bims-mepmim Biomed News
on Metabolites in pathological microenvironments and immunometabolism
Issue of 2023–08–06
27 papers selected by
Erika Mariana Palmieri, NIH/NCI Laboratory of Cancer ImmunoMetabolism
  1. Ketolysis drives CD8+ T cell effector function through effects on histone acetylation.
  2. Sulfur metabolic response in macrophage limits excessive inflammatory response by creating a negative feedback loop.
  3. Metabolic switch from fatty acid oxidation to glycolysis in knock-in mouse model of Barth syndrome.
  4. CXCL9:SPP1 macrophage polarity identifies a network of cellular programs that control human cancers.
  5. Microglial expression of CD83 governs cellular activation and restrains neuroinflammation in experimental autoimmune encephalomyelitis.
  6. Methionine restriction-induced sulfur deficiency impairs antitumour immunity partially through gut microbiota.
  7. Excitatory amino acid transporter 1 supports adult hippocampal neural stem cell self-renewal.
  8. Inosine enhances tumor mitochondrial respiration by inducing Rag GTPases and nascent protein synthesis under nutrient starvation.
  9. Completion of mitochondrial division requires the intermembrane space protein Mdi1/Atg44.
  10. Genetic inhibition of CARD9 accelerates the development of atherosclerosis in mice through CD36 dependent-defective autophagy.
  11. Investigation of hydrated channels and proton pathways in a high-resolution cryo-EM structure of mammalian complex I.
  12. Inhibition of the serotonin transporter induces dysfunction of human brown adipose tissue.
  13. Gut epithelium modulates fungal pathogenesis.
  14. SLC15A4 controls endolysosomal TLR7-9 responses by recruiting the innate immune adaptor TASL.
  15. 1-Oleoyl-lysophosphatidylethanolamine stimulates RORγt activity in TH17 cells.
  16. The serotonin transporter sustains human brown adipose tissue thermogenesis.
  17. Enolase represents a metabolic checkpoint controlling the differential exhaustion programmes of hepatitis virus-specific CD8+ T cells.
  18. NLRP12 senses heme and PAMPs to drive necrotic cell death and inflammation.
  19. Vitamin D induces SIRT1 activation through K610 deacetylation in colon cancer.
  20. Increased cardiac PFK-2 protects against high-fat diet-induced cardiomyopathy and mediates beneficial systemic metabolic effects.
  21. Methionine and H2S alter cancer-immune dialogue.
  22. Loss of PERK function promotes ferroptosis by downregulating SLC7A11 (System Xc⁻) in colorectal cancer.
  23. Microbial energy metabolism fuels an intestinal macrophage niche in solitary isolated lymphoid tissues through purinergic signaling.
  24. EP1 activation inhibits doxorubicin-cardiomyocyte ferroptosis via Nrf2.
  25. Ceramides increase fatty acid utilization in intestinal progenitors to enhance stemness and increase tumor risk.
  26. Mitochondria dysregulation contributes to secondary neurodegeneration progression post-contusion injury in human 3D in vitro triculture brain tissue model.
  27. The ratio of key metabolic transcripts is a predictive biomarker of breast cancer metastasis to the lung.
  1. Immunity. 2023 Jul 20. pii: S1074-7613(23)00314-X. [Epub ahead of print]
    Ketolysis drives CD8+ T cell effector function through effects on histone acetylation.
    Katarzyna M Luda, Joseph Longo, Susan M Kitchen-Goosen, Lauren R Duimstra, Eric H Ma, McLane J Watson, Brandon M Oswald, Zhen Fu, Zachary Madaj, Ariana Kupai, Bradley M Dickson, Lisa M DeCamp, Michael S Dahabieh, Shelby E Compton, Robert Teis, Irem Kaymak, Kin H Lau, Daniel P Kelly, Patrycja Puchalska, Kelsey S Williams, Connie M Krawczyk, Dominique Lévesque, François-Michel Boisvert, Ryan D Sheldon, Scott B Rothbart, Peter A Crawford, Russell G Jones.
      Environmental nutrient availability influences T cell metabolism, impacting T cell function and shaping immune outcomes. Here, we identified ketone bodies (KBs)-including β-hydroxybutyrate (βOHB) and acetoacetate (AcAc)-as essential fuels supporting CD8+ T cell metabolism and effector function. βOHB directly increased CD8+ T effector (Teff) cell cytokine production and cytolytic activity, and KB oxidation (ketolysis) was required for Teff cell responses to bacterial infection and tumor challenge. CD8+ Teff cells preferentially used KBs over glucose to fuel the tricarboxylic acid (TCA) cycle in vitro and in vivo. KBs directly boosted the respiratory capacity and TCA cycle-dependent metabolic pathways that fuel CD8+ T cell function. Mechanistically, βOHB was a major substrate for acetyl-CoA production in CD8+ T cells and regulated effector responses through effects on histone acetylation. Together, our results identify cell-intrinsic ketolysis as a metabolic and epigenetic driver of optimal CD8+ T cell effector responses.
    Keywords:  CD8(+) T cells; TCA cycle; acetyl-CoA; cancer immunology; effector function; epigenetics; ketolysis; ketone bodies; metabolism
    DOI:  https://doi.org/10.1016/j.immuni.2023.07.002
  2. Redox Biol. 2023 Jul 29. pii: S2213-2317(23)00235-5. [Epub ahead of print]65 102834
    Sulfur metabolic response in macrophage limits excessive inflammatory response by creating a negative feedback loop.
    Haruna Takeda, Shohei Murakami, Zun Liu, Tomohiro Sawa, Masatomo Takahashi, Yoshihiro Izumi, Takeshi Bamba, Hideyo Sato, Takaaki Akaike, Hiroki Sekine, Hozumi Motohashi.
      The excessive inflammatory response of macrophages plays a vital role in the pathogenesis of various diseases. The dynamic metabolic alterations in macrophages, including amino acid metabolism, are known to orchestrate their inflammatory phenotype. To explore a new metabolic pathway that regulates the inflammatory response, we examined metabolome changes in mouse peritoneal macrophages (PMs) in response to lipopolysaccharide (LPS) and found a coordinated increase of cysteine and its related metabolites, suggesting an enhanced demand for cysteine during the inflammatory response. Because Slc7a11, which encodes a cystine transporter xCT, was remarkably upregulated upon the pro-inflammatory challenge and found to serve as a major channel of cysteine supply, we examined the inflammatory behavior of Slc7a11 knockout PMs (xCT-KO PMs) to clarify an impact of the increased cysteine demand on inflammation. The xCT-KO PMs exhibited a prolonged upregulation of pro-inflammatory genes, which was recapitulated by cystine depletion in the culture media of wild-type PMs, suggesting that cysteine facilitates the resolution of inflammation. Detailed analysis of the sulfur metabolome revealed that supersulfides, such as cysteine persulfide, were increased in PMs in response to LPS, which was abolished in xCT-KO PMs. Supplementation of N-acetylcysteine tetrasulfide (NAC-S2), a supersulfide donor, attenuated the pro-inflammatory gene expression in xCT-KO PMs. Thus, activated macrophages increase cystine uptake via xCT and produce supersulfides, creating a negative feedback loop to limit excessive inflammation. Our study highlights the finely tuned regulation of macrophage inflammatory response by sulfur metabolism.
    Keywords:  Cysteine; Inflammation; LPS; Macrophage; Persulfide; xCT
    DOI:  https://doi.org/10.1016/j.redox.2023.102834
  3. EMBO Mol Med. 2023 Aug 03. e17399
    Metabolic switch from fatty acid oxidation to glycolysis in knock-in mouse model of Barth syndrome.
    Arpita Chowdhury, Angela Boshnakovska, Abhishek Aich, Aditi Methi, Ana Maria Vergel Leon, Ivan Silbern, Christian Lüchtenborg, Lukas Cyganek, Jan Prochazka, Radislav Sedlacek, Jiri Lindovsky, Dominic Wachs, Zuzana Nichtova, Dagmar Zudova, Gizela Koubkova, André Fischer, Henning Urlaub, Britta Brügger, Dörthe M Katschinski, Jan Dudek, Peter Rehling.
      Mitochondria are central for cellular metabolism and energy supply. Barth syndrome (BTHS) is a severe disorder, due to dysfunction of the mitochondrial cardiolipin acyl transferase tafazzin. Altered cardiolipin remodeling affects mitochondrial inner membrane organization and function of membrane proteins such as transporters and the oxidative phosphorylation (OXPHOS) system. Here, we describe a mouse model that carries a G197V exchange in tafazzin, corresponding to BTHS patients. TAZG197V mice recapitulate disease-specific pathology including cardiac dysfunction and reduced oxidative phosphorylation. We show that mutant mitochondria display defective fatty acid-driven oxidative phosphorylation due to reduced levels of carnitine palmitoyl transferases. A metabolic switch in ATP production from OXPHOS to glycolysis is apparent in mouse heart and patient iPSC cell-derived cardiomyocytes. An increase in glycolytic ATP production inactivates AMPK causing altered metabolic signaling in TAZG197V . Treatment of mutant cells with AMPK activator reestablishes fatty acid-driven OXPHOS and protects mice against cardiac dysfunction.
    Keywords:  Barth syndrome; cardiolipin; cardiomyopathy; mitochondria; tafazzin
    DOI:  https://doi.org/10.15252/emmm.202317399
  4. Science. 2023 Aug 04. 381(6657): 515-524
    CXCL9:SPP1 macrophage polarity identifies a network of cellular programs that control human cancers.
    Ruben Bill, Pratyaksha Wirapati, Marius Messemaker, Whijae Roh, Beatrice Zitti, Florent Duval, Máté Kiss, Jong Chul Park, Talia M Saal, Jan Hoelzl, David Tarussio, Fabrizio Benedetti, Stéphanie Tissot, Lana Kandalaft, Marco Varrone, Giovanni Ciriello, Thomas A McKee, Yan Monnier, Maxime Mermod, Emily M Blaum, Irena Gushterova, Anna L K Gonye, Nir Hacohen, Gad Getz, Thorsten R Mempel, Allon M Klein, Ralph Weissleder, William C Faquin, Peter M Sadow, Derrick Lin, Sara I Pai, Moshe Sade-Feldman, Mikael J Pittet.
      Tumor microenvironments (TMEs) influence cancer progression but are complex and often differ between patients. Considering that microenvironment variations may reveal rules governing intratumoral cellular programs and disease outcome, we focused on tumor-to-tumor variation to examine 52 head and neck squamous cell carcinomas. We found that macrophage polarity-defined by CXCL9 and SPP1 (CS) expression but not by conventional M1 and M2 markers-had a noticeably strong prognostic association. CS macrophage polarity also identified a highly coordinated network of either pro- or antitumor variables, which involved each tumor-associated cell type and was spatially organized. We extended these findings to other cancer indications. Overall, these results suggest that, despite their complexity, TMEs coordinate coherent responses that control human cancers and for which CS macrophage polarity is a relevant yet simple variable.
    DOI:  https://doi.org/10.1126/science.ade2292
  5. Nat Commun. 2023 08 01. 14(1): 4601
    Microglial expression of CD83 governs cellular activation and restrains neuroinflammation in experimental autoimmune encephalomyelitis.
    Pia Sinner, Katrin Peckert-Maier, Hashem Mohammadian, Christine Kuhnt, Christina Draßner, Vasiliki Panagiotakopoulou, Simon Rauber, Mathias Linnerbauer, Zhana Haimon, Dmytro Royzman, Deborah Kronenberg-Versteeg, Andreas Ramming, Alexander Steinkasserer, Andreas B Wild.
      Microglial activation during neuroinflammation is crucial for coordinating the immune response against neuronal tissue, and the initial response of microglia determines the severity of neuro-inflammatory diseases. The CD83 molecule has been recently shown to modulate the activation status of dendritic cells and macrophages. Although the expression of CD83 is associated with early microglia activation in various disease settings, its functional relevance for microglial biology has been elusive. Here, we describe a thorough assessment of CD83 regulation in microglia and show that CD83 expression in murine microglia is not only associated with cellular activation but also with pro-resolving functions. Using single-cell RNA-sequencing, we reveal that conditional deletion of CD83 results in an over-activated state during neuroinflammation in the experimental autoimmune encephalomyelitis model. Subsequently, CD83-deficient microglia recruit more pathogenic immune cells to the central nervous system, deteriorating resolving mechanisms and exacerbating the disease. Thus, CD83 in murine microglia orchestrates cellular activation and, consequently, also the resolution of neuroinflammation.
    DOI:  https://doi.org/10.1038/s41467-023-40370-2
  6. Nat Metab. 2023 Aug 03.
    Methionine restriction-induced sulfur deficiency impairs antitumour immunity partially through gut microbiota.
    Ming Ji, Xiaojiang Xu, Qing Xu, Yun-Chung Hsiao, Cody Martin, Svetlana Ukraintseva, Vladimir Popov, Konstantin G Arbeev, Tom A Randall, Xiaoyue Wu, Liz M Garcia-Peterson, Juan Liu, Xin Xu, M Andrea Azcarate-Peril, Yisong Wan, Anatoliy I Yashin, Karthik Anantharaman, Kun Lu, Jian-Liang Li, Igor Shats, Xiaoling Li.
      Restriction of methionine (MR), a sulfur-containing essential amino acid, has been reported to repress cancer growth and improve therapeutic responses in several preclinical settings. However, how MR impacts cancer progression in the context of the intact immune system is unknown. Here we report that while inhibiting cancer growth in immunocompromised mice, MR reduces T cell abundance, exacerbates tumour growth and impairs tumour response to immunotherapy in immunocompetent male and female mice. Mechanistically, MR reduces microbial production of hydrogen sulfide, which is critical for immune cell survival/activation. Dietary supplementation of a hydrogen sulfide donor or a precursor, or methionine, stimulates antitumour immunity and suppresses tumour progression. Our findings reveal an unexpected negative interaction between MR, sulfur deficiency and antitumour immunity and further uncover a vital role of gut microbiota in mediating this interaction. Our study suggests that any possible anticancer benefits of MR require careful consideration of both the microbiota and the immune system.
    DOI:  https://doi.org/10.1038/s42255-023-00854-3
  7. iScience. 2023 Jul 21. 26(7): 107068
    Excitatory amino acid transporter 1 supports adult hippocampal neural stem cell self-renewal.
    Joshua D Rieskamp, Ileanexis Rosado-Burgos, Jacob E Christofi, Eliza Ansar, Dalia Einstein, Ashley E Walters, Valentina Valentini, John P Bruno, Elizabeth D Kirby.
      Within the adult mammalian dentate gyrus (DG) of the hippocampus, glutamate stimulates neural stem cell (NSC) self-renewing proliferation, providing a link between adult neurogenesis and local circuit activity. Here, we show that glutamate-induced self-renewal of adult DG NSCs requires glutamate transport via excitatory amino acid transporter 1 (EAAT1) to stimulate lipogenesis. Loss of EAAT1 prevented glutamate-induced self-renewing proliferation of NSCs in vitro and in vivo, with little role evident for canonical glutamate receptors. Transcriptomics and further pathway manipulation revealed that glutamate simulation of NSCs relied on EAAT1 transport-stimulated lipogenesis. Our findings demonstrate a critical, direct role for EAAT1 in stimulating NSCs to support neurogenesis in adulthood, thereby providing insights into a non-canonical mechanism by which NSCs sense and respond to their niche.
    Keywords:  Biochemistry; Cell biology; Molecular biology; Neurology
    DOI:  https://doi.org/10.1016/j.isci.2023.107068
  8. Cell Death Dis. 2023 Aug 02. 14(8): 492
    Inosine enhances tumor mitochondrial respiration by inducing Rag GTPases and nascent protein synthesis under nutrient starvation.
    Mei-Xin Li, Xiao-Ting Wu, Wen-Qiang Jing, Wen-Kui Hou, Sheng Hu, Wei Yan.
      Metabolic heterogeneity of tumor microenvironment (TME) is a hallmark of cancer and a big barrier to cancer treatment. Cancer cells display diverse capacities to utilize alternative carbon sources, including nucleotides, under poor nutrient circumstances. However, whether and how purine, especially inosine, regulates mitochondrial metabolism to buffer nutrient starvation has not been well-defined yet. Here, we identify the induction of 5'-nucleotidase, cytosolic II (NT5C2) gene expression promotes inosine accumulation and maintains cancer cell survival in the nutrient-poor region. Inosine elevation further induces Rag GTPases abundance and mTORC1 signaling pathway by enhancing transcription factor SP1 level in the starved tumor. Besides, inosine supplementary stimulates the synthesis of nascent TCA cycle enzymes, including citrate synthesis (CS) and aconitase 1 (ACO1), to further enhance oxidative phosphorylation of breast cancer cells under glucose starvation, leading to the accumulation of iso-citric acid. Inhibition of the CS activity or knockdown of ACO1 blocks the rescue effect of inosine on cancer survival under starvation. Collectively, our finding highlights the vital signal role of inosine linking mitochondrial respiration and buffering starvation, beyond serving as direct energy carriers or building blocks for genetic code in TME, shedding light on future cancer treatment by targeting inosine metabolism.
    DOI:  https://doi.org/10.1038/s41419-023-06017-2
  9. J Cell Biol. 2023 Oct 02. pii: e202303147. [Epub ahead of print]222(10):
    Completion of mitochondrial division requires the intermembrane space protein Mdi1/Atg44.
    Olivia M Connor, Srujan K Matta, Jonathan R Friedman.
      Mitochondria are highly dynamic double membrane-bound organelles that maintain their shape in part through fission and fusion. Mitochondrial fission is performed by a dynamin-related protein, Dnm1 (Drp1 in humans), that constricts and divides the mitochondria in a GTP hydrolysis-dependent manner. However, it is unclear whether factors inside mitochondria help coordinate the process and if Dnm1/Drp1 activity is sufficient to complete the fission of both mitochondrial membranes. Here, we identify an intermembrane space protein required for mitochondrial fission in yeast, which we propose to name Mdi1 (also named Atg44). Loss of Mdi1 causes mitochondrial hyperfusion due to defects in fission, but not the lack of Dnm1 recruitment to mitochondria. Mdi1 is conserved in fungal species, and its homologs contain an amphipathic α-helix, mutations of which disrupt mitochondrial morphology. One model is that Mdi1 distorts mitochondrial membranes to enable Dnm1 to robustly complete fission. Our work reveals that Dnm1 cannot efficiently divide mitochondria without the coordinated function of Mdi1 inside mitochondria.
    DOI:  https://doi.org/10.1083/jcb.202303147
  10. Nat Commun. 2023 08 01. 14(1): 4622
    Genetic inhibition of CARD9 accelerates the development of atherosclerosis in mice through CD36 dependent-defective autophagy.
    Yujiao Zhang, Marie Vandestienne, Jean-Rémi Lavillegrand, Jeremie Joffre, Icia Santos-Zas, Aonghus Lavelle, Xiaodan Zhong, Wilfried Le Goff, Maryse Guérin, Rida Al-Rifai, Ludivine Laurans, Patrick Bruneval, Coralie Guérin, Marc Diedisheim, Melanie Migaud, Anne Puel, Fanny Lanternier, Jean-Laurent Casanova, Clément Cochain, Alma Zernecke, Antoine-Emmanuel Saliba, Michal Mokry, Jean-Sebastien Silvestre, Alain Tedgui, Ziad Mallat, Soraya Taleb, Olivia Lenoir, Cécile Vindis, Stéphane M Camus, Harry Sokol, Hafid Ait-Oufella.
      Caspase recruitment-domain containing protein 9 (CARD9) is a key signaling pathway in macrophages but its role in atherosclerosis is still poorly understood. Global deletion of Card9 in Apoe-/- mice as well as hematopoietic deletion in Ldlr-/- mice increases atherosclerosis. The acceleration of atherosclerosis is also observed in Apoe-/-Rag2-/-Card9-/- mice, ruling out a role for the adaptive immune system in the vascular phenotype of Card9 deficient mice. Card9 deficiency alters macrophage phenotype through CD36 overexpression with increased IL-1β production, increased lipid uptake, higher cell death susceptibility and defective autophagy. Rapamycin or metformin, two autophagy inducers, abolish intracellular lipid overload, restore macrophage survival and autophagy flux in vitro and finally abolish the pro-atherogenic effects of Card9 deficiency in vivo. Transcriptomic analysis of human CARD9-deficient monocytes confirms the pathogenic signature identified in murine models. In summary, CARD9 is a key protective pathway in atherosclerosis, modulating macrophage CD36-dependent inflammatory responses, lipid uptake and autophagy.
    DOI:  https://doi.org/10.1038/s41467-023-40216-x
  11. Sci Adv. 2023 Aug 02. 9(31): eadi1359
    Investigation of hydrated channels and proton pathways in a high-resolution cryo-EM structure of mammalian complex I.
    Daniel N Grba, Injae Chung, Hannah R Bridges, Ahmed-Noor A Agip, Judy Hirst.
      Respiratory complex I, a key enzyme in mammalian metabolism, captures the energy released by reduction of ubiquinone by NADH to drive protons across the inner mitochondrial membrane, generating the proton-motive force for ATP synthesis. Despite remarkable advances in structural knowledge of this complicated membrane-bound enzyme, its mechanism of catalysis remains controversial. In particular, how ubiquinone reduction is coupled to proton pumping and the pathways and mechanisms of proton translocation are contested. We present a 2.4-Å resolution cryo-EM structure of complex I from mouse heart mitochondria in the closed, active (ready-to-go) resting state, with 2945 water molecules modeled. By analyzing the networks of charged and polar residues and water molecules present, we evaluate candidate pathways for proton transfer through the enzyme, for the chemical protons for ubiquinone reduction, and for the protons transported across the membrane. Last, we compare our data to the predictions of extant mechanistic models, and identify key questions to answer in future work to test them.
    DOI:  https://doi.org/10.1126/sciadv.adi1359
  12. Nat Metab. 2023 Aug 03.
    Inhibition of the serotonin transporter induces dysfunction of human brown adipose tissue.
      
    DOI:  https://doi.org/10.1038/s42255-023-00851-6
  13. Science. 2023 Aug 04. 381(6657): 483-484
    Gut epithelium modulates fungal pathogenesis.
    Woan-Yu Lin, Iliyan D Iliev.
      Specialized epithelium secretes an antifungal peptide.
    DOI:  https://doi.org/10.1126/science.adj1240
  14. Cell Rep. 2023 Jul 31. pii: S2211-1247(23)00927-0. [Epub ahead of print]42(8): 112916
    SLC15A4 controls endolysosomal TLR7-9 responses by recruiting the innate immune adaptor TASL.
    Haobo Zhang, Léa Bernaleau, Maeva Delacrétaz, Ed Hasanovic, Ales Drobek, Hermann Eibel, Manuele Rebsamen.
      Endolysosomal Toll-like receptors (TLRs) play crucial roles in immune responses to pathogens, while aberrant activation of these pathways is associated with autoimmune diseases, including systemic lupus erythematosus (SLE). The endolysosomal solute carrier family 15 member 4 (SLC15A4) is required for TLR7/8/9-induced responses and disease development in SLE models. SLC15A4 has been proposed to affect TLR7-9 activation through its transport activity, as well as by assembling an IRF5-activating complex with TASL, but the relative contribution of these functions remains unclear. Here, we show that the essential role of SLC15A4 is to recruit TASL to endolysosomes, while its transport activity is dispensable when TASL is tethered to this compartment. Endolysosomal-localized TASL rescues TLR7-9-induced IRF5 activation as well as interferon β and cytokine production in SLC15A4-deficient cells. SLC15A4 acts as signaling scaffold, and this function is essential to control TLR7-9-mediated inflammatory responses. These findings support targeting the SLC15A4-TASL complex as a potential therapeutic strategy for SLE and related diseases.
    Keywords:  CP: Immunology; IRF5; SLC15A4; SLE; TASL; Toll-like receptors; autoimmunity; lysosome
    DOI:  https://doi.org/10.1016/j.celrep.2023.112916
  15. Sci Immunol. 2023 Aug 04. 8(86): eadd4346
    1-Oleoyl-lysophosphatidylethanolamine stimulates RORγt activity in TH17 cells.
    Yusuke Endo, Toshio Kanno, Takahiro Nakajima, Kazutaka Ikeda, Yoshitaka Taketomi, Satoru Yokoyama, Shigemi Sasamoto, Hikari K Asou, Keisuke Miyako, Yoshinori Hasegawa, Yusuke Kawashima, Osamu Ohara, Makoto Murakami, Toshinori Nakayama.
      Metabolic fluxes involving fatty acid biosynthesis play essential roles in controlling the differentiation of T helper 17 (TH17) cells. However, the exact enzymes and lipid metabolites involved, as well as their link to promoting the core gene transcriptional signature required for the differentiation of TH17 cells, remain largely unknown. From a pooled CRISPR-based screen and unbiased lipidomics analyses, we identified that 1-oleoyl-lysophosphatidylethanolamine could act as a lipid modulator of retinoid-related orphan receptor gamma t (RORγt) activity in TH17 cells. In addition, we specified five enzymes, including Gpam, Gpat3, Lplat1, Pla2g12a, and Scd2, suggestive of the requirement of glycerophospholipids with monounsaturated fatty acids being required for the transcription of Il17a. 1-Oleoyl-lysophosphatidylethanolamine was reduced in Pla2g12a-deficient TH17 cells, leading to the abolition of interleukin-17 (IL-17) production and disruption to the core transcriptional program required for the differentiation of TH17 cells. Furthermore, mice with T cell-specific deficiency of Pla2g12a failed to develop disease in an experimental autoimmune encephalomyelitis model of multiple sclerosis. Thus, our data indicate that 1-oleoyl-lysophosphatidylethanolamine is a lipid metabolite that promotes RORγt-induced TH17 cell differentiation and the pathogenicity of TH17 cells.
    DOI:  https://doi.org/10.1126/sciimmunol.add4346
  16. Nat Metab. 2023 Aug 03.
    The serotonin transporter sustains human brown adipose tissue thermogenesis.
    Karla J Suchacki, Lynne E Ramage, T'ng Choong Kwok, Alexandra Kelman, Ben T McNeill, Stewart Rodney, Matthew Keegan, Calum Gray, Gillian MacNaught, Dilip Patel, Alison M Fletcher, Joanna P Simpson, Roderick N Carter, Robert K Semple, Natalie Z M Homer, Nicholas M Morton, Edwin J R van Beek, Sonia J Wakelin, Roland H Stimson.
      Activation of brown adipose tissue (BAT) in humans is a strategy to treat obesity and metabolic disease. Here we show that the serotonin transporter (SERT), encoded by SLC6A4, prevents serotonin-mediated suppression of human BAT function. RNA sequencing of human primary brown and white adipocytes shows that SLC6A4 is highly expressed in human, but not murine, brown adipocytes and BAT. Serotonin decreases uncoupled respiration and reduces uncoupling protein 1 via the 5-HT2B receptor. SERT inhibition by the selective serotonin reuptake inhibitor (SSRI) sertraline prevents uptake of extracellular serotonin, thereby potentiating serotonin's suppressive effect on brown adipocytes. Furthermore, we see that sertraline reduces BAT activation in healthy volunteers, and SSRI-treated patients demonstrate no 18F-fluorodeoxyglucose uptake by BAT at room temperature, unlike matched controls. Inhibition of BAT thermogenesis may contribute to SSRI-induced weight gain and metabolic dysfunction, and reducing peripheral serotonin action may be an approach to treat obesity and metabolic disease.
    DOI:  https://doi.org/10.1038/s42255-023-00839-2
  17. Gut. 2023 Aug 04. pii: gutjnl-2022-328734. [Epub ahead of print]
    Enolase represents a metabolic checkpoint controlling the differential exhaustion programmes of hepatitis virus-specific CD8+ T cells.
    Frances Winkler, Anna V Hipp, Carlos Ramirez, Bianca Martin, Matteo Villa, Emilia Neuwirt, Oliver Gorka, Jeroen Aerssens, Susanne E Johansson, Nisha Rana, Sian Llewellyn-Lacey, David A Price, Marcus Panning, Olaf Groß, Erika L Pearce, Carl M Hermann, Kathrin Schumann, Luciana Hannibal, Christoph Neumann-Haefelin, Tobias Boettler, Percy Knolle, Maike Hofmann, Dirk Wohlleber, Robert Thimme, Bertram Bengsch.
       OBJECTIVE: Exhausted T cells with limited effector function are enriched in chronic hepatitis B and C virus (HBV and HCV) infection. Metabolic regulation contributes to exhaustion, but it remains unclear how metabolism relates to different exhaustion states, is impacted by antiviral therapy, and if metabolic checkpoints regulate dysfunction.
    DESIGN: Metabolic state, exhaustion and transcriptome of virus-specific CD8+ T cells from chronic HBV-infected (n=31) and HCV-infected patients (n=52) were determined ex vivo and during direct-acting antiviral (DAA) therapy. Metabolic flux and metabolic checkpoints were tested in vitro. Intrahepatic virus-specific CD8+ T cells were analysed by scRNA-Seq in a HBV-replicating murine in vivo model of acute and chronic infection.
    RESULTS: HBV-specific (core18-27, polymerase455-463) and HCV-specific (NS31073-1081, NS31406-1415, NS5B2594-2602) CD8+ T cell responses exhibit heterogeneous metabolic profiles connected to their exhaustion states. The metabolic state was connected to the exhaustion profile rather than the aetiology of infection. Mitochondrial impairment despite intact glucose uptake was prominent in severely exhausted T cells linked to elevated liver inflammation in chronic HCV infection and in HBV polymerase455-463 -specific CD8+ T cell responses. In contrast, relative metabolic fitness was observed in HBeAg-negative HBV infection in HBV core18-27-specific responses. DAA therapy partially improved mitochondrial programmes in severely exhausted HCV-specific T cells and enriched metabolically fit precursors. We identified enolase as a metabolic checkpoint in exhausted T cells. Metabolic bypassing improved glycolysis and T cell effector function. Similarly, enolase deficiency was observed in intrahepatic HBV-specific CD8+ T cells in a murine model of chronic infection.
    CONCLUSION: Metabolism of HBV-specific and HCV-specific T cells is strongly connected to their exhaustion severity. Our results highlight enolase as metabolic regulator of severely exhausted T cells. They connect differential bioenergetic fitness with distinct exhaustion subtypes and varying liver disease, with implications for therapeutic strategies.
    Keywords:  alpha beta T cells; chronic viral hepatitis; hepatitis B; hepatitis C; immunology in hepatology
    DOI:  https://doi.org/10.1136/gutjnl-2022-328734
  18. Mol Cell. 2023 Aug 03. pii: S1097-2765(23)00519-1. [Epub ahead of print]83(15): 2621-2623
    NLRP12 senses heme and PAMPs to drive necrotic cell death and inflammation.
    Elliott M Bernard, Petr Broz.
      Red blood cell rupture (hemolysis) activates innate immunity and inflammation by releasing heme. Sundaram et al.1 implicate the immune sensor NLRP12 in hemolytic disease, showing that it controls necrotic cell death induction in response to heme combined with pathogen-associated molecules.
    DOI:  https://doi.org/10.1016/j.molcel.2023.07.005
  19. Elife. 2023 08 02. pii: RP86913. [Epub ahead of print]12
    Vitamin D induces SIRT1 activation through K610 deacetylation in colon cancer.
    José Manuel García-Martínez, Ana Chocarro-Calvo, Javier Martínez-Useros, María Jesús Fernández-Aceñero, M Carmen Fiuza, José Cáceres-Rentero, Antonio De la Vieja, Antonio Barbáchano, Alberto Muñoz, María Jesús Larriba, Custodia García Jiménez.
      Posttranslational modifications of epigenetic modifiers provide a flexible and timely mechanism for rapid adaptations to the dynamic environment of cancer cells. SIRT1 is an NAD+-dependent epigenetic modifier whose activity is classically associated with healthy aging and longevity, but its function in cancer is not well understood. Here, we reveal that 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3, calcitriol), the active metabolite of vitamin D (VD), promotes SIRT1 activation through auto-deacetylation in human colon carcinoma cells, and identify lysine 610 as an essential driver of SIRT1 activity. Remarkably, our data show that the post-translational control of SIRT1 activity mediates the antiproliferative action of 1,25(OH)2D3. This effect is reproduced by the SIRT1 activator SRT1720, suggesting that SIRT1 activators may offer new therapeutic possibilities for colon cancer patients who are VD deficient or unresponsive. Moreover, this might be extrapolated to inflammation and other VD deficiency-associated and highly prevalent diseases in which SIRT1 plays a prominent role.
    Keywords:  VDR; acetylation; cancer biology; colorrectal cancer; human; vitamin D
    DOI:  https://doi.org/10.7554/eLife.86913
  20. iScience. 2023 Jul 21. 26(7): 107131
    Increased cardiac PFK-2 protects against high-fat diet-induced cardiomyopathy and mediates beneficial systemic metabolic effects.
    Maria F Mendez Garcia, Satoshi Matsuzaki, Albert Batushansky, Ryan Newhardt, Caroline Kinter, Yan Jin, Shivani N Mann, Michael B Stout, Haiwei Gu, Ying Ann Chiao, Michael Kinter, Kenneth M Humphries.
      A healthy heart adapts to changes in nutrient availability and energy demands. In metabolic diseases like type 2 diabetes (T2D), increased reliance on fatty acids for energy production contributes to mitochondrial dysfunction and cardiomyopathy. A principal regulator of cardiac metabolism is 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK-2), which is a central driver of glycolysis. We hypothesized that increasing PFK-2 activity could mitigate cardiac dysfunction induced by high-fat diet (HFD). Wild type (WT) and cardiac-specific transgenic mice expressing PFK-2 (GlycoHi) were fed a low fat or HFD for 16 weeks to induce metabolic dysfunction. Metabolic phenotypes were determined by measuring mitochondrial bioenergetics and performing targeted quantitative proteomic and metabolomic analysis. Increasing cardiac PFK-2 had beneficial effects on cardiac and mitochondrial function. Unexpectedly, GlycoHi mice also exhibited sex-dependent systemic protection from HFD, including increased glucose homeostasis. These findings support improving glycolysis via PFK-2 activity can mitigate mitochondrial and functional changes that occur with metabolic syndrome.
    Keywords:  Metabolomics; Molecular biology; Physiology; Proteomics
    DOI:  https://doi.org/10.1016/j.isci.2023.107131
  21. Nat Metab. 2023 Aug 03.
    Methionine and H2S alter cancer-immune dialogue.
    Emeline Joulia, Christian M Metallo.
      
    DOI:  https://doi.org/10.1038/s42255-023-00862-3
  22. Redox Biol. 2023 Jul 28. pii: S2213-2317(23)00234-3. [Epub ahead of print]65 102833
    Loss of PERK function promotes ferroptosis by downregulating SLC7A11 (System Xc⁻) in colorectal cancer.
    Krishan Kumar Saini, Priyank Chaturvedi, Abhipsa Sinha, Manish Pratap Singh, Muqtada Ali Khan, Ayushi Verma, Mushtaq Ahmad Nengroo, Saumya Ranjan Satrusal, Sanjeev Meena, Akhilesh Singh, Sameer Srivastava, Jayanta Sarkar, Dipak Datta.
      Ferroptosis, a genetically and biochemically distinct form of programmed cell death, is characterised by an iron-dependent accumulation of lipid peroxides. Therapy-resistant tumor cells display vulnerability toward ferroptosis. Endoplasmic Reticulum (ER) stress and Unfolded Protein Response (UPR) play a critical role in cancer cells to become therapy resistant. Tweaking the balance of UPR to make cancer cells susceptible to ferroptotic cell death could be an attractive therapeutic strategy. To decipher the emerging contribution of ER stress in the ferroptotic process, we observe that ferroptosis inducer RSL3 promotes UPR (PERK, ATF6, and IRE1α), along with overexpression of cystine-glutamate transporter SLC7A11 (System Xc-). Exploring the role of a particular UPR arm in modulating SLC7A11 expression and subsequent ferroptosis, we notice that PERK is selectively critical in inducing ferroptosis in colorectal carcinoma. PERK inhibition reduces ATF4 expression and recruitment to the promoter of SLC7A11 and results in its downregulation. Loss of PERK function not only primes cancer cells for increased lipid peroxidation but also limits in vivo colorectal tumor growth, demonstrating active signs of ferroptotic cell death in situ. Further, by performing TCGA data mining and using colorectal cancer patient samples, we demonstrate that the expression of PERK and SLC7A11 is positively correlated. Overall, our experimental data indicate that PERK is a negative regulator of ferroptosis and loss of PERK function sensitizes colorectal cancer cells to ferroptosis. Therefore, small molecule PERK inhibitors hold huge promise as novel therapeutics and their potential can be harnessed against the apoptosis-resistant condition.
    Keywords:  Cancer; ER stress; Ferroptosis; PERK; SLC7A11; UPR
    DOI:  https://doi.org/10.1016/j.redox.2023.102833
  23. Sci Immunol. 2023 Aug 04. 8(86): eabq4573
    Microbial energy metabolism fuels an intestinal macrophage niche in solitary isolated lymphoid tissues through purinergic signaling.
    Pailin Chiaranunt, Kyle Burrows, Louis Ngai, Siu Ling Tai, Eric Y Cao, Helen Liang, Homaira Hamidzada, Anthony Wong, Julia Gschwend, Pascal Flüchter, Meggie Kuypers, Tijana Despot, Abdul Momen, Sung Min Lim, Thierry Mallevaey, Christoph Schneider, Tyrrell Conway, Hiromi Imamura, Slava Epelman, Arthur Mortha.
      Maintaining macrophage (MΦ) heterogeneity is critical to ensure intestinal tissue homeostasis and host defense. The gut microbiota and host factors are thought to synergistically guide intestinal MΦ development, although the exact nature, regulation, and location of such collaboration remain unclear. Here, we report that microbial biochemical energy metabolism promotes colony-stimulating factor 2 (CSF2) production by group 3 innate lymphoid cells (ILC3s) within solitary isolated lymphoid tissues (SILTs) in a cell-extrinsic, NLRP3/P2X7R-dependent fashion in the steady state. Tissue-infiltrating monocytes accumulating around SILTs followed a spatially constrained, distinct developmental trajectory into SILT-associated MΦs (SAMs). CSF2 regulated the mitochondrial membrane potential and reactive oxygen species production of SAMs and contributed to the antimicrobial defense against enteric bacterial infections. Collectively, these findings identify SILTs and CSF2-producing ILC3s as a microanatomic niche for intestinal MΦ development and functional programming fueled by the integration of commensal microbial energy metabolism.
    DOI:  https://doi.org/10.1126/sciimmunol.abq4573
  24. Redox Biol. 2023 Jul 24. pii: S2213-2317(23)00226-4. [Epub ahead of print]65 102825
    EP1 activation inhibits doxorubicin-cardiomyocyte ferroptosis via Nrf2.
    Bei Wang, Yuxuan Jin, Jiao Liu, Qian Liu, Yujun Shen, Shengkai Zuo, Ying Yu.
      Chemotherapeutic agents, such as doxorubicin (DOX), may cause cardiomyopathy, even life-threatening arrhythmias in cancer patients. Ferroptosis-an iron-dependent oxidative form of programmed necrosis, plays a pivotal role in DOX-induced cardiomyopathy (DIC). Prostaglandins (PGs) are bioactive signaling molecules that profoundly modulate cardiac performance in both physiologic and pathologic conditions. Here, we found that PGE2 production and its E-prostanoid 1 receptor (EP1) expression were upregulated in erastin (a ferroptosis inducer) or DOX-treated cardiomyocytes. EP1 inhibition markedly aggravated erastin or DOX-induced cardiomyocyte ferroptosis, whereas EP1 activation exerted opposite effect. Genetic depletion of EP1 in cardiomyocytes worsens DOX-induced cardiac injury in mice, which was efficiently rescued by the ferroptosis inhibitor Ferrostatin-1 (Fer-1). Mechanistically, EP1 activation protected cardiomyocytes from DOX-induced ferroptosis by promoting nuclear factor erythroid 2-related factor 2 (Nrf2)-driven anti-oxidative gene expression, such as glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11). EP1 was coupled with Gαq to elicit intracellular Ca2+ flux and activate the PKC/Nrf2 cascade in ferroptotic cardiomyocytes. EP1 activation also prevents DOX-induced ferroptosis in human cardiomyocytes. Thus, PGE2/EP1 axis protects cardiomyocytes from DOX-induced ferroptosis by activating PKC/Nrf2 signaling and activation of EP1 may represent an attractive strategy for DIC prevention and treatment.
    Keywords:  Cardiomyocyte ferroptosis; DOX-induced cardiomyopathy; EP1; Nrf2
    DOI:  https://doi.org/10.1016/j.redox.2023.102825
  25. Gastroenterology. 2023 Aug 02. pii: S0016-5085(23)04837-0. [Epub ahead of print]
    Ceramides increase fatty acid utilization in intestinal progenitors to enhance stemness and increase tumor risk.
    Ying Li, Bhagirath Chaurasia, M Mahidur Rahman, Vincent Kaddai, J Alan Maschek, Jordan A Berg, Joseph L Wilkerson, Ziad S Mahmassani, James Cox, Peng Wei, Peter J Meikle, Donald Atkinson, Liping Wang, Annelise M Poss, Mary C Playdon, Trevor S Tippetts, Esraa M Mousa, Kesara Nittayaboon, Pon Velayutham Anandh Babu, Micah J Drummond, Hans Clevers, James A Shayman, Yoshio Hirabayashi, William L Holland, Jared Rutter, Bruce Edgar, Scott A Summers.
       BACKGROUND AND AIMS: Cancers of the alimentary tract including esophageal adenocarcinomas, colorectal cancers, and cancers of the gastric cardia are common comorbidities of obesity. Prolonged, excessive delivery of macronutrients to the cells lining the gut can increase one's risk for these cancers by inducing imbalances in the rate of intestinal stem cell proliferation vs. differentiation, which can produce polyps and other aberrant growths. We investigated whether ceramides, which are sphingolipids that serve as a signals of nutritional excess, alter stem cell behaviors to influence cancer risk.
    METHODS: We profiled sphingolipids and sphingolipid-synthesizing enzymes in human adenomas and tumors. Thereafter, we manipulated expression of sphingolipid-producing enzymes, including serine palmitoyltransferase (SPT), in intestinal progenitors of mice, cultured organoids, and Drosophila to discern whether sphingolipids altered stem cell proliferation and metabolism.
    RESULTS: SPT, which diverts dietary fatty- and amino-acids into the biosynthetic pathway that produces ceramides and other sphingolipids, is a critical modulator of intestinal stem cell homeostasis. SPT and other enzymes in the sphingolipid biosynthesis pathway are upregulated in human intestinal adenomas. They produce ceramides which serve as pro-stemness signals that stimulate peroxisome-proliferator activated receptor alpha and induce fatty acid binding protein-1. These actions lead to increased lipid utilization and enhanced proliferation of intestinal progenitors.
    CONCLUSION: Ceramides serve as critical links between dietary macronutrients, epithelial regeneration, and cancer risk.
    Keywords:  Stem cell; ceramides; colorectal cancer; metabolism; sphingolipids
    DOI:  https://doi.org/10.1053/j.gastro.2023.07.017
  26. Cell Death Dis. 2023 Aug 03. 14(8): 496
    Mitochondria dysregulation contributes to secondary neurodegeneration progression post-contusion injury in human 3D in vitro triculture brain tissue model.
    Volha Liaudanskaya, Nicholas J Fiore, Yang Zhang, Yuka Milton, Marilyn F Kelly, Marly Coe, Ariana Barreiro, Victoria K Rose, Matthew R Shapiro, Adam S Mullis, Anna Shevzov-Zebrun, Mathew Blurton-Jones, Michael J Whalen, Aviva J Symes, Irene Georgakoudi, Thomas J F Nieland, David L Kaplan.
      Traumatic Brain injury-induced disturbances in mitochondrial fission-and-fusion dynamics have been linked to the onset and propagation of neuroinflammation and neurodegeneration. However, cell-type-specific contributions and crosstalk between neurons, microglia, and astrocytes in mitochondria-driven neurodegeneration after brain injury remain undefined. We developed a human three-dimensional in vitro triculture tissue model of a contusion injury composed of neurons, microglia, and astrocytes and examined the contributions of mitochondrial dysregulation to neuroinflammation and progression of injury-induced neurodegeneration. Pharmacological studies presented here suggest that fragmented mitochondria released by microglia are a key contributor to secondary neuronal damage progression after contusion injury, a pathway that requires astrocyte-microglia crosstalk. Controlling mitochondrial dysfunction thus offers an exciting option for developing therapies for TBI patients.
    DOI:  https://doi.org/10.1038/s41419-023-05980-0
  27. Cancer Res. 2023 Aug 01. pii: CAN-23-0153. [Epub ahead of print]
    The ratio of key metabolic transcripts is a predictive biomarker of breast cancer metastasis to the lung.
    Deepti Mathur, Chen Liao, Wendy Lin, Alessandro La Ferlita, Salvatore Alaimo, Samuel Taylor, Yi Zhong, Christine Iacobuzio-Donahue, Alfredo Ferro, Joao B Xavier.
      Understanding the rewired metabolism underlying organ-specific metastasis in breast cancer could help identify strategies to improve the treatment and prevention of metastatic disease. Here, we used a systems biology approach to compare metabolic fluxes used by parental breast cancer cells and their brain- and lung-homing derivatives. Divergent lineages had distinct, heritable metabolic fluxes. Lung-homing cells maintained high glycolytic flux despite low levels of glycolytic intermediates, constitutively activating a pathway sink into lactate. This strong Warburg effect was associated with a high ratio of lactate dehydrogenase (LDH) to pyruvate dehydrogenase (PDH) expression, which correlated with lung metastasis in patients with breast cancer. While feature classification models trained on clinical characteristics alone were unable to predict tropism, the LDH/PDH ratio was a significant predictor of metastasis to the lung but not to other organs, independent of other transcriptomic signatures. High lactate efflux was also a trait in lung-homing metastatic pancreatic cancer cells, suggesting that lactate production may be a convergent phenotype in lung metastasis. Together, these analyses highlight the essential role that metabolism plays in organ-specific cancer metastasis and identify a putative biomarker for predicting lung metastasis in breast cancer patients.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-23-0153
This page is being maintained by Thomas Krichel. It was last updated on 2024‒11‒22 at 4:20.