Molecules. 2022 May 13. pii: 3125. [Epub ahead of print]27(10):
    The Reversible Carnitine Palmitoyltransferase 1 Inhibitor (Teglicar) Ameliorates the Neurodegenerative Phenotype in a Drosophila Huntington's Disease Model by Acting on the Expression of Carnitine-Related Genes.
    Carla Bertapelle, Maria Rosaria Carillo, Nunzio Antonio Cacciola, Yulii V Shidlovskii, Gianfranco Peluso, Filomena Anna Digilio.
      Huntington's disease (HD) is a dramatic neurodegenerative disorder caused by the abnormal expansion of a CAG triplet in the huntingtin gene, producing an abnormal protein. As it leads to the death of neurons in the cerebral cortex, the patients primarily present with neurological symptoms, but recently metabolic changes resulting from mitochondrial dysfunction have been identified as novel pathological features. The carnitine shuttle is a complex consisting of three enzymes whose function is to transport the long-chain fatty acids into the mitochondria. Here, its pharmacological modification was used to test the hypothesis that shifting metabolism to lipid oxidation exacerbates the HD symptoms. Behavioural and transcriptional analyses were carried out on HD Drosophila model, to evaluate the involvement of the carnitine cycle in this pathogenesis. Pharmacological inhibition of CPT1, the rate-limiting enzyme of the carnitine cycle, ameliorates the HD symptoms in Drosophila, likely acting on the expression of carnitine-related genes.
    Keywords:  Drosophila melanogaster; Huntington’s disease; L-carnitine; carnitine shuttle; mitochondria; neurodegeneration; β-oxidation
    DOI:  https://doi.org/10.3390/molecules27103125
  58. J Nutr Biochem. 2022 May 21. pii: S0955-2863(22)00122-X. [Epub ahead of print] 109051
    Metabolomes of Lewis lung carcinoma metastases and normal lung tissue from mice fed different diets.
    Lin Yan, Sneha Sundaram, Bret M Rust, Matthew J Picklo, Michael R Bukowski.
      Metastasis is a devastating aspect of cancer. This study tested the hypothesis that metabolome of metastases differs from that of host organs by using the spontaneous metastasis model of Lewis lung carcinoma (LLC). In a 2 × 2 design, male C57BL/6 mice with or without a subcutaneous LLC inoculation were fed the standard AIN93G diet or a high-fat diet (HFD) for 12 weeks. Lung metastases from injected mice and the lungs from non-injected mice were harvested at the end of study for untargeted metabolomics of primary metabolism by using gas chromatography time-of-flight mass spectrometry (GC-TOF-MS). We identified 91 metabolites for metabolomic analysis. The analysis demonstrated that amino acid and energy metabolism were altered the most in LLC metastases compared to the lungs. A 60% decrease in glutamine and a 25-fold elevation in sorbitol were observed in metastases. Cholesterol and its metabolite dihydrocholesterol were 50% lower in metastases than in the lungs. The HFD elevated arachidonic acid and its precursor linoleic acid in the lungs from non-cancer-bearing mice, reflecting the dietary fatty acid composition of the HFD. This elevation did not occur in metastases from HFD-fed LLC-bearing mice, suggesting alterations in lipid metabolism during LLC metastatic progression. Differences in metabolome between pulmonary LLC metastases and the normal healthy lungs can be useful in designing targeted studies for prevention and treatment of cancer spread using this LLC spontaneous metastasis model.
    Keywords:  Lewis lung carcinoma; diet; metabolome; metastasis; mice
    DOI:  https://doi.org/10.1016/j.jnutbio.2022.109051
  59. Anal Bioanal Chem. 2022 May 25.
    Tiffany Porta Siegel (Ed.): MALDI mass spectrometry imaging: from fundamentals to spatial omics.
    Nicole Strittmatter.
      
    DOI:  https://doi.org/10.1007/s00216-022-04127-y
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