bims-mepmim Biomed News
on Metabolites in pathological microenvironments and immunometabolism
Issue of 2022‒06‒19
37 papers selected by
Erika Mariana Palmieri
NIH/NCI Laboratory of Cancer ImmunoMetabolism
  1. Metabolism and polarization regulation of macrophages in the tumor microenvironment.
  2. Fumarate suppresses B-cell activation and function through direct inactivation of LYN.
  3. Combining metabolic phenotype determination with metabolomics and transcriptional analyses to reveal pathways regulated by hydroxycarboxylic acid receptor 2.
  4. Insulin-inducible THRSP maintains mitochondrial function and regulates sphingolipid metabolism in human adipocytes.
  5. ATP citrate lyase links increases in glycolysis to diminished release of vesicular suppressor of cytokine signaling 3 by alveolar macrophages.
  6. Mycobacterium avium subsp. paratuberculosis exploits miRNA expression to modulate lipid metabolism and macrophage polarisation pathways during infection.
  7. Monocarboxylate transporter 1 deficiency impacts CD8+ T lymphocytes proliferation and recruitment to adipose tissue during obesity.
  8. Lipid-associated macrophages in the tumor-adipose microenvironment facilitate breast cancer progression.
  9. Single-Cell Metabolic Profiling of Macrophages Using 3D OrbiSIMS: Correlations with Phenotype.
  10. Ketone body 3-hydroxybutyrate enhances adipocyte function.
  11. Fatty acid metabolism in T-cell function and differentiation.
  12. CD38 reduces mitochondrial fitness and cytotoxic T cell response against viral infection in lupus patients by suppressing mitophagy.
  13. Immune signatures of CD4 and CD68 predicts disease progression in cutaneous T cell lymphoma.
  14. Mitochondrial Respiration-Dependent ANT2-UCP2 Interaction.
  15. Metabolic-scale gene activation screens identify SLCO2B1 as a heme transporter that enhances cellular iron availability.
  16. High glucose-induced inhibition of osteoblast like MC3T3-E1 differentiation promotes mitochondrial perturbations.
  17. High-Fat Diet-Induced Obesity Alters Dendritic Cell Homeostasis by Enhancing Mitochondrial Fatty Acid Oxidation.
  18. Activated Stellate Cell Paracrine HGF Exacerbated Pancreatic Cancer Cell Ferroptosis Resistance.
  19. The role of glutathione peroxidase-1 in health and disease.
  20. Regulation of Adipose Tissue Biology by Long-Chain Fatty Acids: Metabolic Effects and Molecular Mechanisms.
  21. Endogenous glutamine is rate-limiting for anti-CD3 and anti-CD28 induced CD4+ T-cell proliferation and glycolytic activity under hypoxia and normoxia.
  22. Targeting the methionine addiction of cancer.
  23. Tumor-associated macrophage membrane-camouflaged pH-responsive polymeric micelles for combined cancer chemotherapy-sensitized immunotherapy.
  24. Adipocyte-derived kynurenine promotes obesity and insulin resistance by activating the AhR/STAT3/IL-6 signaling.
  25. TMBIM5 loss of function alters mitochondrial matrix ion homeostasis and causes a skeletal myopathy.
  26. SARS-CoV-2 couples evasion of inflammatory response to activated nucleotide synthesis.
  27. Metabolic routing maintains the unique fatty acid composition of phosphoinositides.
  28. Acidosis significantly alters immune checkpoint expression profiles of T cells from oesophageal adenocarcinoma patients.
  29. Integration of Transcriptomics and Metabolomics Reveals the Antitumor Mechanism Underlying Tadalafil in Colorectal Cancer.
  30. Substrate-Specific Coupling of O2 Activation to Hydroxylations of Aromatic Compounds by Rieske Non-heme Iron Dioxygenases.
  31. Janus-faced citrate in aging and metabolism.
  32. Obese Skeletal Muscle-Expressed Interferon Regulatory Factor 4 Transcriptionally Regulates Mitochondrial Branched-Chain Aminotransferase Reprogramming Metabolome.
  33. Indoleamine 2,3-dioxygenase 1 activation in mature cDC1 promotes tolerogenic education of inflammatory cDC2 via metabolic communication.
  34. Engineering Next-Generation CAR-T Cells: Overcoming Tumor Hypoxia and Metabolism.
  35. Remote solid cancers rewire hepatic nitrogen metabolism via host nicotinamide-N-methyltransferase.
  36. Mitochondrial H2S Regulates BCAA Catabolism in Heart Failure.
  37. The microRNA-29 family - role in metabolism and metabolic disease.
  1. Cancer Lett. 2022 Jun 08. pii: S0304-3835(22)00250-6. [Epub ahead of print]543 215766
    Metabolism and polarization regulation of macrophages in the tumor microenvironment.
    Jia Wang, Shichao Mi, Muyao Ding, Xue Li, Shengtao Yuan.
      The occurrence and development of tumors depend on the tumor microenvironment (TME), which consists of various types of cellular and acellular components. Tumor-associated macrophages (TAMs) are the most abundant stromal cell types in the TME. The competition for nutrients between tumor cells and macrophages leads to a limited supply of nutrients, such as glucose, lipids, and amino acids, to immune cells, which affects the differentiation and function of macrophages. Other factors in the TME, such as cytokines, chemokines, and immune checkpoints, also affect the polarization and function of macrophages. Remodeling the tumor microenvironment induces changes in macrophage nutrient uptake and polarization status, which enhance anti-tumor immunity and oxidative stress resistance and suppress immune escape. This review summarizes the influence factors on tumor progression and immune function under different conditions of macrophages. It also demonstrates the metabolic heterogeneity and phenotypic plasticity of macrophages, which provides novel strategies for anti-tumor treatment.
    Keywords:  Immune checkpoints; Phenotypic plasticity; Tumor immunotherapy; Tumor microenvironment; Tumor-associated macrophages metabolism
    DOI:  https://doi.org/10.1016/j.canlet.2022.215766
  2. Nat Chem Biol. 2022 Jun 16.
    Fumarate suppresses B-cell activation and function through direct inactivation of LYN.
    Jie Cheng, Ying Liu, Jinxin Yan, Lina Zhao, Yinglin Zhou, Xuyang Shen, Yunan Chen, Yining Chen, Xianbin Meng, Xinxiang Zhang, Peng Jiang.
      Activated B cells increase central carbon metabolism to fulfill their bioenergetic demands, yet the mechanistic basis for this, as well as metabolic regulation in B cells, remains largely unknown. Here, we demonstrate that B-cell activation reprograms the tricarboxylic acid cycle and boosts the expression of fumarate hydratase (FH), leading to decreased cellular fumarate abundance. Fumarate accumulation by FH inhibition or dimethyl-fumarate treatment suppresses B-cell activation, proliferation and antibody production. Mechanistically, fumarate is a covalent inhibitor of tyrosine kinase LYN, a key component of the BCR signaling pathway. Fumarate can directly succinate LYN at C381 and abrogate LYN activity, resulting in a block to B-cell activation and function in vitro and in vivo. Therefore, our findings uncover a previously unappreciated metabolic regulation of B cells, and reveal LYN is a natural sensor of fumarate, connecting cellular metabolism to B-cell antigen receptor signaling.
    DOI:  https://doi.org/10.1038/s41589-022-01052-0
  3. Discov Oncol. 2022 Jun 13. 13(1): 47
    Combining metabolic phenotype determination with metabolomics and transcriptional analyses to reveal pathways regulated by hydroxycarboxylic acid receptor 2.
    Philipp Rabe, Mareike Gehmlich, Anna Peters, Petra Krumbholz, Anders Nordström, Claudia Stäubert.
      BACKGROUND: The adaptation of cellular metabolism is considered a hallmark of cancer. Oncogenic signaling pathways support tumorigenesis and cancer progression through the induction of certain metabolic phenotypes associated with altered regulation of key metabolic enzymes. Hydroxycarboxylic acid receptor 2 (HCA2) is a G protein-coupled receptor previously shown to act as a tumor suppressor. Here, we aimed to unveil the connection between cellular metabolism and HCA2 in BT-474 cells. Moreover, we intend to clarify how well this metabolic phenotype is reflected in transcriptional changes and metabolite levels as determined by global metabolomics analyses.METHODS: We performed both, siRNA mediated knockdown of HCA2 and stimulation with the HCA2-specific agonist monomethyl fumarate. Seahorse technology was used to determine the role of HCA2 in BT-474 breast cancer cell metabolism and its potential to induce a switch in the metabolic phenotype in the presence of different energy substrates. Changes in the mRNA expression of metabolic enzymes were detected with real-time quantitative PCR (RT-qPCR). Untargeted liquid chromatography-mass spectrometry (LC-MS) metabolic profiling was used to determine changes in metabolite levels.
    RESULTS: Knockdown or stimulation of HCA2 induced changes in the metabolic phenotype of BT474 cells dependent on the availability of energy substrates. The presence of HCA2 was associated with increased glycolytic flux with no fatty acids available. This was reflected in the increased mRNA expression of the glycolytic enzymes PFKFB4 and PKM2, which are known to promote the Warburg effect and have been described as prognostic markers in different types of cancer. With exogenous palmitate present, HCA2 caused elevated fatty acid oxidation and likely lipolysis. The increase in lipolysis was also detectable at the transcriptional level of ATGL and the metabolite levels of palmitic and stearic acid.
    CONCLUSIONS: We combined metabolic phenotype determination with metabolomics and transcriptional analyses and identified HCA2 as a regulator of glycolytic flux and fatty acid metabolism in BT-474 breast cancer cells. Thus, HCA2, for which agonists are already widely used to treat diseases such as psoriasis or hyperlipidemia, may prove useful as a target in combination cancer therapy.
    Keywords:  Cancer metabolism; GPR109A; HCA2; LC-MS; Metabolite profile; Metabolite-sensing GPCR
    DOI:  https://doi.org/10.1007/s12672-022-00503-3
  4. Mol Med. 2022 Jun 17. 28(1): 68
    Insulin-inducible THRSP maintains mitochondrial function and regulates sphingolipid metabolism in human adipocytes.
    Maria A Ahonen, Marcus Höring, Van Dien Nguyen, Sami Qadri, Juuso H Taskinen, Meghana Nagaraj, Martin Wabitsch, Pamela Fischer-Posovszky, You Zhou, Gerhard Liebisch, P A Nidhina Haridas, Hannele Yki-Järvinen, Vesa M Olkkonen.
      BACKGROUND: Thyroid hormone responsive protein (THRSP) is a lipogenic nuclear protein that is highly expressed in murine adipose tissue, but its role in humans remains unknown.METHODS: We characterized the insulin regulation of THRSP in vivo in human adipose tissue biopsies and in vitro in Simpson-Golabi-Behmel syndrome (SGBS) adipocytes. To this end, we measured whole-body insulin sensitivity using the euglycemic insulin clamp technique in 36 subjects [age 40 ± 9 years, body mass index (BMI) 27.3 ± 5.0 kg/m2]. Adipose tissue biopsies were obtained at baseline and after 180 and 360 min of euglycemic hyperinsulinemia for measurement of THRSP mRNA concentrations. To identify functions affected by THRSP, we performed a transcriptomic analysis of THRSP-silenced SGBS adipocytes. Mitochondrial function was assessed by measuring mitochondrial respiration as well as oxidation and uptake of radiolabeled oleate and glucose. Lipid composition in THRSP silencing was studied by lipidomic analysis.
    RESULTS: We found insulin to increase THRSP mRNA expression 5- and 8-fold after 180 and 360 min of in vivo euglycemic hyperinsulinemia. This induction was impaired in insulin-resistant subjects, and THRSP expression was closely correlated with whole-body insulin sensitivity. In vitro, insulin increased both THRSP mRNA and protein concentrations in SGBS adipocytes in a phosphoinositide 3-kinase (PI3K)-dependent manner. A transcriptomic analysis of THRSP-silenced adipocytes showed alterations in mitochondrial functions and pathways of lipid metabolism, which were corroborated by significantly impaired mitochondrial respiration and fatty acid oxidation. A lipidomic analysis revealed decreased hexosylceramide concentrations, supported by the transcript concentrations of enzymes regulating sphingolipid metabolism.
    CONCLUSIONS: THRSP is regulated by insulin both in vivo in human adipose tissue and in vitro in adipocytes, and its expression is downregulated by insulin resistance. As THRSP silencing decreases mitochondrial respiration and fatty acid oxidation, its downregulation in human adipose tissue could contribute to mitochondrial dysfunction. Furthermore, disturbed sphingolipid metabolism could add to metabolic dysfunction in obese adipose tissue.
    Keywords:  Hexosylceramide; Insulin sensitivity; Oxidation; Thyroid hormone
    DOI:  https://doi.org/10.1186/s10020-022-00496-3
  5. Biochim Biophys Acta Mol Basis Dis. 2022 Jun 11. pii: S0925-4439(22)00129-6. [Epub ahead of print]1868(10): 166458
    ATP citrate lyase links increases in glycolysis to diminished release of vesicular suppressor of cytokine signaling 3 by alveolar macrophages.
    Mikel D Haggadone, Jennifer Speth, Hanna S Hong, Loka R Penke, Eric Zhang, Costas A Lyssiotis, Marc Peters-Golden.
      Extracellular vesicles (EVs) are important vectors for intercellular communication. Lung-resident alveolar macrophages (AMs) tonically secrete EVs containing suppressor of cytokine signaling 3 (SOCS3), a cytosolic protein that promotes homeostasis in the distal lung via its actions in recipient neighboring epithelial cells. AMs are metabolically distinct and exhibit low levels of glycolysis at steady state. To our knowledge, whether cellular metabolism influences the packaging and release of an EV cargo molecule has never been explored in any cellular context. Here, we report that increases in glycolysis following in vitro exposure of AMs to the growth and activating factor granulocyte-macrophage colony-stimulating factor inhibit the release of vesicular SOCS3 by primary AMs. Glycolytically diminished SOCS3 secretion requires export of citrate from the mitochondria to the cytosol and its subsequent conversion to acetyl-CoA by ATP citrate lyase. Our data for the first time implicate perturbations in intracellular metabolites in the regulation of vesicular cargo packaging and secretion.
    Keywords:  ATP citrate lyase; Alveolar macrophage; Extracellular vesicle; Glycolysis; Granulocyte-macrophage colony-stimulating factor; Suppressor of cytokine signaling 3
    DOI:  https://doi.org/10.1016/j.bbadis.2022.166458
  6. Sci Rep. 2022 Jun 11. 12(1): 9681
    Mycobacterium avium subsp. paratuberculosis exploits miRNA expression to modulate lipid metabolism and macrophage polarisation pathways during infection.
    Kathryn Wright, Rachel Mizzi, Karren M Plain, Auriol C Purdie, Kumudika de Silva.
      Pathogenic mycobacteria including Mycobacterium avium subsp. paratuberculosis (MAP), the causative agent of Johne's disease, manipulate host macrophages to persist and cause disease. In mycobacterial infection, highly plastic macrophages, shift between inflammatory M1 and permissive M2 phenotypes which alter the disease outcome and allow bacteria to survive intracellularly. Here we examine the impact of MAP infection on polarised macrophages and how increased lipid availability alters macrophage phenotype and bacterial persistence. Further, we assess if host microRNA (miRNA) are sensitive to macrophage polarisation state and how MAP can drive their expression to overcome innate responses. Using in vitro MAP infection, we find that increasing lipid availability through supplementing culture media with exogenous lipid increases cellular nitric oxide production. Lipid-associated miRs -19a, -129, -24, and -24-3p are differentially expressed following macrophage polarisation and lipid supplementation and are further regulated during MAP infection. Collectively, our results highlight the importance of host lipid metabolism in MAP infection and demonstrate control of miRNA expression by MAP to favour intracellular persistence.
    DOI:  https://doi.org/10.1038/s41598-022-13503-8
  7. iScience. 2022 Jun 17. 25(6): 104435
    Monocarboxylate transporter 1 deficiency impacts CD8+ T lymphocytes proliferation and recruitment to adipose tissue during obesity.
    C Macchi, A Moregola, M F Greco, M Svecla, F Bonacina, S Dhup, R K Dadhich, M Audano, P Sonveaux, C Mauro, N Mitro, M Ruscica, G D Norata.
      Lactate sits at the crossroad of metabolism, immunity, and inflammation. The expression of cellular lactate transporter MCT1 (known as Slc16a1) increases during immune cell activation to cope with the metabolic reprogramming. We investigated the impact of MCT1 deficiency on CD8+ T cell function during obesity-related inflammatory conditions. The absence of MCT1 impaired CD8+ T cell proliferation with a shift of ATP production to mitochondrial oxidative phosphorylation. In Slc16a1 f/f Tcell cre mice fed a high-fat diet, a reduction in the number of CD8+ T cells, which infiltrated epididymal visceral adipose tissue (epiWAT) or subcutaneous adipose tissue, was observed. Adipose tissue weight and adipocyte area were significantly reduced together with downregulation of adipogenic genes only in the epiWAT. Our findings highlight a distinct effect of MCT1 deficiency in CD8+ T cells in the crosstalk with adipocytes and reinforce the concept that targeting immunometabolic reprogramming in lymphocyte could impact the immune-adipose tissue axis in obesity.
    Keywords:  Biological sciences; Immunology; Metabolomics; Proteomics
    DOI:  https://doi.org/10.1016/j.isci.2022.104435
  8. Oncoimmunology. 2022 ;11(1): 2085432
    Lipid-associated macrophages in the tumor-adipose microenvironment facilitate breast cancer progression.
    Zhou Liu, Zhijie Gao, Bei Li, Juanjuan Li, Yangyang Ou, Xin Yu, Zun Zhang, Siqin Liu, Xiaoyu Fu, Hongzhong Jin, Juan Wu, Si Sun, Shengrong Sun, Qi Wu.
      The tumor-adipose microenvironment (TAME) is a universal microecosystem, that is characterized by the dysfunction of lipid metabolism, such as excessive free fatty acids (FFAs). Macrophages are the most abundant immune cell type within TAME, although their diversity in the TAME is not clear. We first reveal that infiltration of M2-like macrophages in the TAME is associated with poor survival in breast cancer. To explore lipid-associated alterations in the TAME, we also detected the levels of FFAs transporters including fatty acid binding proteins (FABPs) and fatty acid transport protein 1 (FATP1). The results indicated that expression of fatty acid transporters in the TAME is tightly linked to the function of macrophages and predicts survival in breast cancer. To explore the impact of FFAs transporters on the function of macrophages, we performed single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics. Consequently, we identified a special subpopulation of macrophages defined as lipid-associated macrophages (LAMs), highly expressed macrophage markers (CD163, SPP1 and C1QC), genes involved in lipid metabolism (FABP3, FABP4, FABP5, LPL and LIPA) and some lipid receptors (LGALS3 and TREM2). Functionally, LAMs were characterized by a canonical functional signature of M2-like macrophages, lipid accumulation and enhancing phagocytosis, and they were mostly distributed in tumor-adipose junctional regions. Finally, the allograft cancer mouse models confirmed that LAMs depletion in the TAME synergizes the antitumorigenic effects of anti-PD1 therapy. In summary, we defined a novel subtype of macrophages in the TAME, that has unique features and clinical outcomes.
    Keywords:  breast cancer; lipid-associated macrophage; tumor-adipose microenvironment
    DOI:  https://doi.org/10.1080/2162402X.2022.2085432
  9. Anal Chem. 2022 Jun 17.
    Single-Cell Metabolic Profiling of Macrophages Using 3D OrbiSIMS: Correlations with Phenotype.
    Waraporn Suvannapruk, Max K Edney, Dong-Hyun Kim, David J Scurr, Amir M Ghaemmaghami, Morgan R Alexander.
      Macrophages are important immune cells that respond to environmental cues acquiring a range of activation statuses represented by pro-inflammatory (M1) and anti-inflammatory (M2) phenotypes at each end of their spectrum. Characterizing the metabolic signature (metabolic profiling) of different macrophage subsets is a powerful tool to understand the response of the human immune system to different stimuli. Here, the recently developed 3D OrbiSIMS instrument is applied to yield useful insight into the metabolome from individual cells after in vitro differentiation of macrophages into naïve, M1, and M2 phenotypes using different cytokines. This analysis strategy not only requires more than 6 orders of magnitude less sample than traditional mass spectrometry approaches but also allows the study of cell-to-cell variance. Characteristic metabolites in macrophage subsets are identified using a targeted lipid and data-driven multivariate approach highlighting amino acids and other small molecules. The diamino acids alanylasparagine and lipid sphingomyelin SM(d18/16:0) are uniquely found in M1 macrophages, while pyridine and pyrimidine are observed at increased intensity in M2 macrophages, findings which link to known biological pathways. The first demonstration of this capability illustrates the great potential of direct cell analysis for in situ metabolite profiling with the 3D OrbiSIMS to probe functional phenotype at the single-cell level using molecular signatures and to understand the response of the human body to implanted devices and immune diseases.
    DOI:  https://doi.org/10.1021/acs.analchem.2c01375
  10. Sci Rep. 2022 Jun 16. 12(1): 10080
    Ketone body 3-hydroxybutyrate enhances adipocyte function.
    Shigeki Nishitani, Atsunori Fukuhara, Issei Tomita, Shinji Kume, Jihoon Shin, Yosuke Okuno, Michio Otsuki, Hiroshi Maegawa, Iichiro Shimomura.
      Ketone bodies, including 3HBA, are endogenous products of fatty acid oxidation, and Hmgcs2 is the first rate-limiting enzyme of ketogenesis. From database analysis and in vivo and in vitro experiments, we found that adipose tissue and adipocytes express Hmgcs2, and that adipocytes produce and secrete 3HBA. Treatment with 3HBA enhanced the gene expression levels of the antioxidative stress factors, PPARγ, and lipogenic factors in adipose tissue in vivo and in adipocytes in vitro, accompanied by reduced ROS levels. Knockdown of endogenous Hmgcs2 in adipocytes markedly decreased 3HBA levels in adipocytes and decreased the gene expression levels of the antioxidative stress factors, PPARγ, and lipogenic factors with increased ROS levels. Conversely, overexpression of Hmgcs2 in adipocytes increased 3HBA secretion from adipocytes and enhanced the gene expression levels of the antioxidative stress factors, PPARγ, and lipogenic factors. These results demonstrate that 3HBA plays significant roles in enhancing the physiological function of adipocytes.
    DOI:  https://doi.org/10.1038/s41598-022-14268-w
  11. Int Immunol. 2022 Jun 14. pii: dxac025. [Epub ahead of print]
    Fatty acid metabolism in T-cell function and differentiation.
    Yusuke Endo, Toshio Kanno, Takahiro Nakajima.
      Immunometabolism has recently emerged as a field of study examining the intersection between immunology and metabolism. Studies in this area have yielded new findings on the roles of a diverse range of metabolic pathways and metabolites, which have been found to control many aspects of T-cell biology, including cell differentiation, function, and fate. A particularly important finding has been the discovery that to meet the energy requirements associated with their proliferation, activation, and specific functions, T cells switch their metabolic signatures during differentiation. For example, whereas the induction of de novo fatty acid biosynthesis and fatty acid uptake programs are required for antigen-stimulation-induced proliferation and differentiation of effector T cells, fatty acid catabolism via β-oxidation is essential for the generation of memory T cells and the differentiation of regulatory T cells. In this review, we discuss recent advances in our understanding of the metabolism in different stages of T cells and how fatty acid metabolism in these cells controls their specific functions.
    Keywords:  ACC1; fatty acid biosynthesis; immunological memory
    DOI:  https://doi.org/10.1093/intimm/dxac025
  12. Sci Adv. 2022 Jun 17. 8(24): eabo4271
    CD38 reduces mitochondrial fitness and cytotoxic T cell response against viral infection in lupus patients by suppressing mitophagy.
    Ping-Min Chen, Eri Katsuyama, Abhigyan Satyam, Hao Li, Jose Rubio, Sungwook Jung, Sylvia Andrzejewski, J David Becherer, Maria G Tsokos, Reza Abdi, George C Tsokos.
      Infection is one of the major causes of mortality in patients with systemic lupus erythematosus (SLE). We previously found that CD38, an ectoenzyme that regulates the production of NAD+, is up-regulated in CD8+ T cells of SLE patients and correlates with the risk of infection. Here, we report that CD38 reduces CD8+ T cell function by negatively affecting mitochondrial fitness through the inhibition of multiple steps of mitophagy, a process that is critical for mitochondria quality control. Using a murine lupus model, we found that administration of a CD38 inhibitor in a CD8+ T cell-targeted manner reinvigorated their effector function, reversed the defects in autophagy and mitochondria, and improved viral clearance. We conclude that CD38 represents a target to mitigate infection rates in people with SLE.
    DOI:  https://doi.org/10.1126/sciadv.abo4271
  13. Am J Transl Res. 2022 ;14(5): 3037-3051
    Immune signatures of CD4 and CD68 predicts disease progression in cutaneous T cell lymphoma.
    Sanling Huang, Mengying Liao, Siliang Chen, Ping Zhang, Fangzhou Xu, Hongyu Zhang.
      BACKGROUND: Cutaneous T-cell lymphoma (CTCL) is highly heterogeneous, and its prognosis is closely related to the disease stage. The tumor microenvironment (TME) is an important component of tumor tissue, driving cancer cell growth, progression, and metastasis. However, the diagnostic value of TME in CTCL has not yet been studied in-depth. To date, no study has performed a comprehensive evaluation of the significance of the TME in CTCL.METHODS: Using xCell methods based on bulk RNA sequencing data, we inferred immune cell fraction in the TME in 126 patients and assessed the prognostic importance of immune cells. Consensus clustering was performed to determine the TME subtypes and characterize the transcriptome of each subtype. Based on the TME subtypes, we established the disease progression model using random forest algorithms and logistic regression. The efficacy of the model was examined using an additional 49-patient cohort. Finally, we validated our finding at the protein level using immunochemistry in a 16-patient cohort.
    RESULTS: Patients with advanced CTCL presented with a more active immunity overall than those with early stage. Random forest algorithms revealed that the immune cells CD4, macrophages, and dendritic cells (DCs) were the most effective prognosis predictors. Therefore, we constructed a risk model using logistic regression based on these immune cells. The TME score could be used to effectively predict disease conditions in three datasets with the AUC of 0.9414, 0.7912, and 0.7665, respectively. Immunochemistry at the protein level revealed that helper T cells and the macrophage markers CD4 and CD68 could successfully distinguish different CTCL stages in patients, whereas the DC marker langerin showed no change with disease progression.
    CONCLUSION: We found advanced-stage CTCL was associated with an active immune microenvironment, and the immune signatures CD4 and CD68 showed a relatively high accuracy in predicting CTCL disease progression.
    Keywords:  CD4; CD68; Cutaneous T-cell lymphoma; macrophages; tumor microenvironment
  14. Front Physiol. 2022 ;13 866590
    Mitochondrial Respiration-Dependent ANT2-UCP2 Interaction.
    Tomas A Schiffer, Liza Löf, Radiosa Gallini, Masood Kamali-Moghaddam, Mattias Carlström, Fredrik Palm.
      Adenine nucleotide translocases (ANTs) and uncoupling proteins (UCPs) are known to facilitate proton leak across the inner mitochondrial membrane. However, it remains to be unravelled whether UCP2/3 contribute to significant amount of proton leak in vivo. Reports are indicative of UCP2 dependent proton-coupled efflux of C4 metabolites from the mitochondrial matrix. Previous studies have suggested that UCP2/3 knockdown (KD) contributes to increased ANT-dependent proton leak. Here we investigated the hypothesis that interaction exists between the UCP2 and ANT2 proteins, and that such interaction is regulated by the cellular metabolic demand. Protein-protein interaction was evaluated using reciprocal co-immunoprecipitation and in situ proximity ligation assay. KD of ANT2 and UCP2 was performed by siRNA in human embryonic kidney cells 293A (HEK293A) cells. Mitochondrial and cellular respiration was measured by high-resolution respirometry. ANT2-UCP2 interaction was demonstrated, and this was dependent on cellular metabolism. Inhibition of ATP synthase promoted ANT2-UCP2 interaction whereas high cellular respiration, induced by adding the mitochondrial uncoupler FCCP, prevented interaction. UCP2 KD contributed to increased carboxyatractyloside (CATR) sensitive proton leak, whereas ANT2 and UCP2 double KD reduced CATR sensitive proton leak, compared to UCP2 KD. Furthermore, proton leak was reduced in double KD compared to UCP2 KD. In conclusion, our results show that there is an interaction between ANT2-UCP2, which appears to be dynamically regulated by mitochondrial respiratory activity. This may have implications in the regulation of mitochondrial efficiency or cellular substrate utilization as increased activity of UCP2 may promote a switch from glucose to fatty acid metabolism.
    Keywords:  adenine nucleotide translocase-2; mitochondria; protein interaction; proximity ligation assay; uncoupling protein-2
    DOI:  https://doi.org/10.3389/fphys.2022.866590
  15. Mol Cell. 2022 Jun 09. pii: S1097-2765(22)00491-9. [Epub ahead of print]
    Metabolic-scale gene activation screens identify SLCO2B1 as a heme transporter that enhances cellular iron availability.
    Gokhan Unlu, Benjamin Prizer, Ranya Erdal, Hsi-Wen Yeh, Erol C Bayraktar, Kıvanç Birsoy.
      Iron is the most abundant transition metal essential for numerous cellular processes. Although most mammalian cells acquire iron through transferrin receptors, molecular players of iron utilization under iron restriction are incompletely understood. To address this, we performed metabolism-focused CRISPRa gain-of-function screens, which revealed metabolic limitations under stress conditions. Iron restriction screens identified not only expected members of iron utilization pathways but also SLCO2B1, a poorly characterized membrane carrier. SLCO2B1 expression is sufficient to increase intracellular iron, bypass the essentiality of the transferrin receptor, and enable proliferation under iron restriction. Mechanistically, SLCO2B1 mediates heme analog import in cellular assays. Heme uptake by SLCO2B1 provides sufficient iron for proliferation through heme oxygenases. Notably, SLCO2B1 is predominantly expressed in microglia in the brain, and primary Slco2b1-/- mouse microglia exhibit strong defects in heme analog import. Altogether, our work identifies SLCO2B1 as a microglia-enriched plasma membrane heme importer and provides a genetic platform to identify metabolic limitations under stress conditions.
    Keywords:  CRISPRa; SLCO2B1; heme; iron; metabolic limitation
    DOI:  https://doi.org/10.1016/j.molcel.2022.05.024
  16. PLoS One. 2022 ;17(6): e0270001
    High glucose-induced inhibition of osteoblast like MC3T3-E1 differentiation promotes mitochondrial perturbations.
    Claudia Medeiros, Joseph M Wallace.
      Diabetes mellitus is a metabolic disorder that causes health concerns worldwide. Patients with diabetes exhibit multisystemic symptoms, including loss of bone quality over time. The progressive deterioration of bone promotes failure to withstand damage and increases the risk of fractures. Much of the molecular and metabolic mechanism(s) in diabetic bone remains unclear. In vitro studies suggest that hyperglycemia inhibits mineralization, affecting bone formation and function. In this study, inhibition of osteoblast differentiation was induced using hyperglycemia to assess whether high glucose promotes mitochondrial impairment along with altered bone matrix formation. It was hypothesized that bone energy metabolism would be altered in these cells as calcium deposition, a key phase for bone function, is suppressed. Early passages of osteoblast like MC3T3-E1 cells were differentiated under normal and high glucose conditions. To investigate osteoblast differentiation, we quantified calcium accumulation by alizarin red staining and analyzed immunoblots of key proteins. To assess mitochondrial function, we quantified mitochondrial DNA (mtDNA), detected expression and function of key proteins from the Tricarboxylic (TCA) cycle, measured mitochondrial respiration, and fuel oxidation of alternative nutrients. Results confirmed previous work showing that mineralization was inhibited and AKT expression was reduced in high glucose-treated bone cells. Unexpectedly, high glucose-treated osteoblast cells utilize both mitochondrial respiration and glycolysis to maintain energy demands with partial help of fatty acid for reliance of baseline bioenergetics. These metabolic shifts suggest that hyperglycemia maintain bone metabolic needs in an early differentiated state concurrent to the inhibition in bone matrix formation.
    DOI:  https://doi.org/10.1371/journal.pone.0270001
  17. J Immunol. 2022 Jun 13. pii: ji2100567. [Epub ahead of print]
    High-Fat Diet-Induced Obesity Alters Dendritic Cell Homeostasis by Enhancing Mitochondrial Fatty Acid Oxidation.
    I-Chun Chen, Deepika Awasthi, Chia-Lang Hsu, Minkyung Song, Chang-Suk Chae, Andrew J Dannenberg, Juan R Cubillos-Ruiz.
      Obesity is associated with increased cancer risk and weak responses to vaccination and sepsis treatment. Although dendritic cells (DCs) are fundamental for the initiation and maintenance of competent immune responses against pathogens and tumors, how obesity alters the normal physiology of these myeloid cells remains largely unexplored. In this study, we report that obesity caused by prolonged high-fat diet feeding disrupts the metabolic and functional status of mouse splenic DCs (SpDCs). High-fat diet-induced obesity drastically altered the global transcriptional profile of SpDCs, causing severe changes in the expression of gene programs implicated in lipid metabolism and mitochondrial function. SpDCs isolated from obese mice demonstrated enhanced mitochondrial respiration provoked by increased fatty acid oxidation (FAO), which drove the intracellular accumulation of reactive oxygen species that impaired Ag presentation to T cells. Accordingly, treatment with the FAO inhibitor etomoxir, or antioxidants such as vitamin E or N-acetyl-l-cysteine, restored the Ag-presenting capacity of SpDCs isolated from obese mice. Our findings reveal a major detrimental effect of obesity in DC physiology and suggest that controlling mitochondrial FAO or reactive oxygen species overproduction may help improve DC function in obese individuals.
    DOI:  https://doi.org/10.4049/jimmunol.2100567
  18. Oxid Med Cell Longev. 2022 ;2022 2985249
    Activated Stellate Cell Paracrine HGF Exacerbated Pancreatic Cancer Cell Ferroptosis Resistance.
    Qiwei Wu, Lian Song, Yaxin Guo, Sai Liu, Wenyao Wang, Huli Liu, Aihua Gong, Xiang Liao, Haitao Zhu, Dongqing Wang.
      As a refractory tumor, pancreatic carcinoma is more vulnerable to ferroptosis, a novel regulated cell death mode. However, the exact role of pancreatic stellate cells (PSCs) in pancreatic cancer ferroptosis is still unclear. Using the coculture system, we revealed that activated PSCs promote pancreatic cancer cell ferroptosis resistance. Mechanistically, activated PSCs secreted HGF, which further activated the HGF receptor, c-MET, in pancreatic cancer cells, prevented lipid peroxidation, and ultimately triggered pancreatic cancer cell ferroptosis resistance in vitro and in vivo. TCGA and GEPIA databases also revealed a strong correlation between c-MET and antiferroptosis indicators. Our study supplied the evidence for the cross-talk between activated PSCs and pancreatic cancer cells in ferroptosis, which suggested a strategy to inhibit PSC paracrine signaling for preventing pancreatic carcinoma ferroptosis resistance.
    DOI:  https://doi.org/10.1155/2022/2985249
  19. Free Radic Biol Med. 2022 Jun 09. pii: S0891-5849(22)00224-6. [Epub ahead of print]
    The role of glutathione peroxidase-1 in health and disease.
    Diane E Handy, Joseph Loscalzo.
      Glutathione peroxidase 1 (GPx1) is an important cellular antioxidant enzyme that is found in the cytoplasm and mitochondria of mammalian cells. Like most selenoenzymes, it has a single redox-sensitive selenocysteine amino acid that is important for the enzymatic reduction of hydrogen peroxide and soluble lipid hydroperoxides. Glutathione provides the source of reducing equivalents for its function. As an antioxidant enzyme, GPx1 modulates the balance between necessary and harmful levels of reactive oxygen species. In this review, we discuss how selenium availability and modifiers of selenocysteine incorporation alter GPx1 expression to promote disease states. We review the role of GPx1 in cardiovascular and metabolic health, provide examples of how GPx1 modulates stroke and provides neuroprotection, and consider how GPx1 may contribute to cancer risk. Overall, GPx1 is protective against the development and progression of many chronic diseases; however, there are some situations in which increased expression of GPx1 may promote cellular dysfunction and disease owing to its removal of essential reactive oxygen species.
    Keywords:  Angiogenesis; Atherosclerosis; Cancer; Cardiac protection; Endothelial dysfunction; Glutathione peroxidase 1; Inflammation; Neurodegeneration; Oxidative stress; Selenium; Selenocysteine; Stroke
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2022.06.004
  20. J Obes Metab Syndr. 2022 Jun 13.
    Regulation of Adipose Tissue Biology by Long-Chain Fatty Acids: Metabolic Effects and Molecular Mechanisms.
    Sunhye Shin.
      Long-chain fatty acids (LCFA) modulate metabolic, oxidative, and inflammatory responses, and the physiological effects of LCFA are determined by chain length and the degree of saturation. Adipose tissues comprise multiple cell types, and play a significant role in energy storage and expenditure. Fatty acid uptake and oxidation are the pathways through which fatty acids participate in the regulation of energy homeostasis, and their dysregulation can lead to the development of obesity and chronic obesity-related disorders, including type 2 diabetes, cardiovascular diseases, and certain types of cancer. Numerous studies have reported that many aspects of adipose tissue biology are influenced by the number and position of double bonds in LCFA, and these effects are mediated by various signaling pathways, including those regulating adipocyte differentiation (adipogenesis), thermogenesis, and inflammation in adipose tissue. This review aims to describe the underlying molecular mechanisms by which different types of LCFA influence adipose tissue metabolism, and to further clarify their relevance to metabolic dysregulation associated with obesity. A better understanding of the effects of LCFA on adipose tissue metabolism may lead to improved nutraceutical strategies to address obesity and obesity-associated diseases.
    Keywords:  Adipogenesis; Beige adipocytes; Dietary fats; Inflammation; Macrophages; Thermogenesis
    DOI:  https://doi.org/10.7570/jomes22014
  21. Biochem J. 2022 Jun 17. 479(11): 1221-1235
    Endogenous glutamine is rate-limiting for anti-CD3 and anti-CD28 induced CD4+ T-cell proliferation and glycolytic activity under hypoxia and normoxia.
    Jonas A Wik, Azazul Chowdhury, Shrikant Kolan, Nasser E Bastani, Gaoyang Li, Kazi Alam, Franco Grimolizzi, Bjørn S Skålhegg.
      To meet the demand for energy and biomass, T lymphocytes (T cells) activated to proliferation and clonal expansion, require uptake and metabolism of glucose (Gluc) and the amino acid (AA) glutamine (Gln). Whereas exogenous Gln is converted to glutamate (Glu) by glutaminase (GLS), Gln is also synthesized from the endogenous pool of AA through Glu and activity of glutamine synthase (GS). Most of this knowledge comes from studies on cell cultures under ambient oxygen conditions (normoxia, 21% O2). However, in vivo, antigen induced T-cell activation often occurs under moderately hypoxic (1-4% O2) conditions and at various levels of exogenous nutrients. Here, CD4+ T cells were stimulated for 72 h with antibodies targeting the CD3 and CD28 markers at normoxia and hypoxia (1% O2). This was done in the presence and absence of the GLS and GS inhibitors, Bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl) ethyl sulfide (BPTES) and methionine sulfoximine (MSO) and at various combinations of exogenous Gluc, Gln and pyruvate (Pyr) for the last 12 h of stimulation. We found that T-cell proliferation, viability and levels of endogenous AA were significantly influenced by the availability of exogenous Gln, Gluc and Pyr as well as inhibition of GLS and GS. Moreover, inhibition of GLS and GS and levels of oxygen differentially influenced oxygen consumption rate (OCR) and extracellular acidification rate (ECAR). Finally, BPTES-dependent down-regulation of ECAR was associated with reduced hexokinase (HK) activity at both normoxia and hypoxia. Our results demonstrate that Gln availability and metabolism is rate-limiting for CD4+ T-cell activity.
    Keywords:  BPTES; CD4+ T cells; glutamine; hypoxia; metabolism; normoxia
    DOI:  https://doi.org/10.1042/BCJ20220144
  22. Am J Cancer Res. 2022 ;12(5): 2249-2276
    Targeting the methionine addiction of cancer.
    Joni C Sedillo, Vincent L Cryns.
      Methionine is the initiator amino acid for protein synthesis, the methyl source for most nucleotide, chromatin, and protein methylation, and the carbon backbone for various aspects of the cellular antioxidant response and nucleotide biosynthesis. Methionine is provided in the diet and serum methionine levels fluctuate based on dietary methionine content. Within the cell, methionine is recycled from homocysteine via the methionine cycle, which is linked to nutrient status via one-carbon metabolism. Unlike normal cells, many cancer cells, both in vitro and in vivo, show high methionine cycle activity and are dependent on exogenous methionine for continued growth. However, the molecular mechanisms underlying the methionine dependence of diverse malignancies are poorly understood. Methionine deprivation initiates widespread metabolic alterations in cancer cells that enable them to survive despite limited methionine availability, and these adaptive alterations can be specifically targeted to enhance the activity of methionine deprivation, a strategy we have termed "metabolic priming". Chemotherapy-resistant cell populations such as cancer stem cells, which drive treatment-resistance, are also sensitive to methionine deprivation, suggesting dietary methionine restriction may inhibit metastasis and recurrence. Several clinical trials in cancer are investigating methionine restriction in combination with other agents. This review will explore new insights into the mechanisms of methionine dependence in cancer and therapeutic efforts to translate these insights into enhanced clinical activity of methionine restriction in cancer.
    Keywords:  Methionine; cancer therapy; epigenetics; metabolism; nutrition; one-carbon; oxidative stress
  23. Int J Pharm. 2022 Jun 11. pii: S0378-5173(22)00466-5. [Epub ahead of print] 121911
    Tumor-associated macrophage membrane-camouflaged pH-responsive polymeric micelles for combined cancer chemotherapy-sensitized immunotherapy.
    Tingting Du, Yuchi Wang, Zhiyong Luan, Chaoyue Zhao, Kangjuan Yang.
      The low immunogenicity and tumor immunosuppressive microenvironment (TIM) are two major obstacles for cancer immunotherapy. Synergistically immunogenic cell death induction and tumor-associated macrophages depletion could perfectly overcome this limitation. Herein, a tumor-associated macrophage (TAMs) membrane-camouflaged pH-responsive doxorubicin (DOX) loaded hyaluronic acid (HA)-g-poly (histidine) polymeric micelles (DHP@M2) was fabricated for the first time. DHP@M2 could effectively accumulated into tumor regions via TAMs membrane mediated immune camouflage. In acidic tumor microenvironment, particle size of DHP was enlarged due to decrease hydrophobic interaction of inner core, which caused a "membrane escape effect" to expose inner HA residue. Together high expression of α4β1 integrin, DHP@M2 could reach CD44/VCAM-1 dual-targetability to facilitate intracellular DOX accumulation for efficient ICD induction. Meanwhile, TAMs membrane could absorb colony stimulating factor 1(CSF1) through high expression of its receptor (CSF1R) on TAMs membrane to deplete TAMs in tumor tissues and relieved TIM. This strategy could efficiently induce cytotoxic T lymphocyte (CTLs) infiltration for antitumor immune response and inhibit tumor progression in 4T1 tumor bearing Balb/c mice. Therefore, DHP@M2 is suitable for cancer chemotherapy-sensitized immunotherapy.
    Keywords:  cell membrane; dual-targetability; immunogenic cell death; pH-responsive; polymeric micelle; tumor-associated macrophage (TAMs)
    DOI:  https://doi.org/10.1016/j.ijpharm.2022.121911
  24. Nat Commun. 2022 Jun 17. 13(1): 3489
    Adipocyte-derived kynurenine promotes obesity and insulin resistance by activating the AhR/STAT3/IL-6 signaling.
    Teng Huang, Jia Song, Jia Gao, Jia Cheng, Hao Xie, Lu Zhang, Yu-Han Wang, Zhichao Gao, Yi Wang, Xiaohui Wang, Jinhan He, Shiwei Liu, Qilin Yu, Shu Zhang, Fei Xiong, Qing Zhou, Cong-Yi Wang.
      Aberrant amino acid metabolism is a common event in obesity. Particularly, subjects with obesity are characterized by the excessive plasma kynurenine (Kyn). However, the primary source of Kyn and its impact on metabolic syndrome are yet to be fully addressed. Herein, we show that the overexpressed indoleamine 2,3-dioxygenase 1 (IDO1) in adipocytes predominantly contributes to the excessive Kyn, indicating a central role of adipocytes in Kyn metabolism. Depletion of Ido1 in adipocytes abrogates Kyn accumulation, protecting mice against obesity. Mechanistically, Kyn impairs lipid homeostasis in adipocytes via activating the aryl hydrocarbon receptor (AhR)/Signal transducer and activator of transcription 3 /interleukin-6 signaling. Genetic ablation of AhR in adipocytes abolishes the effect of Kyn. Moreover, supplementation of vitamin B6 ameliorated Kyn accumulation, protecting mice from obesity. Collectively, our data support that adipocytes are the primary source of increased circulating Kyn, while elimination of accumulated Kyn could be a viable strategy against obesity.
    DOI:  https://doi.org/10.1038/s41467-022-31126-5
  25. Life Sci Alliance. 2022 Oct;pii: e202201478. [Epub ahead of print]5(10):
    TMBIM5 loss of function alters mitochondrial matrix ion homeostasis and causes a skeletal myopathy.
    Li Zhang, Felicia Dietsche, Bruno Seitaj, Liliana Rojas-Charry, Nadina Latchman, Dhanendra Tomar, Rob Ci Wüst, Alexander Nickel, Katrin Bm Frauenknecht, Benedikt Schoser, Sven Schumann, Michael J Schmeisser, Johannes Vom Berg, Thorsten Buch, Stefanie Finger, Philip Wenzel, Christoph Maack, John W Elrod, Jan B Parys, Geert Bultynck, Axel Methner.
      Ion fluxes across the inner mitochondrial membrane control mitochondrial volume, energy production, and apoptosis. TMBIM5, a highly conserved protein with homology to putative pH-dependent ion channels, is involved in the maintenance of mitochondrial cristae architecture, ATP production, and apoptosis. Here, we demonstrate that overexpressed TMBIM5 can mediate mitochondrial calcium uptake. Under steady-state conditions, loss of TMBIM5 results in increased potassium and reduced proton levels in the mitochondrial matrix caused by attenuated exchange of these ions. To identify the in vivo consequences of TMBIM5 dysfunction, we generated mice carrying a mutation in the channel pore. These mutant mice display increased embryonic or perinatal lethality and a skeletal myopathy which strongly correlates with tissue-specific disruption of cristae architecture, early opening of the mitochondrial permeability transition pore, reduced calcium uptake capability, and mitochondrial swelling. Our results demonstrate that TMBIM5 is an essential and important part of the mitochondrial ion transport system machinery with particular importance for embryonic development and muscle function.
    DOI:  https://doi.org/10.26508/lsa.202201478
  26. Proc Natl Acad Sci U S A. 2022 Jun 28. 119(26): e2122897119
    SARS-CoV-2 couples evasion of inflammatory response to activated nucleotide synthesis.
    Chao Qin, Youliang Rao, Hao Yuan, Ting-Yu Wang, Jun Zhao, Bianca Espinosa, Yongzhen Liu, Shu Zhang, Ali Can Savas, Qizhi Liu, Mehrnaz Zarinfar, Stephanie Rice, Jill Henley, Lucio Comai, Nicholas A Graham, Casey Chen, Chao Zhang, Pinghui Feng.
      Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) evolves rapidly under the pressure of host immunity, as evidenced by waves of emerging variants despite effective vaccinations, highlighting the need for complementing antivirals. We report that targeting a pyrimidine synthesis enzyme restores inflammatory response and depletes the nucleotide pool to impede SARS-CoV-2 infection. SARS-CoV-2 deploys Nsp9 to activate carbamoyl-phosphate synthetase, aspartate transcarbamoylase, and dihydroorotase (CAD) that catalyzes the rate-limiting steps of the de novo pyrimidine synthesis. Activated CAD not only fuels de novo nucleotide synthesis but also deamidates RelA. While RelA deamidation shuts down NF-κB activation and subsequent inflammatory response, it up-regulates key glycolytic enzymes to promote aerobic glycolysis that provides metabolites for de novo nucleotide synthesis. A newly synthesized small-molecule inhibitor of CAD restores antiviral inflammatory response and depletes the pyrimidine pool, thus effectively impeding SARS-CoV-2 replication. Targeting an essential cellular metabolic enzyme thus offers an antiviral strategy that would be more refractory to SARS-CoV-2 genetic changes.
    Keywords:  CAD; SARS-CoV-2; deamidation; inflammatory response; metabolism
    DOI:  https://doi.org/10.1073/pnas.2122897119
  27. EMBO Rep. 2022 Jun 16. e54532
    Metabolic routing maintains the unique fatty acid composition of phosphoinositides.
    Yeun Ju Kim, Nivedita Sengupta, Mira Sohn, Amrita Mandal, Joshua G Pemberton, Uimook Choi, Tamas Balla.
      Phosphoinositide lipids (PPIn) are enriched in stearic- and arachidonic acids (38:4) but how this enrichment is established and maintained during phospholipase C (PLC) activation is unknown. Here we show that the metabolic fate of newly synthesized phosphatidic acid (PA), the lipid precursor of phosphatidylinositol (PI), is influenced by the fatty acyl-CoA used with preferential routing of the arachidonoyl-enriched species toward PI synthesis. Furthermore, during agonist stimulation the unsaturated forms of PI(4,5P)2 are replenished significantly faster than the more saturated ones, suggesting a favored recycling of the unsaturated forms of the PLC-generated hydrolytic products. Cytidine diphosphate diacylglycerol synthase 2 (CDS2) but not CDS1 was found to contribute to increased PI resynthesis during PLC activation. Lastly, while the lipid transfer protein, Nir2 is found to contribute to rapid PPIn resynthesis during PLC activation, the faster re-synthesis of the 38:4 species does not depend on Nir2. Therefore, the fatty acid side-chain composition of the lipid precursors used for PI synthesis is an important determinant of their metabolic fates, which also contributes to the maintenance of the unique fatty acid profile of PPIn lipids.
    Keywords:  diacylglycerol; lipid transfer proteins; phosphatidic acid; phosphatidylinositol; phospholipase C
    DOI:  https://doi.org/10.15252/embr.202154532
  28. Cancer Immunol Immunother. 2022 Jun 16.
    Acidosis significantly alters immune checkpoint expression profiles of T cells from oesophageal adenocarcinoma patients.
    Maria Davern, Noel E Donlon, Fiona O'Connell, Caoimhe Gaughan, Cillian O'Donovan, Mohammed Habash, Andrew D Sheppard, Michael MacLean, Margaret R Dunne, Jenny Moore, Hugo Temperley, Melissa J Conroy, Christine Butler, Anshul Bhardwaj, Narayanasamy Ravi, Claire L Donohoe, John V Reynolds, Joanne Lysaght.
      Tumour acidosis contributes to cancer progression by inhibiting anti-tumour immunity. However, the effect of acidosis on anti-tumour T cell phenotypes in oesophageal adenocarcinoma (OAC) is unknown. Therefore, this study investigated the effect of acidosis on anti-tumour T cell profiles and if immune checkpoint blockade (ICB) could enhance anti-tumour T cell immunity under acidosis. Acidic conditions substantially altered immune checkpoint expression profiles of OAC patient-derived T cells, upregulating TIM-3, LAG-3 and CTLA-4. Severe acidosis (pH 5.5) significantly decreased the percentage of central memory CD4+ T cells, an effect that was attenuated by ICB treatment. ICB increased T cell production of IFN-γ under moderate acidosis (pH 6.6) but not severe acidosis (pH 5.5) and decreased IL-10 production by T cells under severe acidic conditions only. A link between lactate and metastasis was also depicted; patients with nodal metastasis had higher serum lactate levels (p = 0.07) which also positively correlated with circulating levels of pro-angiogenic factor Tie-2. Our findings establish that acidosis-induced upregulation of immune checkpoints on T cells may potentially contribute to immune evasion and disease progression in OAC. However, acidic conditions curtailed ICB efficacy, supporting a rationale for utilizing systemic oral buffers to neutralize tumour acidity to improve ICB efficacy. Study schematic-PBMCs were isolated from OAC patients (A) and expanded ex vivo for 7 days using anti-CD3/28 +IL-2 T cell activation protocol (B) and further cultured for 48 h under increasing acidic conditions in the absence or presence of immune checkpoint blockade (nivolumab, ipilimumab or dual nivolumab + ipilimumab) (C). Immunophenotyping was then carried out to assess immune checkpoint expression profiles and anti-tumour T cell phenotypes (D). Serum lactate was assessed in OAC patients (E-F) and levels were correlated with patient demographics (G) and the levels of circulating immune/pro-angiogenic cytokines that were determined by multiplex ELISA (H). Key Findings-severe acidic conditions upregulated multiple immune checkpoints on T cells (I). Efficacy of ICB was curtailed under severe acidic conditions (J). Circulating lactate levels positively correlated with circulating levels of pro-angiogenic factor tie-2 and higher serum lactate levels were found in patients who had nodal metastasis (K).
    Keywords:  A2aR; Acidosis; Immune checkpoints; Lactate; Oesophageal adenocarcinoma; Tie-2
    DOI:  https://doi.org/10.1007/s00262-022-03228-y
  29. Front Pharmacol. 2022 ;13 793499
    Integration of Transcriptomics and Metabolomics Reveals the Antitumor Mechanism Underlying Tadalafil in Colorectal Cancer.
    Pan Zhao, Yao Shen, Mengyang Li, Hanjun Dan, Zhiming Zhao, Jian Zhang.
      The potential role of tadalafil, a PDE5 inhibitor, in anticancer activity and prolonged survival has been proposed. However, the systematic effects of tadalafil in colorectal cancer were not fully understood. In this study, we assessed the anti-tumor activity of tadalafil in human colorectal cancer cells. A systematic perspective of the tadalafil-induced anti-tumor mechanism was provided by the integration of transcriptomics and metabolomics. We found that differentially expressed genes (DEGs) were mainly involved in microRNAs in cancer, purine metabolism, glycosphingolipid biosynthesis, arginine biosynthesis, and amino acid metabolism. Amino acid metabolism, especially alanine, aspartate, and glutamate metabolism was the most of the differentially accumulated metabolites (DAMs) through the analysis of metabolomics. The conjoint analysis of DEGs and DAMs presented that they were also mainly involved in alanine, aspartate, and glutamate metabolism. Amino acid metabolism-related genes, GPT, GGT5, and TAT, were significantly decreased after tadalafil treatment. In particular, the disturbance of alanine, aspartate, and glutamate metabolism may be the explanation for the major mechanism resulting from tadalafil anti-tumor activity.
    Keywords:  alanine; aspartate, and glutamate metabolism; colorectal cancer; metabolomics; tadalafil; transcriptomics
    DOI:  https://doi.org/10.3389/fphar.2022.793499
  30. ACS Catal. 2022 Jun 03. 12(11): 6444-6456
    Substrate-Specific Coupling of O2 Activation to Hydroxylations of Aromatic Compounds by Rieske Non-heme Iron Dioxygenases.
    Sarah G Pati, Charlotte E Bopp, Hans-Peter E Kohler, Thomas B Hofstetter.
      Rieske dioxygenases catalyze the initial steps in the hydroxylation of aromatic compounds and are critical for the metabolism of xenobiotic substances. Because substrates do not bind to the mononuclear non-heme FeII center, elementary steps leading to O2 activation and substrate hydroxylation are difficult to delineate, thus making it challenging to rationalize divergent observations on enzyme mechanisms, reactivity, and substrate specificity. Here, we show for nitrobenzene dioxygenase, a Rieske dioxygenase capable of transforming nitroarenes to nitrite and substituted catechols, that unproductive O2 activation with the release of the unreacted substrate and reactive oxygen species represents an important path in the catalytic cycle. Through correlation of O2 uncoupling for a series of substituted nitroaromatic compounds with 18O and 13C kinetic isotope effects of dissolved O2 and aromatic substrates, respectively, we show that O2 uncoupling occurs after the rate-limiting formation of FeIII-(hydro)peroxo species from which substrates are hydroxylated. Substituent effects on the extent of O2 uncoupling suggest that the positioning of the substrate in the active site rather than the susceptibility of the substrate for attack by electrophilic oxygen species is responsible for unproductive O2 uncoupling. The proposed catalytic cycle provides a mechanistic basis for assessing the very different efficiencies of substrate hydroxylation vs unproductive O2 activation and generation of reactive oxygen species in reactions catalyzed by Rieske dioxygenases.
    DOI:  https://doi.org/10.1021/acscatal.2c00383
  31. Aging (Albany NY). 2022 Jun 17. undefined(undefined):
    Janus-faced citrate in aging and metabolism.
    Wei-Sheng Lin, Pei-Yu Wang.
      
    Keywords:  citrate transporter; insulin; ketogenesis
    DOI:  https://doi.org/10.18632/aging.204138
  32. Diabetes. 2022 Jun 17. pii: db220260. [Epub ahead of print]
    Obese Skeletal Muscle-Expressed Interferon Regulatory Factor 4 Transcriptionally Regulates Mitochondrial Branched-Chain Aminotransferase Reprogramming Metabolome.
    Ting Yao, Hongmei Yan, Xiaopeng Zhu, Qiongyue Zhang, Xingyu Kong, Shanshan Guo, Yonghao Feng, Hui Wang, Yinghui Hua, Jing Zhang, Steven D Mittelman, Peter Tontonoz, Zhenqi Zhou, Tiemin Liu, Xingxing Kong.
      In addition to the significant role in physical activity, skeletal muscle also contributes to health through the storage and use of macronutrients associated with energy homeostasis. However, the mechanisms of regulating integrated metabolism in skeletal muscle were not well-defined. Here, we compared the skeletal muscle transcriptome from obese and lean controls in different species (human and mouse), and found that interferon regulatory factor 4 (IRF4), an inflammation-immune transcription factor, conservatively increased in obese subjects. Thus, we investigated that IRF4 gain of function in the skeletal muscle predisposed to obesity and insulin resistance. Conversely, mice with specific IRF4 loss in skeletal muscle showed protection against the metabolic effects of the high-fat diet (HFD), increased branched-chain amino acids (BCAAs) level of serum and muscle, and re-programmed metabolome in serum. Mechanistically, IRF4 could transcriptionally upregulate mitochondrial branched-chain aminotransferase (BCATm) expression; subsequently, the enhanced BCATm could counteract the effects caused by IRF4 deletion. Furthermore, we demonstrated that IRF4 ablation in skeletal muscle enhanced mitochondrial activity, BCAAs and fatty acid oxidation in a BCATm-dependent manner. Taken together, these studies, for the first time, established IRF4 as a novel metabolic driver of macronutrients via BCATm in skeletal muscle in terms of diet-induced obesity (DIO).
    DOI:  https://doi.org/10.2337/db22-0260
  33. Immunity. 2022 Jun 14. pii: S1074-7613(22)00233-3. [Epub ahead of print]55(6): 1032-1050.e14
    Indoleamine 2,3-dioxygenase 1 activation in mature cDC1 promotes tolerogenic education of inflammatory cDC2 via metabolic communication.
    Marco Gargaro, Giulia Scalisi, Giorgia Manni, Carlos G Briseño, Prachi Bagadia, Vivek Durai, Derek J Theisen, Sunkyung Kim, Marilena Castelli, Chenling A Xu, Gerd Meyer Zu Hörste, Giuseppe Servillo, Maria A Della Fazia, Giulia Mencarelli, Doriana Ricciuti, Eleonora Padiglioni, Nicola Giacchè, Carolina Colliva, Roberto Pellicciari, Mario Calvitti, Teresa Zelante, Dietmar Fuchs, Ciriana Orabona, Louis Boon, Alban Bessede, Marco Colonna, Paolo Puccetti, Theresa L Murphy, Kenneth M Murphy, Francesca Fallarino.
      Conventional dendritic cells (cDCs), cDC1 and cDC2, act both to initiate immunity and maintain self-tolerance. The tryptophan metabolic enzyme indoleamine 2,3-dioxygenase 1 (IDO1) is used by cDCs in maintaining tolerance, but its role in different subsets remains unclear. At homeostasis, only mature CCR7+ cDC1 expressed IDO1 that was dependent on IRF8. Lipopolysaccharide treatment induced maturation and IDO1-dependent tolerogenic activity in isolated immature cDC1, but not isolated cDC2. However, both human and mouse cDC2 could induce IDO1 and acquire tolerogenic function when co-cultured with mature cDC1 through the action of cDC1-derived l-kynurenine. Accordingly, cDC1-specific inactivation of IDO1 in vivo exacerbated disease in experimental autoimmune encephalomyelitis. This study identifies a previously unrecognized metabolic communication in which IDO1-expressing cDC1 cells extend their immunoregulatory capacity to the cDC2 subset through their production of tryptophan metabolite l-kynurenine. This metabolic axis represents a potential therapeutic target in treating autoimmune demyelinating diseases.
    Keywords:  AhR; IDO1; IL-6; RelB; dendritic cells; immunotolerance; kynurenine; metabolites; neuroinflammation; tryptophan metabolism
    DOI:  https://doi.org/10.1016/j.immuni.2022.05.013
  34. Annu Rev Chem Biomol Eng. 2022 Jun 10. 13 193-216
    Engineering Next-Generation CAR-T Cells: Overcoming Tumor Hypoxia and Metabolism.
    Torahito A Gao, Yvonne Y Chen.
      T cells engineered to express chimeric antigen receptors (CARs) have shown remarkable success in treating B-cell malignancies, reflected by multiple US Food and Drug Administration-approved CAR-T cell products currently on the market. However, various obstacles have thus far limited the use of approved products and constrained the efficacy of CAR-T cell therapy against solid tumors. Overcoming these obstacles will necessitate multidimensional CAR-T cell engineering approaches and better understanding of the intricate tumor microenvironment (TME). Key challenges include treatment-related toxicity, antigen escape and heterogeneity, and the highly immunosuppressive profile of the TME. Notably, the hypoxic and nutrient-deprived nature of the TME severely attenuates CAR-T cell fitness and efficacy, highlighting the need for more sophisticated engineering strategies. In this review, we examine recent advances in protein- and cell-engineering strategies to improve CAR-T cell safety and efficacy, with an emphasis on overcoming immunosuppression induced by tumor metabolism and hypoxia.
    Keywords:  CAR-T cell; adoptive cell therapy; chimeric antigen receptor; genetic engineering; hypoxia; metabolism
    DOI:  https://doi.org/10.1146/annurev-chembioeng-092120-092914
  35. Nat Commun. 2022 Jun 15. 13(1): 3346
    Remote solid cancers rewire hepatic nitrogen metabolism via host nicotinamide-N-methyltransferase.
    Rin Mizuno, Hiroaki Hojo, Masatomo Takahashi, Soshiro Kashio, Sora Enya, Motonao Nakao, Riyo Konishi, Mayuko Yoda, Ayano Harata, Junzo Hamanishi, Hiroshi Kawamoto, Masaki Mandai, Yutaka Suzuki, Masayuki Miura, Takeshi Bamba, Yoshihiro Izumi, Shinpei Kawaoka.
      Cancers disrupt host homeostasis in various manners but the identity of host factors underlying such disruption remains largely unknown. Here we show that nicotinamide-N-methyltransferase (NNMT) is a host factor that mediates metabolic dysfunction in the livers of cancer-bearing mice. Multiple solid cancers distantly increase expression of Nnmt and its product 1-methylnicotinamide (MNAM) in the liver. Multi-omics analyses reveal suppression of the urea cycle accompanied by accumulation of amino acids, and enhancement of uracil biogenesis in the livers of cancer-bearing mice. Importantly, genetic deletion of Nnmt leads to alleviation of these metabolic abnormalities, and buffers cancer-dependent weight loss and reduction of the voluntary wheel-running activity. Our data also demonstrate that MNAM is capable of affecting urea cycle metabolites in the liver. These results suggest that cancers up-regulate the hepatic NNMT pathway to rewire liver metabolism towards uracil biogenesis rather than nitrogen disposal via the urea cycle, thereby disrupting host homeostasis.
    DOI:  https://doi.org/10.1038/s41467-022-30926-z
  36. Circ Res. 2022 Jun 14. 101161CIRCRESAHA121319817
    Mitochondrial H2S Regulates BCAA Catabolism in Heart Failure.
    Zhen Li, Huijing Xia, Thomas E Sharp, Kyle B LaPenna, John W Elrod, Kevin M Casin, Ken Liu, John W Calvert, Vinh Q Chau, Fadi N Salloum, Shi Xu, Ming Xian, Noriyuki Nagahara, Traci T Goodchild, David J Lefer.
      BACKGROUND: Hydrogen sulfide (H2S) exerts mitochondria-specific actions that include the preservation of oxidative phosphorylation, biogenesis, and ATP synthesis, while inhibiting cell death. 3-MST (3-mercaptopyruvate sulfurtransferase) is a mitochondrial H2S-producing enzyme whose functions in the cardiovascular disease are not fully understood. In the current study, we investigated the effects of global 3-MST deficiency in the setting of pressure overload-induced heart failure.METHODS: Human myocardial samples obtained from patients with heart failure undergoing cardiac surgeries were probed for 3-MST protein expression. 3-MST knockout mice and C57BL/6J wild-type mice were subjected to transverse aortic constriction to induce pressure overload heart failure with reduced ejection fraction. Cardiac structure and function, vascular reactivity, exercise performance, mitochondrial respiration, and ATP synthesis efficiency were assessed. In addition, untargeted metabolomics were utilized to identify key pathways altered by 3-MST deficiency.
    RESULTS: Myocardial 3-MST was significantly reduced in patients with heart failure compared with nonfailing controls. 3-MST KO mice exhibited increased accumulation of branched-chain amino acids in the myocardium, which was associated with reduced mitochondrial respiration and ATP synthesis, exacerbated cardiac and vascular dysfunction, and worsened exercise performance following transverse aortic constriction. Restoring myocardial branched-chain amino acid catabolism with 3,6-dichlorobenzo1[b]thiophene-2-carboxylic acid (BT2) and administration of a potent H2S donor JK-1 ameliorates the detrimental effects of 3-MST deficiency in heart failure with reduced ejection fraction.
    CONCLUSIONS: Our data suggest that 3-MST derived mitochondrial H2S may play a regulatory role in branched-chain amino acid catabolism and mediate critical cardiovascular protection in heart failure.
    Keywords:  branched chain amino acid; cell death; heart failure; hydrogen sulfide; mitochondrial respiration
    DOI:  https://doi.org/10.1161/CIRCRESAHA.121.319817
  37. Am J Physiol Cell Physiol. 2022 Jun 15.
    The microRNA-29 family - role in metabolism and metabolic disease.
    Louise T Dalgaard, Anja E Sørensen, Anandwardhan A Hardikar, Mugdha V Joglekar.
      The microRNA-29a family members miR-29a-3p, miR-29b-3p and miR-29c-3p are ubiquitously expressed and consistently increased in various tissues and cell types in conditions of metabolic disease; obesity, insulin resistance and type 2 diabetes. In pancreatic beta cells, miR-29a is required for normal exocytosis, but increased levels are associated with impaired beta cell function. Similarly, in liver miR-29 species are higher in models of insulin resistance and type 2 diabetes, and either knock-out or depletion using a microRNA inhibitor improves hepatic insulin resistance. In skeletal muscle, miR-29 upregulation is associated with insulin resistance and altered substrate oxidation, and similarly, in adipocytes over-expression of miR-29a leads to insulin resistance. Blocking miR-29a using nucleic acid antisense therapeutics show promising results in preclinical animal models of obesity and type 2 diabetes, although the widespread expression pattern of miR-29 family members complicates the exploration of single target tissues. However, in fibrotic diseases, such as in late complications of diabetes and metabolic disease (diabetic kidney disease, non-alcoholic steatohepatitis), miR-29 expression is suppressed by TGFβ allowing increased extracellular matrix collagen to form. In the clinical setting circulating levels of miR-29a and miR-29b are consistently increased in type 2 diabetes and in gestational diabetes, and are also possible prognostic markers for deterioration of glucose tolerance. In conclusion, miR-29 plays an essential role in various organs relevant to intermediary metabolism and its upregulation contribute to impaired glucose metabolism, while it suppresses fibrosis development. Thus, a correct balance of miR-29a levels seems important for cellular and organ homeostasis in metabolism.
    Keywords:  fibrosis; insulin resistance; metabolism; microRNA-29; non-coding RNA
    DOI:  https://doi.org/10.1152/ajpcell.00051.2022
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