bims-mepmim Biomed News
on Metabolites in pathological microenvironments and immunometabolism
Issue of 2022–04–03
fifty-four papers selected by
Erika Mariana Palmieri, NIH/NCI Laboratory of Cancer ImmunoMetabolism
  1. T cell metabolism and possible therapeutic targets in systemic lupus erythematosus: a narrative review.
  2. Lipid metabolic reprogramming by hypoxia-inducible factor-1 in the hypoxic tumour microenvironment.
  3. The Interplay Between TGF-β Signaling and Cell Metabolism.
  4. The mTORC1 Signaling Support Cellular Metabolism to Dictate Decidual NK Cells Function in Early Pregnancy.
  5. An SCD1-dependent mechanoresponsive pathway promotes HCC invasion and metastasis through lipid metabolic reprogramming.
  6. Deacetylation of MTHFD2 by SIRT4 senses stress signal to inhibit cancer cell growth by remodeling folate metabolism.
  7. Glutamate blunts cell-killing effects of neutrophils in tumor microenvironment.
  8. Systemic Lactate Acts as a Metabolic Buffer in Humans and Prevents Nutrient Overflow in the Postprandial Phase.
  9. Scinderin promotes fusion of electron transport chain dysfunctional muscle stem cells with myofibers.
  10. The Role of Zinc in the T-Cell Metabolism in Infection Requires Further Investigation - An Opinion.
  11. HIF-2 in cancer associated fibroblasts polarizes macrophages and creates an immunosuppressive tumor microenvironment in pancreatic cancer.
  12. miRNA-guided reprogramming of glucose and glutamine metabolism and its impact on cell adhesion/migration during solid tumor progression.
  13. Transition of acute kidney injury to chronic kidney disease: role of metabolic reprogramming.
  14. Altered propionate metabolism contributes to tumour progression and aggressiveness.
  15. System-level metabolic modeling facilitates unveiling metabolic signature in exceptional longevity.
  16. Transsulfuration, minor player or crucial for cysteine homeostasis in cancer.
  17. Citrate transporter inhibitors: possible new anticancer agents.
  18. Proteomic analysis reveals the heterogeneity of metabolic reprogramming in lacrimal gland tumors.
  19. Disruption of mitochondrial complex III in cap mesenchyme but not in ureteric progenitors results in defective nephrogenesis associated with amino acid deficiency.
  20. Transient changes to metabolic homeostasis initiate mitochondrial adaptation to endurance exercise.
  21. Metabolomics reveals that CAF-derived lipids promote colorectal cancer peritoneal metastasis by enhancing membrane fluidity.
  22. Hypoxia Induces Saturated Fatty Acids Accumulation and Reduces Unsaturated Fatty Acids Independently of Reverse Tricarboxylic Acid Cycle in L6 Myotubes.
  23. Immunometabolic adaptation and immune plasticity in pregnancy and the bi-directional effects of obesity.
  24. Imaging Sub-Cellular Methionine and Insulin Interplay in Triple Negative Breast Cancer Lipid Droplet Metabolism.
  25. H3K9me3 represses G6PD expression to suppress the pentose phosphate pathway and ROS production to promote human mesothelioma growth.
  26. Metabolic Landscape of Bronchoalveolar Lavage Fluid in Coronavirus Disease 2019 at Single Cell Resolution.
  27. Development of a prognostic metabolic signature in stomach adenocarcinoma.
  28. Palmitoylation of MDH2 by ZDHHC18 activates mitochondrial respiration and accelerates ovarian cancer growth.
  29. PTIP governs NAD+ metabolism by regulating CD38 expression to drive macrophage inflammation.
  30. Macrophage immunometabolism in inflammatory bowel diseases: From pathogenesis to therapy.
  31. miR-378-mediated glycolytic metabolism enriches the Pax7Hi subpopulation of satellite cells.
  32. Neutral ceramidase-dependent regulation of macrophage metabolism directs intestinal immune homeostasis and controls enteric infection.
  33. Bladder cancer cells shift rapidly and spontaneously to cisplatin-resistant oxidative phosphorylation that is trackable in real time.
  34. Transient Antibiotic Tolerance Triggered by Nutrient Shifts From Gluconeogenic Carbon Sources to Fatty Acid.
  35. Targeting the Key Enzymes of Abnormal Fatty Acid β-oxidation as a Potential Strategy for Tumor Therapy.
  36. Switching to the cyclic pentose phosphate pathway powers the oxidative burst in activated neutrophils.
  37. Superior antitumor immunotherapy efficacy of kynureninase modified CAR-T cells through targeting kynurenine metabolism.
  38. Gene expression is a poor predictor of steady-state metabolite abundance in cancer cells.
  39. MRI assessment of glutamine uptake correlates with the distribution of glutamine transporters and cancer stem cell markers.
  40. The role of irisin in metabolic flexibility: beyond adipose tissue browning.
  41. Redox Activation of Mitochondrial DAMPs and the Metabolic Consequences for Development of Autoimmunity.
  42. Ferroptosis-associated molecular classification characterized by distinct tumor microenvironment profiles in colorectal cancer.
  43. Tumor-Derived Lactic Acid Modulates Activation and Metabolic Status of Draining Lymph Node Stroma.
  44. Partial inhibition of mitochondrial-linked pyrimidine synthesis increases tumorigenic potential and lysosome accumulation.
  45. Organelle transporters and inter-organelle communication as drivers of metabolic regulation and cellular homeostasis.
  46. Carbon sources and pathways for citrate secreted by human prostate cancer cells determined by NMR tracing and metabolic modeling.
  47. Quantitative metabolic fluxes regulated by trans-omic networks.
  48. B cells regulate hematopoietic stem cells via cholinergic signaling.
  49. IL-6 promotes chemoresistance via upregulating CD36 mediated fatty acids uptake in acute myeloid leukemia.
  50. New tools to investigate tumor metabolism by NMR/MRI.
  51. Metabolism in atherosclerotic plaques: immunoregulatory mechanisms in the arterial wall.
  52. Impaired metabolism of oligodendrocyte progenitor cells and axons in demyelinated lesion and in the aged CNS.
  53. TOR signaling is required for host lipid metabolic remodelling and survival following enteric infection in Drosophila.
  54. Immunometabolic crosstalk during bacterial infection.
  1. Immunopharmacol Immunotoxicol. 2022 Mar 30. 1-14
    T cell metabolism and possible therapeutic targets in systemic lupus erythematosus: a narrative review.
    Marcela Muñoz-Urbano, Diana C Quintero-González, Gloria Vasquez.
      In the immunopathogenesis of systemic lupus erythematosus (SLE), there is a dysregulation of specific immune cells, including T cells. The metabolic reprogramming in T cells causes different effects. Metabolic programs are critical checkpoints in immune responses and are involved in the etiology of autoimmune disease. For instance, resting lymphocytes generate energy through oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO), whereas activated lymphocytes rapidly shift to the glycolytic pathway. Specifically, mitochondrial dysfunction, oxidative stress, abnormal metabolism (including glucose, lipid, and amino acid metabolism), and mTOR signaling are hallmarks of T lymphocyte metabolic dysfunction in SLE. Herein it is summarized how metabolic defects contribute to T cell responses in SLE, and some epigenetic alterations involved in the disease. Finally, it is shown how metabolic defects could be modified therapeutically.
    Keywords:  SLE; T cell metabolism; fatty acid oxidation; glycolysis; mTOR pathway; mitochondrial dysfunction
    DOI:  https://doi.org/10.1080/08923973.2022.2055568
  2. Pflugers Arch. 2022 Mar 28.
    Lipid metabolic reprogramming by hypoxia-inducible factor-1 in the hypoxic tumour microenvironment.
    Jieun Seo, Jeong-Eun Yun, Sung Joon Kim, Yang-Sook Chun.
      Cancer cells rewire metabolic processes to adapt to the nutrient- and oxygen-deprived tumour microenvironment, thereby promoting their proliferation and metastasis. Previous research has shown that modifying glucose metabolism, the Warburg effect, makes glycolytic cancer cells more invasive and aggressive. Lipid metabolism has also been receiving attention because lipids function as energy sources and signalling molecules. Because obesity is a risk factor for various cancer types, targeting lipid metabolism may be a promising cancer therapy. Here, we review the lipid metabolic reprogramming in cancer cells mediated by hypoxia-inducible factor-1 (HIF-1). HIF-1 is the master transcription factor for tumour growth and metastasis by transactivating genes related to proliferation, survival, angiogenesis, invasion, and metabolism. The glucose metabolic shift (the Warburg effect) is mediated by HIF-1. Recent research on HIF-1-related lipid metabolic reprogramming in cancer has confirmed that HIF-1 also modifies lipid accumulation, β-oxidation, and lipolysis in cancer, triggering its progression. Therefore, targeting lipid metabolic alterations by HIF-1 has therapeutic potential for cancer. We summarize the role of the lipid metabolic shift mediated by HIF-1 in cancer and its putative applications for cancer therapy.
    Keywords:  Cancer therapy; Hypoxia-inducible factor-1; Lipid metabolism; Tumour microenvironment
    DOI:  https://doi.org/10.1007/s00424-022-02683-x
  3. Front Cell Dev Biol. 2022 ;10 846723
    The Interplay Between TGF-β Signaling and Cell Metabolism.
    Huidong Liu, Ye-Guang Chen.
      The transforming growth factor-β (TGF-β) signaling plays a critical role in the development and tissue homeostasis in metazoans, and deregulation of TGF-β signaling leads to many pathological conditions. Mounting evidence suggests that TGF-β signaling can actively alter metabolism in diverse cell types. Furthermore, metabolic pathways, beyond simply regarded as biochemical reactions, are closely intertwined with signal transduction. Here, we discuss the role of TGF-β in glucose, lipid, amino acid, redox and polyamine metabolism with an emphasis on how TGF-β can act as a metabolic modulator and how metabolic changes can influence TGF-β signaling. We also describe how interplay between TGF-β signaling and cell metabolism regulates cellular homeostasis as well as the progression of multiple diseases, including cancer.
    Keywords:  Smad; TGF-β signaling; amino acid metabolism; glucose metabolism; lipid metabolism
    DOI:  https://doi.org/10.3389/fcell.2022.846723
  4. Front Immunol. 2022 ;13 771732
    The mTORC1 Signaling Support Cellular Metabolism to Dictate Decidual NK Cells Function in Early Pregnancy.
    Song Yan, Jie Dong, Chenxi Qian, Shuqiang Chen, Qian Xu, Hui Lei, Xiaohong Wang.
      Cellular metabolism plays an important role in regulating both human and murine NK cell functions. However, it remains unclear whether cellular metabolic process impacts on the function of decidual NK cells (dNK), essential tissue-resident immune cells maintaining the homeostasis of maternal-fetal interface. Remarkably, we found that glycolysis blockage enhances dNK VEGF-A production but restrains its proliferation. Furthermore, levels of IFN-γ and TNF-α secreted by dNK get decreased when glycolysis or oxidative phosphorylation (OXPHOS) is inhibited. Additionally, glycolysis, OXPHOS, and fatty acid oxidation disruption has little effects on the secretion and the CD107a-dependent degranulation of dNK. Mechanistically, we discovered that the mammalian target of rapamycin complex 1 (mTORC1) signaling inhibition leads to decreased glycolysis and OXPHOS in dNK. These limited metabolic processes are associated with attenuated dNK functions, which include restricted production of cytokines including IFN-γ and TNF-α, diminished CD107a-dependent degranulation, and restrained dNK proliferation. Finally, we reported that the protein levels of several glycolysis-associated enzymes are altered and the mTORC1 activity is significantly lower in the decidua of women with recurrent pregnancy loss (RPL) compared with normal pregnancy, which might give new insights about the pathogenesis of RPL. Collectively, our data demonstrate that glucose metabolism and mTORC1 signaling support dNK functions in early pregnancy.
    Keywords:  RPL; cytokines; cytotoxicity; decidual NK cells; mTORC1; metabolism
    DOI:  https://doi.org/10.3389/fimmu.2022.771732
  5. Mol Ther. 2022 Mar 28. pii: S1525-0016(22)00175-7. [Epub ahead of print]
    An SCD1-dependent mechanoresponsive pathway promotes HCC invasion and metastasis through lipid metabolic reprogramming.
    Hua-Hua Liu, Yang Xu, Cao-Jie Li, Shu-Jung Hsu, Xia-Hui Lin, Rui Zhang, Jie Chen, Jun Chen, Dong-Mei Gao, Jie-Feng Cui, Xin-Rong Yang, Zheng-Gang Ren, Rong-Xin Chen.
      Matrix stiffness promotes hepatocellular carcinoma (HCC) metastasis. This study examined the contribution of lipid metabolic reprogramming to matrix stiffness-induced HCC metastasis. HCC cells were cultured on mechanically tunable polyacrylamide gels and subjected to lipidomic analysis. The key enzyme that responded to matrix stiffness and regulated lipid metabolism was identified. The comparative lipidomic screening revealed that stearoyl-CoA desaturase 1 (SCD1) is a mechanoresponsive enzyme that reprogrammed HCC cell lipid metabolism. The genetic and pharmacological inhibition of SCD1 expression/activity altered the cellular lipid composition, which in turn impaired plasma membrane fluidity and inhibited in vitro invasive motility of HCC cells in response to high matrix stiffness. Knockdown of SCD1 suppressed HCC invasion and metastasis in vivo. Conversely, the overexpression of SCD1 or exogenous administration of its product oleic acid augmented plasma membrane fluidity and rescued in vitro invasive migration in HCC cells cultured on soft substrates, mimicking the effects imposed by high matrix stiffness. In human HCC tissues, collagen content, a marker of increasing matrix stiffness, and increased expression of SCD1 together predicted poor survival of HCC patients. An SCD1-dependent mechanoresponsive pathway that responds to increasing matrix stiffness in the tumor microenvironment promotes HCC invasion and metastasis through lipid metabolic reprogramming.
    DOI:  https://doi.org/10.1016/j.ymthe.2022.03.015
  6. J Mol Cell Biol. 2022 Mar 29. pii: mjac020. [Epub ahead of print]
    Deacetylation of MTHFD2 by SIRT4 senses stress signal to inhibit cancer cell growth by remodeling folate metabolism.
    Fan Zhang, Di Wang, Jintao Li, Ying Su, Suling Liu, Qun-Ying Lei, Miao Yin.
      Folate metabolism plays an essential role in tumor development. Various cancers display therapeutic response to reagents targeting key enzymes of folate cycle, but obtaining chemo-resistance later. Therefore, novel targets in folate metabolism are highly demanded. Methylenetetrahydrofolate dehydrogenase/methylenetetrahydrofolate cyclohydrolase 2 (MTHFD2) is one of the key enzymes in folate metabolism and its expression is highly increased in multiple human cancers. However, the underlying mechanism that regulates MTHFD2 expression remains unknown. Here, we elucidate that SIRT4 deacetylates the conserved lysine residue at 50 (K50) in MTHFD2. K50 de-acetylation destabilizes MTHFD2 by elevating Cullin 3 (CUL3) E3 ligase-mediated proteasomal degradation in response to stressful stimuli of folate deprivation, leading to suppression of nicotinamide adenine dinucleotide phosphate (NADPH) production in tumor cells and accumulation of intracellular reactive oxygen species (ROS), which in turn inhibits the growth of breast cancer cells. Collectively, our study reveals that SIRT4 senses folate availability to control MTHFD2 K50 acetylation and its protein stability, bridging nutrient/folate stress and cellular redox to act on cancer cell growth.
    Keywords:  CUL3; MTHFD2; SIRT4; acetylation; breast cancer; folate metabolism
    DOI:  https://doi.org/10.1093/jmcb/mjac020
  7. Cancer Sci. 2022 Apr 01.
    Glutamate blunts cell-killing effects of neutrophils in tumor microenvironment.
    Tiantian Xiong, Ping He, Mi Zhou, Dan Zhong, Teng Yang, Wenhui He, Zhizhen Xu, Zongtao Chen, Yang-Wuyue Liu, Shuang-Shuang Dai.
      Neutrophils are the first defenders of innate system for injury and infection. It is gradually recognized as important participants in tumor initiation and development due to heterogeneity and plasticity of neutrophils. In tumor microenvironment (TME), neutrophils might exert anti-tumor and pro-tumor functions depending on its surroundings. Tumor cells systemically alter intracellular amino acid (AA) metabolism and extracellular AA distribution to meet their proliferation need, leading to metabolic reprogramming and TME reshaping. However, the underlying mechanisms about how altered AAs affect neutrophils in TME are less-explored. Here, we identified that abundant glutamate releasing from tumor cells blunted neutrophils' cell-killing effects toward tumor cells in vitro and in vivo. Mass spectrometric detection, tumor flow and western experiments proved that increased level of pSTAT3/RAB10/ARF4 mediated by glutamate, were accompanied with immunosuppressive phenotypes of neutrophils in TME. We also discovered that Riluzole, FDA-approved glutamate release inhibitor, significantly inhibited tumor growth by restoring neutrophils' cell-killing effects though decreasing glutamate secretion from tumor cells. These findings highlight the importance of tumor-released glutamate on neutrophils transformation in TME, providing new possible cancer treatment targeting at altered glutamate metabolism.
    Keywords:  Glutamate; Neutrophil; Riluzole; STAT3; Tumor microenvironment
    DOI:  https://doi.org/10.1111/cas.15355
  8. Front Nutr. 2022 ;9 785999
    Systemic Lactate Acts as a Metabolic Buffer in Humans and Prevents Nutrient Overflow in the Postprandial Phase.
    Lisa Schlicker, Gang Zhao, Christian-Alexander Dudek, Hanny M Boers, Michael Meyer-Hermann, Doris M Jacobs, Karsten Hiller.
      On an organismal level, metabolism needs to react in a well-orchestrated manner to metabolic challenges such as nutrient uptake. Key metabolic hubs in human blood are pyruvate and lactate, both of which are constantly interconverted by very fast exchange fluxes. The quantitative contribution of different food sources to these metabolite pools remains unclear. Here, we applied in vivo stable isotope labeling to determine postprandial metabolic fluxes in response to two carbohydrate sources of different complexity. Depending on the ingested carbohydrate source, glucose or wheat flour, the net direction of the lactate dehydrogenase, and the alanine amino transferase fluxes were adjusted in a way to ensure sufficient availability, while, at the same time, preventing an overflow in the respective metabolite pools. The systemic lactate pool acts as a metabolic buffer which is fueled in the early- and depleted in the late-postprandial phase and thus plays a key role for systemic metabolic homeostasis.
    Keywords:  glucose; lactate; metabolic flux; metabolic modeling; stable isotope labeling; wheat
    DOI:  https://doi.org/10.3389/fnut.2022.785999
  9. Nat Aging. 2022 ;2(2): 155-169
    Scinderin promotes fusion of electron transport chain dysfunctional muscle stem cells with myofibers.
    Xun Wang, Spencer D Shelton, Bogdan Bordieanu, Anderson R Frank, Yating Yi, Siva Sai Krishna Venigalla, Zhimin Gu, Nicholas P Lenser, Michael Glogauer, Navdeep S Chandel, Hu Zhao, Zhiyu Zhao, David G McFadden, Prashant Mishra.
      Muscle stem cells (MuSCs) experience age-associated declines in number and function, accompanied by mitochondrial electron transport chain (ETC) dysfunction and increased reactive oxygen species (ROS). The source of these changes, and how MuSCs respond to mitochondrial dysfunction, is unknown. We report here that in response to mitochondrial ROS, murine MuSCs directly fuse with neighboring myofibers; this phenomenon removes ETC-dysfunctional MuSCs from the stem cell compartment. MuSC-myofiber fusion is dependent on the induction of Scinderin, which promotes formation of actin-dependent protrusions required for membrane fusion. During aging, we find that the declining MuSC population accumulates mutations in the mitochondrial genome, but selects against dysfunctional variants. In the absence of clearance by Scinderin, the decline in MuSC numbers during aging is repressed; however, ETC-dysfunctional MuSCs are retained and can regenerate dysfunctional myofibers. We propose a model in which ETC-dysfunctional MuSCs are removed from the stem cell compartment by fusing with differentiated tissue.
    DOI:  https://doi.org/10.1038/s43587-021-00164-x
  10. Front Immunol. 2022 ;13 865504
    The Role of Zinc in the T-Cell Metabolism in Infection Requires Further Investigation - An Opinion.
    Consolato M Sergi.
      
    Keywords:  T-cell; metabolism; supplementation; thymus; zinc
    DOI:  https://doi.org/10.3389/fimmu.2022.865504
  11. Gastroenterology. 2022 Mar 28. pii: S0016-5085(22)00314-6. [Epub ahead of print]
    HIF-2 in cancer associated fibroblasts polarizes macrophages and creates an immunosuppressive tumor microenvironment in pancreatic cancer.
    Sundaram Ramakrishnan.
      
    DOI:  https://doi.org/10.1053/j.gastro.2022.03.035
  12. Cell Mol Life Sci. 2022 Mar 29. 79(4): 216
    miRNA-guided reprogramming of glucose and glutamine metabolism and its impact on cell adhesion/migration during solid tumor progression.
    Lorena Quirico, Francesca Orso, Stefania Cucinelli, Mladen Paradzik, Dora Natalini, Giorgia Centonze, Alberto Dalmasso, Sofia La Vecchia, Martina Coco, Valentina Audrito, Chiara Riganti, Paola Defilippi, Daniela Taverna.
      MicroRNAs (miRNAs) are small, non-coding RNAs about 22 nucleotides in length that regulate the expression of target genes post-transcriptionally, and are highly involved in cancer progression. They are able to impact a variety of cell processes such as proliferation, apoptosis and differentiation and can consequently control tumor initiation, tumor progression and metastasis formation. miRNAs can regulate, at the same time, metabolic gene expression which, in turn, influences relevant traits of malignancy such as cell adhesion, migration and invasion. Since the interaction between metabolism and adhesion or cell movement has not, to date, been well understood, in this review, we will specifically focus on miRNA alterations that can interfere with some metabolic processes leading to the modulation of cancer cell movement. In addition, we will analyze the signaling pathways connecting metabolism and adhesion/migration, alterations that often affect cancer cell dissemination and metastasis formation.
    Keywords:  Adhesion; Cancer; Metabolism; Metastasis; miRNAs
    DOI:  https://doi.org/10.1007/s00018-022-04228-y
  13. Metabolism. 2022 Mar 25. pii: S0026-0495(22)00072-5. [Epub ahead of print] 155194
    Transition of acute kidney injury to chronic kidney disease: role of metabolic reprogramming.
    Zijing Zhu, Jijia Hu, Zhaowei Chen, Jun Feng, Xueyan Yang, Wei Liang, Guohua Ding.
      Acute kidney injury (AKI) is a global public health concern associated with high morbidity and mortality. Although advances in medical management have improved the in-hospital mortality of severe AKI patients, the renal prognosis for AKI patients in the later period is not encouraging. Recent epidemiological investigations have indicated that AKI significantly increases the risk for the development of chronic kidney disease (CKD) and end-stage renal disease (ESRD) in the future, further contributing to the economic burden on health care systems. The transition of AKI to CKD is complex and often involves multiple mechanisms. Recent studies have suggested that renal tubular epithelial cells (TECs) are more prone to metabolic reprogramming during AKI, in which the metabolic process in the TECs shifts from fatty acid β-oxidation (FAO) to glycolysis due to hypoxia, mitochondrial dysfunction, and disordered nutrient-sensing pathways. This change is a double-edged role. On the one hand, enhanced glycolysis acts as a compensation pathway for ATP production; on the other hand, long-term shut down of FAO and enhanced glycolysis lead to inflammation, lipid accumulation, and fibrosis, contributing to the transition of AKI to CKD. This review discusses developments and therapies focused on the metabolic reprogramming of TECs during AKI, and the emerging questions in this evolving field.
    Keywords:  Acute kidney injury; Chronic kidney disease; Metabolic reprogramming; Tubular epithelial cells
    DOI:  https://doi.org/10.1016/j.metabol.2022.155194
  14. Nat Metab. 2022 Mar 31.
    Altered propionate metabolism contributes to tumour progression and aggressiveness.
    Ana P Gomes, Didem Ilter, Vivien Low, Stanislav Drapela, Tanya Schild, Edouard Mullarky, Julie Han, Ilaria Elia, Dorien Broekaert, Adam Rosenzweig, Michal Nagiec, Joana B Nunes, Bethany E Schaffer, Anders P Mutvei, John M Asara, Lewis C Cantley, Sarah-Maria Fendt, John Blenis.
      The alteration of metabolic pathways is a critical strategy for cancer cells to attain the traits necessary for metastasis in disease progression. Here, we find that dysregulation of propionate metabolism produces a pro-aggressive signature in breast and lung cancer cells, increasing their metastatic potential. This occurs through the downregulation of methylmalonyl coenzyme A epimerase (MCEE), mediated by an extracellular signal-regulated kinase 2-driven transcription factor Sp1/early growth response protein 1 transcriptional switch driven by metastatic signalling at its promoter level. The loss of MCEE results in reduced propionate-driven anaplerotic flux and intracellular and intratumoral accumulation of methylmalonic acid, a by-product of propionate metabolism that promotes cancer cell invasiveness. Altogether, we present a previously uncharacterized dysregulation of propionate metabolism as an important contributor to cancer and a valuable potential target in the therapeutic treatment of metastatic carcinomas.
    DOI:  https://doi.org/10.1038/s42255-022-00553-5
  15. Aging Cell. 2022 Mar 27. e13595
    System-level metabolic modeling facilitates unveiling metabolic signature in exceptional longevity.
    Gong-Hua Li, Feifei Han, Fu-Hui Xiao, Kang-Su-Yun Gu, Qiu Shen, Weihong Xu, Wen-Xing Li, Yan-Li Wang, Bin Liang, Jing-Fei Huang, Wenzhong Xiao, Qing-Peng Kong.
      Although it is well known that metabolic control plays a crucial role in regulating the health span and life span of various organisms, little is known for the systems metabolic profile of centenarians, the paradigm of human healthy aging and longevity. Meanwhile, how to well characterize the system-level metabolic states in an organism of interest remains to be a major challenge in systems metabolism research. To address this challenge and better understand the metabolic mechanisms of healthy aging, we developed a method of genome-wide precision metabolic modeling (GPMM) which is able to quantitatively integrate transcriptome, proteome and kinetome data in predictive modeling of metabolic networks. Benchmarking analysis showed that GPMM successfully characterized metabolic reprogramming in the NCI-60 cancer cell lines; it dramatically improved the performance of the modeling with an R2 of 0.86 between the predicted and experimental measurements over the performance of existing methods. Using this approach, we examined the metabolic networks of a Chinese centenarian cohort and identified the elevated fatty acid oxidation (FAO) as the most significant metabolic feature in these long-lived individuals. Evidence from serum metabolomics supports this observation. Given that FAO declines with normal aging and is impaired in many age-related diseases, our study suggests that the elevated FAO has potential to be a novel signature of healthy aging of humans.
    Keywords:  GPMM; aging; longevity; metabolic modeling; omics integration; systems biology
    DOI:  https://doi.org/10.1111/acel.13595
  16. Trends Cell Biol. 2022 Mar 29. pii: S0962-8924(22)00060-5. [Epub ahead of print]
    Transsulfuration, minor player or crucial for cysteine homeostasis in cancer.
    Hai-Feng Zhang, Ramon I Klein Geltink, Seth J Parker, Poul H Sorensen.
      Cysteine, a thiol-containing amino acid, is crucial for the synthesis of sulfur-containing biomolecules that control multiple essential cellular activities. Altered cysteine metabolism has been linked to numerous driver oncoproteins and tumor suppressors, as well as to malignant traits in cancer. Cysteine can be acquired from extracellular sources or synthesized de novo via the transsulfuration (TSS) pathway. Limited availability of cystine in tumor interstitial fluids raises the possible dependency on de novo cysteine synthesis via TSS. However, the contribution of TSS to cancer metabolism remains highly contentious. Based on recent findings, we provide new perspectives on this crucial but understudied metabolic pathway in cancer.
    Keywords:  cancer; cysteine metabolism; ferroptosis; glutathione; redox homeostasis; transsulfuration
    DOI:  https://doi.org/10.1016/j.tcb.2022.02.009
  17. Future Med Chem. 2022 Mar 31.
    Citrate transporter inhibitors: possible new anticancer agents.
    Shivaputra A Patil, June A Mayor, Ronald S Kaplan.
      The culmination of 80+ years of cancer research implicates the aberrant metabolism in tumor cells as a root cause of pathogenesis. Citrate is an essential molecule in intermediary metabolism, and its amplified availability to critical pathways in cancer cells via citrate transporters confers a high rate of cancer cell growth and proliferation. Inhibiting the plasma membrane and mitochondrial citrate transporters - whether individually, in combination, or partnered with complementary metabolic targets - in order to combat cancer may prove to be a consequential chemotherapeutic strategy. This review aims to summarize the use of different classes of citrate transporter inhibitors for anticancer activity, either individually or as part of a cocktail.
    Keywords:  anticancer; citrate; drug discovery; mitochondrial citrate transporter (CTP); plasma membrane citrate transporter (PMCT)
    DOI:  https://doi.org/10.4155/fmc-2021-0341
  18. Exp Eye Res. 2022 Mar 26. pii: S0014-4835(22)00132-4. [Epub ahead of print]219 109052
    Proteomic analysis reveals the heterogeneity of metabolic reprogramming in lacrimal gland tumors.
    Jie Yang, Yongyun Li, Weiling Gao, Yiyi Feng, Xiaoyu He, Hongyan Ni, Xin Song, Jiayan Fan.
      Lacrimal gland adenoid cystic carcinoma (ACC) is associated with high recurrence and mortality rates. Many recent studies have focused on the clinical features of the disease, and a better understanding of its underlying molecular mechanisms may help guide future treatment strategies. For proteomics quantitation, we analyzed normal tissues, benign tumor tissues and ACC tissues by LC-MS/MS with Tandem mass tags (TMTs) labeling. Bioinformatics analysis of the KEGG pathway found that, compared with normal tissues, the expression levels of major proteins related to cell metabolism were lower in benign tumors and cancer tissues of the lacrimal gland. In addition, we also performed IHC staining to verify the expression of representative proteins in tissue samples. All of these results indicated that compared with normal tissues, lacrimal gland tumors had unique metabolic reprogramming characteristics. Further Short Time-series Expression Miner (STEM) analysis revealed that glycine, serine and threonine metabolism in ACC tissues was significantly enhanced compared with that in normal tissues and benign tumor tissues. This finding suggested that glycine, serine and threonine metabolism might be the key to the malignant transformation of ACC; thus, assessing the metabolism in these tissues could be an effective approach enabling the early diagnosis of ACC, and the proteins involved in these metabolic pathways could represent therapeutic targets.
    Keywords:  Lacrimal gland tumors; Metabolic reprogramming; Proteomics
    DOI:  https://doi.org/10.1016/j.exer.2022.109052
  19. Kidney Int. 2022 Mar 24. pii: S0085-2538(22)00212-5. [Epub ahead of print]
    Disruption of mitochondrial complex III in cap mesenchyme but not in ureteric progenitors results in defective nephrogenesis associated with amino acid deficiency.
    Nan Guan, Hanako Kobayashi, Ken Ishii, Olena Davidoff, Feng Sha, Talat A Ikizler, Chuan-Ming Hao, Navdeep S Chandel, Volker H Haase.
      Oxidative metabolism in mitochondria regulates cellular differentiation and gene expression through intermediary metabolites and reactive oxygen species. Its role in kidney development and pathogenesis is not completely understood. Here we inactivated ubiquinone-binding protein QPC, a subunit of mitochondrial complex III, in two types of kidney progenitor cells to investigate the role of mitochondrial electron transport in kidney homeostasis. Inactivation of QPC in sine oculis-related homeobox 2 (SIX2)-expressing cap mesenchyme progenitors, which give rise to podocytes and all nephron segments except collecting ducts, resulted in perinatal death from severe kidney dysplasia. This was characterized by decreased proliferation of SIX2 progenitors and their failure to differentiate into kidney epithelium. QPC inactivation in cap mesenchyme progenitors induced activating transcription factor 4-mediated nutritional stress responses and was associated with a reduction in kidney tricarboxylic acid cycle metabolites and amino acid levels, which negatively impacted purine and pyrimidine synthesis. In contrast, QPC inactivation in ureteric tree epithelial cells, which give rise to the kidney collecting system, did not inhibit ureteric differentiation, and resulted in the development of functional kidneys that were smaller in size. Thus, our data demonstrate that mitochondrial oxidative metabolism is critical for the formation of cap mesenchyme-derived nephron segments but dispensable for formation of the kidney collecting system. Hence, our studies reveal compartment-specific needs for metabolic reprogramming during kidney development.
    Keywords:  TCA cycle; amino acids; kidney development; mitochondria; mitochondrial complex III; mitochondrial electron transport chain
    DOI:  https://doi.org/10.1016/j.kint.2022.02.030
  20. Semin Cell Dev Biol. 2022 Mar 26. pii: S1084-9521(22)00096-9. [Epub ahead of print]
    Transient changes to metabolic homeostasis initiate mitochondrial adaptation to endurance exercise.
    Jessica R Dent, Ben Stocks, Dean G Campelj, Andrew Philp.
      Endurance exercise is well established to increase mitochondrial content and function in skeletal muscle, a process termed mitochondrial biogenesis. Current understanding is that exercise initiates skeletal muscle mitochondrial remodeling via modulation of cellular nutrient, energetic and contractile stress pathways. These subtle changes in the cellular milieu are sensed by numerous transduction pathways that serve to initiate and coordinate an increase in mitochondrial gene transcription and translation. The result of these acute signaling events is the promotion of growth and assembly of mitochondria, coupled to a greater capacity for aerobic ATP provision in skeletal muscle. The aim of this review is to highlight the acute metabolic events induced by endurance exercise and the subsequent molecular pathways that sense this transient change in cellular homeostasis to drive mitochondrial adaptation and remodeling.
    Keywords:  Adaptation; Exercise; Metabolism; Mitochondria
    DOI:  https://doi.org/10.1016/j.semcdb.2022.03.022
  21. Int J Biol Sci. 2022 ;18(5): 1912-1932
    Metabolomics reveals that CAF-derived lipids promote colorectal cancer peritoneal metastasis by enhancing membrane fluidity.
    Shaoyong Peng, Yingjie Li, Meijin Huang, Guannan Tang, Yumo Xie, Daici Chen, Yumin Hu, Tiantian Yu, Jian Cai, Zixu Yuan, Huaiming Wang, Hui Wang, Yanxin Luo, Xiaoxia Liu.
      Patients with peritoneal metastasis (PM) of colorectal cancer (CRC) have poorer overall survival outcomes than those without PM. Cancer-associated fibroblasts (CAFs) are a major component of the tumor microenvironment and mediate CRC progression and PM. It is imperative to identify and develop novel therapeutic targets for PM-CRC driven by CAFs. Using lipidomics, we reveal that the abundance of phosphatidylcholine (PC) with unsaturated acyl chains was increased in clinical PM-CRC specimens. Additionally, we found that CAFs were present at a higher relative abundance in primary PM-CRC tumors and that membrane fluidity in CRC cells was increased after incubation with CAF-conditioned medium (CM) through three independent methods: lipidomics, fluorescence recovery after photobleaching (FRAP), and generalized polarization. Then, we found that increased membrane fluidity can enhance glucose uptake and metabolism, as supported by real-time bioenergetics analysis and U-13C glucose labeling. Interestingly, stearoyl-CoA desaturase 1 (SCD), the rate-limiting enzyme in the biosynthesis of unsaturated fatty acids (uS-FAs), was expressed at low levels in PM and associated with poor prognosis in CRC patients. Importantly, by untargeted metabolomics analysis and fatty acid ([U-13C]-stearic acid) tracing analyses, we found that CRC cells take up lipids and lipid-like metabolites secreted from CAFs, which may compensate for low SCD expression. Both in vitro and in vivo experiments demonstrated that sodium palmitate (C16:0) treatment could decrease the CAF-induced change in cell membrane fluidity, limit glucose metabolism, suppress cell invasiveness, and impair tumor growth and intraperitoneal dissemination. An increased C16:0 concentration was shown to induce apoptosis linked to lipotoxicity. Furthermore, C16:0 effectively enhanced the antitumor activity of 5-fluorouracil (5-FU) in vitro and was well tolerated in vivo. Taken together, these findings suggest that adding the saturated fatty acid (S-FA) C16:0 to neoadjuvant chemotherapy may open new opportunities for treating PM-CRC in the future.
    Keywords:  C16:0; Lipidomics; cancer-associated fibroblasts (CAFs); colorectal cancer peritoneal metastasis; glucose metabolism; metabolomics
    DOI:  https://doi.org/10.7150/ijbs.68484
  22. Front Endocrinol (Lausanne). 2022 ;13 663625
    Hypoxia Induces Saturated Fatty Acids Accumulation and Reduces Unsaturated Fatty Acids Independently of Reverse Tricarboxylic Acid Cycle in L6 Myotubes.
    Lukas Vacek, Ales Dvorak, Kamila Bechynska, Vit Kosek, Moustafa Elkalaf, Minh Duc Trinh, Ivana Fiserova, Katerina Pospisilova, Lucie Slovakova, Libor Vitek, Jana Hajslova, Jan Polak.
      Obstructive sleep apnea syndrome, characterized by repetitive episodes of tissue hypoxia, is associated with several metabolic impairments. Role of fatty acids and lipids attracts attention in its pathogenesis for their metabolic effects. Parallelly, hypoxia-induced activation of reverse tricarboxylic acid cycle (rTCA) with reductive glutamine metabolism provides precursor molecules for de novo lipogenesis. Gas-permeable cultureware was used to culture L6-myotubes in chronic hypoxia (12%, 4% and 1% O2) with 13C labelled glutamine and inhibitors of glutamine uptake or rTCA-mediated lipogenesis. We investigated changes in lipidomic profile, 13C appearance in rTCA-related metabolites, gene and protein expression of rTCA-related proteins and glutamine transporters, glucose uptake and lactate production. Lipid content increased by 308% at 1% O2, predominantly composed of saturated fatty acids, while triacylglyceroles containing unsaturated fatty acids and membrane lipids (phosphatidylcholines, phosphatidylethanolamines, phosphatidylinositol) decreased by 20-70%. rTCA labelling of malate, citrate and 2-hydroxyglutarate increased by 4.7-fold, 2.2-fold and 1.9-fold in 1% O2, respectively. ATP-dependent citrate lyase inhibition in 1% O2 decreased lipid amount by 23% and increased intensity of triacylglyceroles containing unsaturated fatty acids by 56-80%. Lactate production increased with hypoxia. Glucose uptake dropped by 75% with progression of hypoxia from 4% to 1% O2. Protein expression remained unchanged. Altogether, hypoxia modified cell metabolism leading to lipid composition alteration and rTCA activation.
    Keywords:  L6 myotubes; glutamin; hypoxia; lipids; obstructive sleep apnea ; reverse TCA
    DOI:  https://doi.org/10.3389/fendo.2022.663625
  23. Clin Exp Immunol. 2022 Feb 24. pii: uxac003. [Epub ahead of print]
    Immunometabolic adaptation and immune plasticity in pregnancy and the bi-directional effects of obesity.
    April Rees, Oliver Richards, Megan Chambers, Benjamin J Jenkins, James G Cronin, Catherine A Thornton.
      Mandatory maternal metabolic and immunological changes are essential to pregnancy success. Parallel changes in metabolism and immune function make immunometabolism an attractive mechanism to enable dynamic immune adaptation during pregnancy. Immunometabolism is a burgeoning field with the underlying principle being that cellular metabolism underpins immune cell function. With whole body changes to the metabolism of carbohydrates, protein and lipids well recognised to occur in pregnancy and our growing understanding of immunometabolism as a determinant of immunoinflammatory effector responses, it would seem reasonable to expect immune plasticity during pregnancy to be linked to changes in the availability and handling of multiple nutrient energy sources by immune cells. While studies of immunometabolism in pregnancy are only just beginning, the recognised bi-directional interaction between metabolism and immune function in the metabolic disorder obesity might provide some of the earliest insights into the role of immunometabolism in immune plasticity in pregnancy. Characterised by chronic low-grade inflammation including in pregnant women, obesity is associated with numerous adverse outcomes during pregnancy and beyond for both mother and child. Concurrent changes in metabolism and immunoinflammation are consistently described but any causative link is not well established. Here we provide an overview of the metabolic and immunological changes that occur in pregnancy and how these might contribute to healthy versus adverse pregnancy outcomes with special consideration of possible interactions with obesity.
    Keywords:  immunometabolism; obesity; plasticity; pregnancy
    DOI:  https://doi.org/10.1093/cei/uxac003
  24. Front Oncol. 2022 ;12 858017
    Imaging Sub-Cellular Methionine and Insulin Interplay in Triple Negative Breast Cancer Lipid Droplet Metabolism.
    Anthony A Fung, Khang Hoang, Honghao Zha, Derek Chen, Wenxu Zhang, Lingyan Shi.
      Triple negative breast cancer (TNBC) is a particularly aggressive cancer subtype that is difficult to diagnose due to its discriminating epidemiology and obscure metabolome. For the first time, 3D spatial and chemometric analyses uncover the unique lipid metabolome of TNBC under the tandem modulation of two key metabolites - insulin and methionine - using non-invasive optical techniques. By conjugating heavy water (D2O) probed Raman scattering with label-free two-photon fluorescence (TPF) microscopy, we observed altered de novo lipogenesis, 3D lipid droplet morphology, and lipid peroxidation under various methionine and insulin concentrations. Quantitative interrogation of both spatial and chemometric lipid metabolism under tandem metabolite modulation confirms significant interaction of insulin and methionine, which may prove to be critical therapeutic targets, and proposes a powerful optical imaging platform with subcellular resolution for metabolic and cancer research.
    Keywords:  DO-SRS; TPF; breast cancer; heavy water; insulin; lipid metabolism; methionine; stimulated Raman scattering
    DOI:  https://doi.org/10.3389/fonc.2022.858017
  25. Oncogene. 2022 Mar 30.
    H3K9me3 represses G6PD expression to suppress the pentose phosphate pathway and ROS production to promote human mesothelioma growth.
    Chunwan Lu, Dafeng Yang, John D Klement, Yolonda L Colson, Nicholas H Oberlies, Cedric J Pearce, Aaron H Colby, Mark W Grinstaff, Zhuoqi Liu, Huidong Shi, Han-Fei Ding, Kebin Liu.
      The role of glucose-6-phosphate dehydrogenase (G6PD) in human cancer is incompletely understood. In a metabolite screening, we observed that inhibition of H3K9 methylation suppressed aerobic glycolysis and enhances the PPP in human mesothelioma cells. Genome-wide screening identified G6PD as an H3K9me3 target gene whose expression is correlated with increased tumor cell apoptosis. Inhibition of aerobic glycolysis enzyme LDHA and G6PD had no significant effects on tumor cell survival. Ablation of G6PD had no significant effect on human mesothelioma and colon carcinoma xenograft growth in athymic mice. However, activation of G6PD with the G6PD-selective activator AG1 induced tumor cell death. AG1 increased tumor cell ROS production and the resultant extrinsic and intrinsic death pathways, mitochondrial processes, and unfolded protein response in tumor cells. Consistent with increased tumor cell death in vitro, AG1 suppressed human mesothelioma xenograft growth in a dose-dependent manner in vivo. Furthermore, AG1 treatment significantly increased tumor-bearing mouse survival in an intra-peritoneum xenograft athymic mouse model. Therefore, in human mesothelioma and colon carcinoma, G6PD is not essential for tumor growth. G6PD acts as a metabolic checkpoint to control metabolic flux towards the PPP to promote tumor cell apoptosis, and its expression is repressed by its promotor H3K9me3 deposition.
    DOI:  https://doi.org/10.1038/s41388-022-02283-0
  26. Front Immunol. 2022 ;13 829760
    Metabolic Landscape of Bronchoalveolar Lavage Fluid in Coronavirus Disease 2019 at Single Cell Resolution.
    Ming-Ming Shao, Meier Shi, Juan Du, Xue-Bin Pei, Bei-Bei Gu, Feng-Shuang Yi.
      Abnormal function of immune cells is one of the key mechanisms leading to severe clinical symptoms in coronavirus disease 2019 patients, and metabolic pathways can destroy the function of the immune system by affecting innate and adaptive immune responses. However, the metabolic characteristics of the immune cells of the SARS-CoV-2 infected organs in situ remaining elusive. We reanalyzed the metabolic-related gene profiles in single-cell RNA sequencing data, drew the metabolic landscape in bronchoalveolar lavage fluid immune cells, and elucidated the metabolic remodeling mechanism that might lead to the progression of COVID-19 and the cytokine storm. Enhanced glycolysis is the most important common metabolic feature of all immune cells in COVID-19 patients. CCL2+ T cells, Group 2 macrophages with high SPP1 expression and myeloid dendritic cells are among the main contributors to the cytokine storm produced by infected lung tissue. Two metabolic analysis methods, including Compass, showed that glycolysis, fatty acid metabolism, bile acid synthesis and purine and pyrimidine metabolism levels of CCL2+ T cells, Group 2 macrophages and myeloid dendritic cells were upregulated and correlated with cytokine storms of COVID-19 patients. This might be the key metabolic regulatory factor for immune cells to produce large quantities of cytokines.
    Keywords:  COVID-19; Metabolic reprogramming; bronchoalveolar lavage fluid; cytokine storm; single cell RNA sequencing
    DOI:  https://doi.org/10.3389/fimmu.2022.829760
  27. Clin Transl Oncol. 2022 Mar 30.
    Development of a prognostic metabolic signature in stomach adenocarcinoma.
    Yu Gong, Siyuan Wu, Sen Dong, Shuai Chen, Gengdi Cai, Kun Bao, Haojun Yang, Yuwen Jiao.
       PURPOSE: The growth and aggressiveness of Stomach adenocarcinoma (STAD) is significantly affected by basic metabolic changes. This study aimed to identify metabolic gene prognostic signatures in STAD.
    METHODS: An integrative analysis of datasets from the Cancer Genome Atlas and Gene Expression Omnibus was performed. A metabolic gene prognostic signature was developed using univariable Cox regression and Kaplan-Meier survival analysis. A nomogram model was developed to predict the prognosis of STAD patients. Finally, Gene Set Enrichment Analysis (GESA) was used to explore the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways significantly associated with the risk grouping.
    RESULTS: A total of 327 metabolism-related differentially expressed genes were identified. Three subtypes of STAD were identified and nine immune cell types, including memory B cell, resting and activated CD4+ memory T cells, were significantly different among the three subgroups. A risk score model including nine survival-related genes which could separate high-risk patients from low-risk patients was developed. The prognosis of STAD patients likely benefited from lower expression levels of genes, including ABCG4, ABCA6, GPX8, KYNU, ST8SIA5, and CYP19A1. Age, radiation therapy, tumor recurrence, and risk score model status were found to be independent risk factors for STAD and were used for developing a nomogram. Nine KEGG pathways, including spliceosome, pentose phosphate pathway, and citrate TCA cycle were significantly enriched in GESA.
    CONCLUSION: We propose a metabolic gene signature and a nomogram for STAD which might be used for predicting the survival of STAD patients and exploring prognostic markers.
    Keywords:  Metabolic prognostic signatures; Prognostic prediction; Stomach adenocarcinoma
    DOI:  https://doi.org/10.1007/s12094-022-02809-8
  28. Sci China Life Sci. 2022 Mar 25.
    Palmitoylation of MDH2 by ZDHHC18 activates mitochondrial respiration and accelerates ovarian cancer growth.
    Xuan Pei, Kai-Yue Li, Yuan Shen, Jin-Tao Li, Ming-Zhu Lei, Cai-Yun Fang, Hao-Jie Lu, Hui-Juan Yang, Wenyu Wen, Miao Yin, Jia Qu, Qun-Ying Lei.
      Epithelial ovarian cancer (EOC) exhibits strong dependency on the tricarboxylic acid (TCA) cycle and oxidative phosphorylation to fuel anabolic process. Here, we show that malate dehydrogenase 2 (MDH2), a key enzyme of the TCA cycle, is palmitoylated at cysteine 138 (C138) residue, resulting in increased activity of MDH2. We next identify that ZDHHC18 acts as a palmitoyltransferase of MDH2. Glutamine deprivation enhances MDH2 palmitoylation by increasing the binding between ZDHHC18 and MDH2. MDH2 silencing represses mitochondrial respiration as well as ovarian cancer cell proliferation both in vitro and in vivo. Intriguingly, re-expression of wild-type MDH2, but not its palmitoylation-deficient C138S mutant, sustains mitochondrial respiration and restores the growth as well as clonogenic capability of ovarian cancer cells. Notably, MDH2 palmitoylation level is elevated in clinical cancer samples from patients with high-grade serous ovarian cancer. These observations suggest that MDH2 palmitoylation catalyzed by ZDHHC18 sustains mitochondrial respiration and promotes the malignancy of ovarian cancer, yielding possibilities of targeting ZDHHC18-mediated MDH2 palmitoylation in the treatment of EOC.
    Keywords:  EOC; MDH2; ZDHHC18; cysteine palmitoylation; glutamine
    DOI:  https://doi.org/10.1007/s11427-021-2048-2
  29. Cell Rep. 2022 Mar 29. pii: S2211-1247(22)00351-5. [Epub ahead of print]38(13): 110603
    PTIP governs NAD+ metabolism by regulating CD38 expression to drive macrophage inflammation.
    Qifan Wang, Jin Hu, Guoqiang Han, Peipei Wang, Sha Li, Jiwei Chang, Kexin Gao, Rong Yin, Yashu Li, Tong Zhang, Jihua Chai, Zhuying Gao, Tiantian Zhang, Ying Cheng, Chengli Guo, Jing Wang, Weidong Liu, Manman Cui, Yu Xu, Jinxuan Hou, Quan-Fei Zhu, Yu-Qi Feng, Haojian Zhang.
      NAD+ metabolism is involved in many biological processes. However, the underlying mechanism of how NAD+ metabolism is regulated remains elusive. Here, we find that PTIP governs NAD+ metabolism in macrophages by regulating CD38 expression and is required for macrophage inflammation. Through integrating histone modifications with NAD+ metabolic gene expression profiling, we identify PTIP as a key factor in regulating CD38 expression, the primary NAD+-consuming enzyme in macrophages. Interestingly, we find that PTIP deletion impairs the proinflammatory response of primary murine and human macrophages, promotes their metabolic switch from glycolysis to oxidative phosphorylation, and alters NAD+ metabolism via downregulating CD38 expression. Mechanistically, an intronic enhancer of CD38 is identified. PTIP regulates CD38 expression by cooperating with acetyltransferase p300 in establishing the CD38 active enhancer with enriched H3K27ac. Overall, our findings reveal a critical role for PTIP in fine-tuning the inflammatory responses of macrophages via regulating NAD+ metabolism.
    Keywords:  CD38; CP: Immunology; CP: Metabolism; NAD(+); PTIP; inflammation; macrophage
    DOI:  https://doi.org/10.1016/j.celrep.2022.110603
  30. Pharmacol Ther. 2022 Mar 25. pii: S0163-7258(22)00070-5. [Epub ahead of print] 108176
    Macrophage immunometabolism in inflammatory bowel diseases: From pathogenesis to therapy.
    Xiaohua Pan, Qing Zhu, Xiaoliang Dong, Jiahong Li, He Liu, Zhengran Ren, Binbin Li, Li-Long Pan, Jia Sun.
      Inflammatory bowel disease (IBD), comprised of ulcerative colitis and Crohn's disease, is a chronic relapsing inflammatory disease of the gastrointestinal tract that closely related to immune dysfunction. Macrophages are the key gatekeeper of intestinal immune homeostasis and have vital influence on IBD. Hence, macrophages have been recognized as attractive targets to develop new therapeutic approaches for the disease. Recently, the growing field of immunometabolism has reinforced that metabolism reprogramming is a key determinant that dictates macrophage functions and subsequent disease progression. Herein, we elaborated how metabolic alterations underlie intestinal macrophage phenotype and function during IBD, and how microenvironmental cues trigger their metabolic reprogramming processes. More importantly, we deciphered the distinguishing characteristic of macrophage immunometabolism in IBD from other inflammatory diseases, and also summarized potential therapeutic approaches for IBD by manipulating cellular metabolism of macrophages. Finally, we discussed the major opportunities and challenges of harnessing metabolism to modulate aberrant macrophage responses in IBD. Altogether, our overview provides a framework for understanding the critical roles and potential therapeutic targets of macrophage immunometabolism in IBD.
    Keywords:  Gut microbiota; Immunometabolism; Inflammation; Inflammatory bowel disease; Macrophage; Therapy
    DOI:  https://doi.org/10.1016/j.pharmthera.2022.108176
  31. Cell Regen. 2022 Apr 02. 11(1): 11
    miR-378-mediated glycolytic metabolism enriches the Pax7Hi subpopulation of satellite cells.
    Hu Li, Lin Kang, Rimao Wu, Changyin Li, Qianying Zhang, Ran Zhong, Lijing Jia, Dahai Zhu, Yong Zhang.
      Adult skeletal muscle stem cells, also known satellite cells (SCs), are a highly heterogeneous population and reside between the basal lamina and the muscle fiber sarcolemma. Myofibers function as an immediate niche to support SC self-renewal and activation during muscle growth and regeneration. Herein, we demonstrate that microRNA 378 (miR-378) regulates glycolytic metabolism in skeletal muscle fibers, as evidenced by analysis of myofiber-specific miR-378 transgenic mice (TG). Subsequently, we evaluate SC function and muscle regeneration using miR-378 TG mice. We demonstrate that miR-378 TG mice significantly attenuate muscle regeneration because of the delayed activation and differentiation of SCs. Furthermore, we show that the miR-378-mediated metabolic switch enriches Pax7Hi SCs, accounting for impaired muscle regeneration in miR-378 TG mice. Mechanistically, our data suggest that miR-378 targets the Akt1/FoxO1 pathway, which contributes the enrichment of Pax7Hi SCs in miR-378 TG mice. Together, our findings indicate that miR-378 is a target that links fiber metabolism to muscle stem cell heterogeneity and provide a genetic model to approve the metabolic niche role of myofibers in regulating muscle stem cell behavior and function.
    Keywords:  glycolytic metabolism; miRNAs; muscle regeneration; satellite cells
    DOI:  https://doi.org/10.1186/s13619-022-00112-z
  32. Cell Rep. 2022 Mar 29. pii: S2211-1247(22)00304-7. [Epub ahead of print]38(13): 110560
    Neutral ceramidase-dependent regulation of macrophage metabolism directs intestinal immune homeostasis and controls enteric infection.
    Rui Sun, Xuemei Gu, Chao Lei, Liang Chen, Shenghui Chu, Guangzhong Xu, Mark A Doll, Yi Tan, Wenke Feng, Leah Siskind, Craig J McClain, Zhongbin Deng.
      It is not clear how the complex interactions between diet and intestinal immune cells protect the gut from infection. Neutral ceramidase (NcDase) plays a critical role in digesting dietary sphingolipids. We find that NcDase is an essential factor that controls intestinal immune cell dynamics. Mice lacking NcDase have reduced cluster of differentiation (CD) 8αβ+ T cells and interferon (IFN)-γ+ T cells and increased macrophages in the intestine and fail to clear bacteria after Citrobacter rodentium infection. Mechanistically, cellular NcDase or extracellular vesicle (EV)-related NcDase generates sphingosine, which promotes macrophage-driven Th1 immunity. Loss of NcDase influences sphingosine-controlled glycolytic metabolism in macrophages, which regulates the bactericidal activity of macrophages. Importantly, administration of dietary sphingomyelin and genetic deletion or pharmacological inhibition of SphK1 can protect against C. rodentium infection. Our findings demonstrate that sphingosine profoundly alters macrophage glycolytic metabolism, leading to intestinal macrophage activation and T cell polarization, which prevent pathogen colonization of the gut.
    Keywords:  CP: Immunology; CP: Microbiology; Th1 cells; ceramide; defense; extracellular vesicles; glycolysis; inflammasomes; innate; intestine; mucosal immunology; sphingolipid
    DOI:  https://doi.org/10.1016/j.celrep.2022.110560
  33. Sci Rep. 2022 Apr 01. 12(1): 5518
    Bladder cancer cells shift rapidly and spontaneously to cisplatin-resistant oxidative phosphorylation that is trackable in real time.
    Tong Xu, Jason A Junge, Alireza Delfarah, Yi-Tsung Lu, Cosimo Arnesano, Maheen Iqbal, Kevin Delijani, Tien-Chan Hsieh, Emmanuelle Hodara, Hemal H Mehta, Pinchas Cohen, Nicholas A Graham, Scott E Fraser, Amir Goldkorn.
      Genetic mutations have long been recognized as drivers of cancer drug resistance, but recent work has defined additional non-genetic mechanisms of plasticity, wherein cancer cells assume a drug resistant phenotype marked by altered epigenetic and transcriptional states. Currently, little is known about the real-time, dynamic nature of this phenotypic shift. Using a bladder cancer model of nongenetic plasticity, we discovered that rapid transition to drug resistance entails upregulation of mitochondrial gene expression and a corresponding metabolic shift towards the tricarboxylic acid cycle and oxidative phosphorylation. Based on this distinction, we were able to track cancer cell metabolic profiles in real time using fluorescence lifetime microscopy (FLIM). We observed single cells transitioning spontaneously to an oxidative phosphorylation state over hours to days, a trend that intensified with exposure to cisplatin chemotherapy. Conversely, pharmacological inhibition of oxidative phosphorylation significantly reversed the FLIM metabolic signature and reduced cisplatin resistance. These rapid, spontaneous metabolic shifts offer a new means of tracking nongenetic cancer plasticity and forestalling the emergence of drug resistance.
    DOI:  https://doi.org/10.1038/s41598-022-09438-9
  34. Front Microbiol. 2022 ;13 854272
    Transient Antibiotic Tolerance Triggered by Nutrient Shifts From Gluconeogenic Carbon Sources to Fatty Acid.
    Christopher J Hartline, Ruixue Zhang, Fuzhong Zhang.
      Nutrient shifts from glycolytic-to-gluconeogenic carbon sources can create large sub-populations of extremely antibiotic tolerant bacteria, called persisters. Positive feedback in Escherichia coli central metabolism was believed to play a key role in the formation of persister cells. To examine whether positive feedback in nutrient transport can also support high persistence to β-lactams, we performed nutrient shifts for E. coli from gluconeogenic carbon sources to fatty acid (FA). We observed tri-phasic antibiotic killing kinetics characterized by a transient period of high antibiotic tolerance, followed by rapid killing then a slower persister-killing phase. The duration of transient tolerance (3-44 h) varies with pre-shift carbon source and correlates strongly with the time needed to accumulate the FA degradation enzyme FadD after the shift. Additionally, FadD accumulation time and thus transient tolerance time can be reduced by induction of the glyoxylate bypass prior to switching, highlighting that two interacting feedback loops simultaneously control the length of transient tolerance. Our results demonstrate that nutrient switches along with positive feedback are not sufficient to trigger persistence in a majority of the population but instead triggers only a temporary tolerance. Additionally, our results demonstrate that the pre-shift metabolic state determines the duration of transient tolerance and that supplying glyoxylate can facilitate antibiotic killing of bacteria.
    Keywords:  antibiotic tolerance; bacterial metabolism; fatty acid pathway; metabolic positive feedback; nutrient shift; persistence
    DOI:  https://doi.org/10.3389/fmicb.2022.854272
  35. Front Biosci (Landmark Ed). 2022 Mar 09. 27(3): 95
    Targeting the Key Enzymes of Abnormal Fatty Acid β-oxidation as a Potential Strategy for Tumor Therapy.
    Hongdan Chen, Zeyu Yang, Yiceng Sun, Supeng Yin, Mi Tang, Fan Zhang.
      Fatty acid metabolism has attracted extensive attention for its key role in the occurrence and development of tumors. Fatty acids not only participate in the biosynthesis of phospholipids in the membrane to overcome the demand for rapidly proliferating membrane lipids but also provide ATP, signaling molecules, and NADPH through β-oxidation to maintain tumor survival and growth. However, the specific role of fatty acid β-oxidation in tumors and the description of multiple potential targets in this process are not comprehensive and systematic. Therefore, this review summarizes the function of fatty acid β-oxidation in tumors and studies of key enzymes that catalyze related reactions in various stages to improve the overall understanding of fatty acid β-oxidation and search for novel tumor treatment strategies and ideas.
    Keywords:  ATP; NADPH; fatty acid β-oxidation; review; tumor
    DOI:  https://doi.org/10.31083/j.fbl2703095
  36. Nat Metab. 2022 Mar;4(3): 389-403
    Switching to the cyclic pentose phosphate pathway powers the oxidative burst in activated neutrophils.
    Emily C Britt, Jorgo Lika, Morgan A Giese, Taylor J Schoen, Gretchen L Seim, Zhengping Huang, Pui Y Lee, Anna Huttenlocher, Jing Fan.
      Neutrophils are cells at the frontline of innate immunity that can quickly activate effector functions to eliminate pathogens upon stimulation. However, little is known about the metabolic adaptations that power these functions. Here we show rapid metabolic alterations in neutrophils upon activation, particularly drastic reconfiguration around the pentose phosphate pathway, which is specifically and quantitatively coupled to an oxidative burst. During this oxidative burst, neutrophils switch from glycolysis-dominant metabolism to a unique metabolic mode termed 'pentose cycle', where all glucose-6-phosphate is diverted into oxidative pentose phosphate pathway and net flux through upper glycolysis is reversed to allow substantial recycling of pentose phosphates. This reconfiguration maximizes NADPH yield to fuel superoxide production via NADPH oxidase. Disruptions of pentose cycle greatly suppress oxidative burst, the release of neutrophil extracellular traps and pathogen killing by neutrophils. Together, these results demonstrate the remarkable metabolic flexibility of neutrophils, which is essential for their functions as the first responders in innate immunity.
    DOI:  https://doi.org/10.1038/s42255-022-00550-8
  37. Oncoimmunology. 2022 ;11(1): 2055703
    Superior antitumor immunotherapy efficacy of kynureninase modified CAR-T cells through targeting kynurenine metabolism.
    Quanjun Yang, Juan Hao, Mengyi Chi, Yaxian Wang, Bo Xin, Jinglu Huang, Jin Lu, Jie Li, Xipeng Sun, Chunyan Li, Yan Huo, Jianping Zhang, Yonglong Han, Cheng Guo.
      Accumulated oncometabolites in the tumor microenvironment (TME) suppresses the metabolism, expansion, and function of T cells. Immunosuppressive TME also impeded Chimeric Antigen Receptor (CAR)-T cells mediated cytotoxicity since CAR-T cells had to adapt the in vivo metabolic characteristics with high levels of oncometabolites. We screened oncometabolites for the inhibition of glucose uptake in CD8 + T cells and found Kynurenine (Kyn) showed the strongest inhibiting effect on glucose uptake. In vitro experiments showed that 120 μM Kyn treatment in CD8 + T cells resulted in inhibiting the expansion of CD8 + T cells, decreasing the production of granzyme B and interferon-γ. CAR-T cells mediated cytotoxicity was also impaired by the high Kyn treatment from killing assay. We then explored the anti-tumor effect of Kynureninase (KYNU) modified CAR-T cells through catabolism o oncometabolites Kyn. KYNU over-expression (OE) CAR-T cells showed a superior killing effect against cancer cells even in the immunosuppressive TME with high Kyn levels. In vivo experiments confirmed KYNU-OE CAR-T cells showed an excellent anti-tumor effect in a TME with high Kyn levels since it improved the survival of mice bearing NALM6 cancer cells and NALM6-IDO1 cancer cells. The KYNU-modified CAR-T cells displayed distinct phenotypes related to the expansion, function, and memory differentiation status of CAR-T cells. This study explores an immunotherapy strategy for patients with alterations in Kyn metabolism. KYNU-OE CAR-T cells take advantage of Kyn catabolism to improve anti-tumor activity in the metabolic immunosuppressive TME with high Kyn.
    Keywords:  Chimeric antigen receptor (CAR); Kynurenine; T cell therapy; immunotherapy; oncometabolite
    DOI:  https://doi.org/10.1080/2162402X.2022.2055703
  38. FASEB J. 2022 May;36(5): e22296
    Gene expression is a poor predictor of steady-state metabolite abundance in cancer cells.
    Huaping Li, Jayne A Barbour, Xiaoqiang Zhu, Jason W H Wong.
      Metabolic reprogramming is a hallmark of cancer characterized by global changes in metabolite levels. However, compared with the study of gene expression, profiling of metabolites in cancer samples remains relatively understudied. We obtained metabolomic profiling and gene expression data from 454 human solid cancer cell lines across 24 cancer types from the Cancer Cell Line Encyclopedia (CCLE) database, to evaluate the feasibility of inferring metabolite levels from gene expression data. For each metabolite, we trained multivariable LASSO regression models to identify gene sets that are most predictive of the level of each metabolite profiled. Even when accounting for cell culture conditions or cell lineage in the model, few metabolites could be accurately predicted. In some cases, the inclusion of the upstream and downstream metabolites improved prediction accuracy, suggesting that gene expression is a poor predictor of steady-state metabolite levels. Our analysis uncovered a single robust relationship between the expression of nicotinamide N-methyltransferase (NNMT) and 1-methylnicotinamide (MNA), however, this relationship could only be validated in cancer samples with high purity, as NNMT is not expressed in immune cells. Together, we have trained models that use gene expression profiles to predict the level of individual metabolites. Our analysis suggests that inferring metabolite levels based on the expression of genes is generally challenging in cancer.
    Keywords:  cell line; gene expression; machine learning; metabolite; pan-cancer
    DOI:  https://doi.org/10.1096/fj.202101921RR
  39. Sci Rep. 2022 Apr 01. 12(1): 5511
    MRI assessment of glutamine uptake correlates with the distribution of glutamine transporters and cancer stem cell markers.
    Yoojeong Seo, Joyeon Kang, Tae Il Kim, Chan Gyu Joo.
      Glutamine provides carbon and nitrogen for macromolecular synthesis and participates in adenosine triphosphate (ATP) generation, anabolic metabolism, redox homeostasis, cell signaling, and cancer stem cell (CSC) metabolism. New treatment strategies targeting glutamine metabolism in cancer have emerged recently. We previously reported the magnetic resonance imaging (MRI) assessment of glutamine uptake by tumors and activated glutamine metabolism in CSC. In the present study, using MRI, we determined the correlation between glutamine uptake and the distribution of glutamine transporters, namely ASCT2 and SLC38A2 (SNAT2), glutaminase (GLS), and CSC markers, such as CD44 and CD166, in a mouse xenograft model of HT29 human colorectal cancer cells. MRI data revealed an obvious change in intensity following glutamine administration. Immunohistochemistry (IHC) results indicated that ASCT2 staining was stronger in regions that exhibited high glutamine uptake (p = 0.0079). Significant differences were found in the IHC staining intensities of SNAT2, GLS, and CSC markers in the areas of high and low glutamine uptake (p = 0.0079, p = 0.0159 and p = 0.0079, respectively). We also investigated the effect of an ASCT2 inhibitor on the uptake of glutamine using MRI. A statistically significant difference in the initial glutamine uptake was found after ASCT2 inhibitor administration. To conclude, glutamine uptake is positively correlated with the distribution of ASCT2 and certain CSC markers.
    DOI:  https://doi.org/10.1038/s41598-022-09529-7
  40. Drug Discov Today. 2022 Mar 29. pii: S1359-6446(22)00129-5. [Epub ahead of print]
    The role of irisin in metabolic flexibility: beyond adipose tissue browning.
    Shengnan Shen, Qiwen Liao, Xiuping Chen, Cheng Peng, Ligen Lin.
      Metabolic flexibility is the ability to adapt to physiological and environmental changes in metabolic demand. Irisin was originally discovered as an exercise-induced myokine involved in fat browning. In this review, we summarize emerging evidence for the role of irisin in regulating glucose metabolism and insulin sensitivity in skeletal muscle, neuroplasticity and satiety in central nervous system, β cell function and insulin secretion in the pancreas, bone remodeling, and adipose tissue function, which together orchestrate whole-body metabolic flexibility. Irisin is a key communicating mediator between skeletal muscle and other organs, and its manipulation could be a promising therapeutic strategy for treating obesity and related metabolic disorders. Teaser: This review summarizes recent progress in manipulating metabolic flexibility with irisin, and discusses its potential application as a drug target to treat obesity and related metabolic disorders.
    Keywords:  FNDC5; insulin sensitivity; irisin; metabolic flexibility; obesity; skeletal muscle
    DOI:  https://doi.org/10.1016/j.drudis.2022.03.019
  41. Antioxid Redox Signal. 2022 Mar;36(7-9): 441-461
    Redox Activation of Mitochondrial DAMPs and the Metabolic Consequences for Development of Autoimmunity.
    Andreas Koenig, Iwona A Buskiewicz-Koenig.
      Significance: Reactive oxygen species (ROS) are well known to promote innate immune responses during and in the absence of microbial infections. However, excessive or prolonged exposure to ROS provokes innate immune signaling dysfunction and contributes to the pathogenesis of many autoimmune diseases. The relatively high basal expression of pattern recognition receptors (PRRs) in innate immune cells renders them prone to activation in response to minor intrinsic or extrinsic ROS misbalances in the absence of pathogens. Critical Issues: A prominent source of ROS are mitochondria, which are also major inter-organelle hubs for innate immunity activation, since most PRRs and downstream receptor molecules are directly located either at mitochondria or at mitochondria-associated membranes. Due to their ancestral bacterial origin, mitochondria can also act as quasi-intrinsic self-microbes that mimic a pathogen invasion and become a source of danger-associated molecular patterns (DAMPs) that triggers innate immunity from within. Recent Advances: The release of mitochondrial DAMPs correlates with mitochondrial metabolism changes and increased generation of ROS, which can lead to the oxidative modification of DAMPs. Recent studies suggest that ROS-modified mitochondrial DAMPs possess increased, persistent immunogenicity. Future Directions: Herein, we discuss how mitochondrial DAMP release and oxidation activates PRRs, changes cellular metabolism, and causes innate immune response dysfunction by promoting systemic inflammation, thereby contributing to the onset or progression of autoimmune diseases. The future goal is to understand what the tipping point for DAMPs is to become oxidized, and whether this is a road without return. Antioxid. Redox Signal. 36, 441-461.
    Keywords:  ATP; Carbamoyl phosphate synthetase-1 (CPS1); MAVS oligomerization; N-formyl peptides (NFPs); autoimmunity; cardiolipin (CL); cyclic GMP-AMP synthase (cGAS); cytochrome C; damage-associated molecular pattern (DAMP); innate immunity; metabolism; mitochondria; mitochondrial ROS (mtROS); mitochondrial TFAM; mitochondrial antiviral signaling (MAVS) protein; neutrophil extracellular trap (NET); oxidized ATP; oxidized cardiolipin; oxidized mitochondrial DNA (mtDNA); oxidized mitochondrial RNA (mtRNA); reactive oxygen species (ROS); redox; stimulator of interferon genes (STING); succinate; systemic lupus erythematosus (SLE); transcription factor A
    DOI:  https://doi.org/10.1089/ars.2021.0073
  42. Int J Biol Sci. 2022 ;18(5): 1773-1794
    Ferroptosis-associated molecular classification characterized by distinct tumor microenvironment profiles in colorectal cancer.
    Wenqin Luo, Weixing Dai, Qingguo Li, Shaobo Mo, Lingyu Han, Xiuying Xiao, Ruiqi Gu, Wenqiang Xiang, Li Ye, Renjie Wang, Ye Xu, Sanjun Cai, Guoxiang Cai.
      Ferroptosis is a non-apoptotic form of cell death recognized in recent years. Nonetheless, the potential role of ferroptosis-associated genes in immune regulation and tumor microenvironment formation remains unknown. In this study, we characterized the ferroptosis-associated patterns of colorectal cancer through integrative analyses of multiple datasets with transcriptomics, genomics, and single-cell transcriptome profiling. Three distinct ferroptosis-associated clusters (FAC1, FAC2 and FAC3) were identified from 1251 CRC bulk samples, which were associated with different clinical outcomes and biological pathways. The TME characterization revealed that the three patterns were highly consistent with known immune profiles: immune-desert (FAC1), immune-inflamed (FAC2) and immune-excluded (FAC3), respectively. Ferroptosis-associated immune and stromal-activated genes were obtained and characterized by corresponding function in CRC tumorigenesis. Further single-cell analyses identified the ferroptosis-associated immune responding tumor cells and ferroptosis-associated stromal cells infiltration pattern. Based on the Fersig score, which was extracted from the ferroptosis phenotype-related signature, patients with lower Fersig score were characterized by prolonged survival time and effective immune responses. Collectively, we uncovered the ferroptosis-associated patterns associated with TME diversity and immune response phenotype. The Fersig we constructed could be the potential therapeutic target genes to improve the efficacy of patients' immunotherapy. The Fersig scoring scheme could enhance the understanding of TME infiltration associated with ferroptosis and prediction of immunotherapy efficacy.
    Keywords:  Colorectal cancer; Ferroptosis; Immune activation; Immunotherapy.; Myofibroblast; Stromal cells infiltration; Tumor microenvironment
    DOI:  https://doi.org/10.7150/ijbs.69808
  43. Cancer Immunol Res. 2022 Apr 01. 10(4): 482-497
    Tumor-Derived Lactic Acid Modulates Activation and Metabolic Status of Draining Lymph Node Stroma.
    Angela Riedel, Moutaz Helal, Luisa Pedro, Jonathan J Swietlik, David Shorthouse, Werner Schmitz, Lisa Haas, Timothy Young, Ana S H da Costa, Sarah Davidson, Pranjali Bhandare, Elmar Wolf, Benjamin A Hall, Christian Frezza, Thordur Oskarsson, Jacqueline D Shields.
      Communication between tumors and the stroma of tumor-draining lymph nodes (TDLN) exists before metastasis arises, altering the structure and function of the TDLN niche. Transcriptional profiling of fibroblastic reticular cells (FRC), the dominant stromal population of lymph nodes, has revealed that FRCs in TDLNs are reprogrammed. However, the tumor-derived factors driving the changes in FRCs remain to be identified. Taking an unbiased approach, we have shown herein that lactic acid (LA), a metabolite released by cancer cells, was not only secreted by B16.F10 and 4T1 tumors in high amounts, but also that it was enriched in TDLNs. LA supported an upregulation of Podoplanin (Pdpn) and Thy1 and downregulation of IL7 in FRCs of TDLNs, making them akin to activated fibroblasts found at the primary tumor site. Furthermore, we found that tumor-derived LA altered mitochondrial function of FRCs in TDLNs. Thus, our results demonstrate a mechanism by which a tumor-derived metabolite connected with a low pH environment modulates the function of fibroblasts in TDLNs. How lymph node function is perturbed to support cancer metastases remains unclear. The authors show that tumor-derived LA drains to lymph nodes where it modulates the function of lymph node stromal cells, prior to metastatic colonization.
    DOI:  https://doi.org/10.1158/2326-6066.CIR-21-0778
  44. Mitochondrion. 2022 Mar 25. pii: S1567-7249(22)00025-3. [Epub ahead of print]64 73-81
    Partial inhibition of mitochondrial-linked pyrimidine synthesis increases tumorigenic potential and lysosome accumulation.
    Claus Desler, Jon Ambæk Durhuus, Thomas Lau-Lindestrand Hansen, Sharath Anugula, Nadia Thaulov Zelander, Sisse Bøggild, Lene Juel Rasmussen.
      The correlation between mitochondrial function and oncogenesis is complex and is not fully understood. Here we determine the importance of mitochondrial-linked pyrimidine synthesis for the aggressiveness of cancer cells. The enzyme dihydroorotate dehydrogenase (DHODH) links oxidative phosphorylation to de novo synthesis of pyrimidines. We demonstrate that an inhibition of DHODH results in a respiration-independent significant increase of anchorage-independent growth but does not affect DNA repair ability. Instead, we show an autophagy-independent increase of lysosomes. The results of this study suggest that inhibition of mitochondrial-linked pyrimidine synthesis in cancer cells results in a more aggressive tumor phenotype.
    Keywords:  DNA repair; Lysosome increase; Mitochondria; Mitochondrial-linked pyrimidine synthesis; Tumorigenesis
    DOI:  https://doi.org/10.1016/j.mito.2022.03.005
  45. Mol Metab. 2022 Mar 25. pii: S2212-8778(22)00050-3. [Epub ahead of print] 101481
    Organelle transporters and inter-organelle communication as drivers of metabolic regulation and cellular homeostasis.
    Aakriti Jain, Roberto Zoncu.
      Spatial compartmentalization of metabolic pathways within membrane-separated organelles is key to the ability of eukaryotic cells to precisely regulate their biochemical functions. Membrane-bound organelles such as mitochondria, endoplasmic reticulum (ER) and lysosomes enable the concentration of metabolic precursors within optimized chemical environments, greatly accelerating the efficiency of both anabolic and catabolic reactions, enabling division of labor and optimal utilization of resources. However, metabolic compartmentalization also poses a challenge to cells because it creates spatial discontinuities that must be bridged for reaction cascades to be connected and completed. To do so, cells employ different methods to coordinate metabolic fluxes occurring in different organelles, such as membrane-localized transporters to facilitate regulated metabolite exchange between mitochondria and lysosomes, non-vesicular transport pathways via physical contact sites connecting the ER with both mitochondria and lysosomes, as well as localized regulatory signaling processes that coordinately regulate the activity of all these organelles. Effective communication among these systems is essential to cellular health and function, whereas disruption of inter-organelle communication is an emerging driver in a multitude of diseases, from cancer to neurodegeneration.
    Keywords:  Contact sites; Lysosome; Metabolism; Mitochondria; Transporters; mTORC1
    DOI:  https://doi.org/10.1016/j.molmet.2022.101481
  46. Proc Natl Acad Sci U S A. 2022 Apr 05. 119(14): e2024357119
    Carbon sources and pathways for citrate secreted by human prostate cancer cells determined by NMR tracing and metabolic modeling.
    Frits H A van Heijster, Vincent Breukels, Kees C F J Jansen, Jack A Schalken, Arend Heerschap.
      SignificanceThe human prostate accumulates high luminal citrate levels to serve sperm viability. There is only indirect qualitative evidence about metabolic pathways and carbon sources maintaining these levels. Human citrate-secreting prostate cancer cells were supplied with 13C-labeled substrates, and NMR spectra of extracellular fluid were recorded. We report absolute citrate production rates of prostate cells and direct evidence that glucose is the main carbon source for secreted citrate. Pyruvate carboxylase provides sufficient anaplerotic carbons to support citrate secretion. Glutamine carbons exchange with carbons for secreted citrate but are likely not involved in its net synthesis. Moreover, we developed metabolic models employing the 13C distribution in extracellular citrate as input to assess intracellular pathways followed by carbons toward citrate.
    Keywords:  Krebs cycle; cancer; carbon-13; citrate; prostate
    DOI:  https://doi.org/10.1073/pnas.2024357119
  47. Biochem J. 2022 Mar 31. 479(6): 787-804
    Quantitative metabolic fluxes regulated by trans-omic networks.
    Satoshi Ohno, Saori Uematsu, Shinya Kuroda.
      Cells change their metabolism in response to internal and external conditions by regulating the trans-omic network, which is a global biochemical network with multiple omic layers. Metabolic flux is a direct measure of the activity of a metabolic reaction that provides valuable information for understanding complex trans-omic networks. Over the past decades, techniques to determine metabolic fluxes, including 13C-metabolic flux analysis (13C-MFA), flux balance analysis (FBA), and kinetic modeling, have been developed. Recent studies that acquire quantitative metabolic flux and multi-omic data have greatly advanced the quantitative understanding and prediction of metabolism-centric trans-omic networks. In this review, we present an overview of 13C-MFA, FBA, and kinetic modeling as the main techniques to determine quantitative metabolic fluxes, and discuss their advantages and disadvantages. We also introduce case studies with the aim of understanding complex metabolism-centric trans-omic networks based on the determination of metabolic fluxes.
    Keywords:  computational models; metabolic flux; metabolism; trans-omics
    DOI:  https://doi.org/10.1042/BCJ20210596
  48. Nat Immunol. 2022 Mar 28.
    B cells regulate hematopoietic stem cells via cholinergic signaling.
    Sweta B Patel, Eric M Pietras.
      
    DOI:  https://doi.org/10.1038/s41590-022-01172-8
  49. Exp Cell Res. 2022 Mar 25. pii: S0014-4827(22)00105-7. [Epub ahead of print]415(1): 113112
    IL-6 promotes chemoresistance via upregulating CD36 mediated fatty acids uptake in acute myeloid leukemia.
    Yanjie Zhang, Hezhou Guo, Zhaoli Zhang, Wei Lu, Jiang Zhu, Jun Shi.
      Chemoresistance contributes to poor survival and high relapse risk in acute myeloid leukemia (AML). As a pro-inflammatory cytokine, interleukin-6 (IL-6) plays a vital role in the chemoresistance of malignancies. However, the underlying mechanisms of chemoresistance in AML have not been widely studied. Lipid metabolism, which contributes to chemoresistance in AML, is enhanced by IL-6 in skeletal muscle cells. We hypothesized that IL-6 promotes the chemoresistance of AML by promoting lipid metabolism. Based on the positive correlation between IL-6 receptor expression and the cellular response to exogenous IL-6, we performed Gene Ontology analysis of a dataset consisting the information of 151 AML patients from The Cancer Genome Atlas. We found that lipid transport-associated genes were upregulated in the high IL-6 receptor expression group. Additionally, IL-6 promoted fatty acid (FA) uptake in both AML cell lines and primary AML cells. Inhibition of FA uptake by sulfo-N-succinimidyl oleate repressed IL-6-induced chemoresistance. Western blotting, quantitative polymerase chain reaction, and chromatin immunoprecipitation assays indicated that IL-6 promoted CD36 expression at both the mRNA and protein levels through stat3 signaling. Knockout of CD36 or stat3 repressed IL-6-induced FA uptake and chemoresistance. Furthermore, in five human AML samples, we validated that compared to CD36-cells, CD36+ primary AML cells were less sensitive to cytosine arabinoside (Ara-c) and that blockade of CD36 re-sensitized CD36+ AML cells to Ara-c. Mice injected with CD36 knockout cells followed by treatment with Ara-c showed markedly decreased leukemia burden and prolonged survival in vivo. Finally, treatment with the CD36 antibody in combination with Ara-c exhibited synergistic effects in vivo. In conclusion, IL-6 promotes chemoresistance in AML through the stat3/CD36-mediated FA uptake. Blockade of CD36 improved the effect of Ara-c, representing a promising strategy for AML therapy.
    Keywords:  Acute myeloid leukemia; CD36; Chemoresistance; Fatty acid uptake; Interleukin-6
    DOI:  https://doi.org/10.1016/j.yexcr.2022.113112
  50. J Magn Reson. 2022 Mar 17. pii: S1090-7807(22)00056-8. [Epub ahead of print]338 107198
    New tools to investigate tumor metabolism by NMR/MRI.
    Silvio Aime, Dario Livio Longo, Francesca Reineri, Simonetta Geninatti Crich.
      Changes in metabolism is an hallmark that characterizes tumour cells from healthy ones. Their detection can be highly relevant for staging the tumor and for monitoring the response to therapeutic treatments. Herein it is shown the readout of these changes can be achieved either by assessing the pH of the extracellular space in the tumour region and by monitoring real time transformations of hyperpolarized C-13 labelled substrates. Mapping pH in a MR image is possible by measuring the CEST response of an administered contrast agent such as Iopamidol that can provide accurate measurements of the heterogeneity of tumour acidosis. Direct detection of relevant enzymatic activities have been acquired by using Pyruvate and Fumarate hyperpolarized by the incorporation of a molecule of para-H2. Finally, it has been found that the tumour transformation involves an increase in the water exchange rate between the intra- and the extra-cellular compartments. A quantitative estimation of these changes can be obtained by acquiring the longitudinal relaxation times of tissue water protons at low magnetic field strength on Fast Field Cycling Relaxometers. This finding has been exploited in an application devoted to the assessment of the presence of residual tumour tissue in the margins of the resected mass in breast conservative surgery.
    Keywords:  CEST; FFC-relaxometry; Hyperpolarized 13C; Intracellular water residence time; Tumour metabolism
    DOI:  https://doi.org/10.1016/j.jmr.2022.107198
  51. Clin Sci (Lond). 2022 Mar 31. 136(6): 435-454
    Metabolism in atherosclerotic plaques: immunoregulatory mechanisms in the arterial wall.
    Maria J Forteza, Daniel F J Ketelhuth.
      Over the last decade, there has been a growing interest to understand the link between metabolism and the immune response in the context of metabolic diseases but also beyond, giving then birth to a new field of research. Termed 'immunometabolism', this interdisciplinary field explores paradigms of both immunology and metabolism to provided unique insights into different disease pathogenic processes, and the identification of new potential therapeutic targets. Similar to other inflammatory conditions, the atherosclerotic inflammatory process in the artery has been associated with a local dysregulated metabolic response. Thus, recent studies show that metabolites are more than just fuels in their metabolic pathways, and they can act as modulators of vascular inflammation and atherosclerosis. In this review article, we describe the most common immunometabolic pathways characterised in innate and adaptive immune cells, and discuss how macrophages' and T cells' metabolism may influence phenotypic changes in the plaque. Moreover, we discuss the potential of targeting immunometabolism to prevent and treat cardiovascular diseases (CVDs).
    Keywords:  T-cells; atherosclerosis; cardiovascular disease; immunometabolism; immunomodulation; macrophages
    DOI:  https://doi.org/10.1042/CS20201293
  52. Curr Opin Pharmacol. 2022 Mar 25. pii: S1471-4892(22)00032-7. [Epub ahead of print]64 102205
    Impaired metabolism of oligodendrocyte progenitor cells and axons in demyelinated lesion and in the aged CNS.
    Jing-Wei Zhao, Di-Xian Wang, Xiao-Ru Ma, Zhao-Jun Dong, Jian-Bin Wu, Fan Wang, Yang Wu.
      The key pathology of multiple sclerosis (MS) comprises demyelination, axonal damage, and neuronal loss, and when MS develops into the progressive phase it is essentially untreatable. Identifying new targets in both axons and oligodendrocyte progenitor cells (OPCs) and rejuvenating the aged OPCs holds promise for this unmet medical need. We summarize here the recent evidence showing that mitochondria in both axons and OPCs are impaired, and lipid metabolism of OPCs within demyelinated lesion and in the aged CNS is disturbed. Given that emerging evidence shows that rewiring cellular metabolism regulates stem cell aging, to protect axons from degeneration and promote differentiation of OPCs, we propose that restoring the impaired metabolism of both OPCs and axons in the aged CNS in a synergistic way could be a promising strategy to enhance remyelination in the aged CNS, leading to novel drug-based approaches to treat the progressive phase of MS.
    DOI:  https://doi.org/10.1016/j.coph.2022.102205
  53. Dis Model Mech. 2022 Apr 01. pii: dmm.049551. [Epub ahead of print]
    TOR signaling is required for host lipid metabolic remodelling and survival following enteric infection in Drosophila.
    Rujuta Deshpande, Byoungchun Lee, Yuemeng Qiao, Savraj S Grewal.
      When infected by enteric pathogenic bacteria, animals need to initiate local and whole-body defence strategies. While most attention has focused on the role innate immune anti-bacterial responses, less is known about how changes in host metabolism contribute to host defence. Using Drosophila as a model system, we identify induction of intestinal target-of-rapamycin (TOR) kinase signaling as a key adaptive metabolic response to enteric infection. We find that enteric infection induces both local and systemic induction of TOR independently of the IMD innate immune pathway, and we see that TOR functions together with IMD signaling to promote infection survival. These protective effects of TOR signaling are associated with re-modelling of host lipid metabolism. Thus, we see that TOR is required to limit excessive infection-mediated wasting of host lipid stores by promoting an increase in the levels of gut- and fat body-expressed lipid synthesis genes. Our data supports a model in which induction of TOR represents a host tolerance response to counteract infection-mediated lipid wasting in order to promote survival.
    Keywords:  Drosophila; Infection; Lipid metabolism; Physiology; TOR
    DOI:  https://doi.org/10.1242/dmm.049551
  54. Nat Microbiol. 2022 Apr;7(4): 497-507
    Immunometabolic crosstalk during bacterial infection.
    Gili Rosenberg, Sebastian Riquelme, Alice Prince, Roi Avraham.
      Following detection of bacteria, macrophages switch their metabolism from oxidative respiration through the tricarboxylic acid cycle to high-rate aerobic glycolysis. This immunometabolic shift enables pro-inflammatory and antimicrobial responses and is facilitated by the accumulation of fatty acids, tricarboxylic acid-derived metabolites and catabolism of amino acids. Recent studies have shown that these immunometabolites are co-opted by pathogens as environmental cues for expression of virulence genes. We review mechanisms by which host immunometabolites regulate bacterial pathogenicity and discuss opportunities for the development of therapeutics targeting metabolic host-pathogen crosstalk.
    DOI:  https://doi.org/10.1038/s41564-022-01080-5
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