bims-mepmim Biomed News
on Metabolites in pathological microenvironments and immunometabolism
Issue of 2024–03–03
twenty-one papers selected by
Erika Mariana Palmieri, NIH/NCI Laboratory of Cancer ImmunoMetabolism
  1. PKM2 diverts glycolytic flux in dependence on mitochondrial one-carbon cycle.
  2. Bicarbonate signalling via G protein-coupled receptor regulates ischaemia-reperfusion injury.
  3. A homoeostatic switch causing glycerol-3-phosphate and phosphoethanolamine accumulation triggers senescence by rewiring lipid metabolism.
  4. Functional hypoxia reduces mitochondrial calcium uptake.
  5. Metabolic rewiring of macrophages by epidermal-derived lactate promotes sterile inflammation in the murine skin.
  6. β-catenin Activation Reprograms Ammonia Metabolism to Promote Senescence Resistance in Hepatocellular Carcinoma.
  7. Histone butyrylation in the mouse intestine is mediated by the microbiota and associated with regulation of gene expression.
  8. Cancer-associated fibroblast-derived acetate promotes pancreatic cancer development by altering polyamine metabolism via the ACSS2-SP1-SAT1 axis.
  9. Intestinal stroma guides monocyte differentiation to macrophages through GM-CSF.
  10. A spatial map of hepatic mitochondria uncovers functional heterogeneity shaped by nutrient-sensing signaling.
  11. Mitochondrial function and reactive oxygen species production during human sperm capacitation: Unraveling key players.
  12. IL-37 dampens immunosuppressive functions of MDSCs via metabolic reprogramming in the tumor microenvironment.
  13. PIEZO1 is a distal nephron mechanosensor and is required for flow-induced K+ secretion.
  14. Mining cholesterol genes from thousands of mouse livers identifies Aldolase C as a regulator of cholesterol biosynthesis.
  15. Hematologic DNMT3A reduction and high-fat diet synergize to promote weight gain and tissue inflammation.
  16. Coculture with macrophages alters ferroptosis susceptibility of triple-negative cancer cells.
  17. Mitochondrial uncoupling proteins protect human airway epithelial ciliated cells from oxidative damage.
  18. Metabolic rewiring and communication in cancer immunity.
  19. MarShie: a clearing protocol for 3D analysis of single cells throughout the bone marrow at subcellular resolution.
  20. S-nitrosothiol homeostasis maintained by ADH5 facilitates STING-dependent host defense against pathogens.
  21. Targeting stromal metabolism in pancreatic ductal adenocarcinoma.
  1. Cell Rep. 2024 Feb 28. pii: S2211-1247(24)00196-7. [Epub ahead of print]43(3): 113868
    PKM2 diverts glycolytic flux in dependence on mitochondrial one-carbon cycle.
    Mohaned Benzarti, Laura Neises, Anais Oudin, Christina Krötz, Elodie Viry, Ernesto Gargiulo, Coralie Pulido, Maryse Schmoetten, Vitaly Pozdeev, Nadia I Lorenz, Michael W Ronellenfitsch, David Sumpton, Marc Warmoes, Christian Jaeger, Antoine Lesur, Björn Becker, Etienne Moussay, Jerome Paggetti, Simone P Niclou, Elisabeth Letellier, Johannes Meiser.
      Modeling tumor metabolism in vitro remains challenging. Here, we used galactose as an in vitro tool compound to mimic glycolytic limitation. In contrast to the established idea that high glycolytic flux reduces pyruvate kinase isozyme M2 (PKM2) activity to support anabolic processes, we have discovered that glycolytic limitation also affects PKM2 activity. Surprisingly, despite limited carbon availability and energetic stress, cells induce a near-complete block of PKM2 to divert carbons toward serine metabolism. Simultaneously, TCA cycle flux is sustained, and oxygen consumption is increased, supported by glutamine. Glutamine not only supports TCA cycle flux but also serine synthesis via distinct mechanisms that are directed through PKM2 inhibition. Finally, deleting mitochondrial one-carbon (1C) cycle reversed the PKM2 block, suggesting a potential formate-dependent crosstalk that coordinates mitochondrial 1C flux and cytosolic glycolysis to support cell survival and proliferation during nutrient-scarce conditions.
    Keywords:  CP: Cancer; CP: Metabolism
    DOI:  https://doi.org/10.1016/j.celrep.2024.113868
  2. Nat Commun. 2024 Feb 27. 15(1): 1530
    Bicarbonate signalling via G protein-coupled receptor regulates ischaemia-reperfusion injury.
    Airi Jo-Watanabe, Toshiki Inaba, Takahiro Osada, Ryota Hashimoto, Tomohiro Nishizawa, Toshiaki Okuno, Sayoko Ihara, Kazushige Touhara, Nobutaka Hattori, Masatsugu Oh-Hora, Osamu Nureki, Takehiko Yokomizo.
      Homoeostatic regulation of the acid-base balance is essential for cellular functional integrity. However, little is known about the molecular mechanism through which the acid-base balance regulates cellular responses. Here, we report that bicarbonate ions activate a G protein-coupled receptor (GPCR), i.e., GPR30, which leads to Gq-coupled calcium responses. Gpr30-Venus knock-in mice reveal predominant expression of GPR30 in brain mural cells. Primary culture and fresh isolation of brain mural cells demonstrate bicarbonate-induced, GPR30-dependent calcium responses. GPR30-deficient male mice are protected against ischemia-reperfusion injury by a rapid blood flow recovery. Collectively, we identify a bicarbonate-sensing GPCR in brain mural cells that regulates blood flow and ischemia-reperfusion injury. Our results provide a perspective on the modulation of GPR30 signalling in the development of innovative therapies for ischaemic stroke. Moreover, our findings provide perspectives on acid/base sensing GPCRs, concomitantly modulating cellular responses depending on fluctuating ion concentrations under the acid-base homoeostasis.
    DOI:  https://doi.org/10.1038/s41467-024-45579-3
  3. Nat Metab. 2024 Feb;6(2): 323-342
    A homoeostatic switch causing glycerol-3-phosphate and phosphoethanolamine accumulation triggers senescence by rewiring lipid metabolism.
    Khaled Tighanimine, José Américo Nabuco Leva Ferreira Freitas, Ivan Nemazanyy, Alexia Bankolé, Delphine Benarroch-Popivker, Susanne Brodesser, Gregory Doré, Lucas Robinson, Paule Benit, Sophia Ladraa, Yara Bou Saada, Bertrand Friguet, Philippe Bertolino, David Bernard, Guillaume Canaud, Pierre Rustin, Eric Gilson, Oliver Bischof, Stefano Fumagalli, Mario Pende.
      Cellular senescence affects many physiological and pathological processes and is characterized by durable cell cycle arrest, an inflammatory secretory phenotype and metabolic reprogramming. Here, by using dynamic transcriptome and metabolome profiling in human fibroblasts with different subtypes of senescence, we show that a homoeostatic switch that results in glycerol-3-phosphate (G3P) and phosphoethanolamine (pEtN) accumulation links lipid metabolism to the senescence gene expression programme. Mechanistically, p53-dependent glycerol kinase activation and post-translational inactivation of phosphate cytidylyltransferase 2, ethanolamine regulate this metabolic switch, which promotes triglyceride accumulation in lipid droplets and induces the senescence gene expression programme. Conversely, G3P phosphatase and ethanolamine-phosphate phospho-lyase-based scavenging of G3P and pEtN acts in a senomorphic way by reducing G3P and pEtN accumulation. Collectively, our study ties G3P and pEtN accumulation to controlling lipid droplet biogenesis and phospholipid flux in senescent cells, providing a potential therapeutic avenue for targeting senescence and related pathophysiology.
    DOI:  https://doi.org/10.1038/s42255-023-00972-y
  4. Redox Biol. 2024 Jan 17. pii: S2213-2317(24)00013-2. [Epub ahead of print]71 103037
    Functional hypoxia reduces mitochondrial calcium uptake.
    Chris Donnelly, Timea Komlódi, Cristiane Cecatto, Luiza H D Cardoso, Anne-Claire Compagnion, Alessandro Matera, Daniele Tavernari, Olivier Campiche, Rosa Chiara Paolicelli, Nadège Zanou, Bengt Kayser, Erich Gnaiger, Nicolas Place.
      Mitochondrial respiration extends beyond ATP generation, with the organelle participating in many cellular and physiological processes. Parallel changes in components of the mitochondrial electron transfer system with respiration render it an appropriate hub for coordinating cellular adaption to changes in oxygen levels. How changes in respiration under functional hypoxia (i.e., when intracellular O2 levels limit mitochondrial respiration) are relayed by the electron transfer system to impact mitochondrial adaption and remodeling after hypoxic exposure remains poorly defined. This is largely due to challenges integrating findings under controlled and defined O2 levels in studies connecting functions of isolated mitochondria to humans during physical exercise. Here we present experiments under conditions of hypoxia in isolated mitochondria, myotubes and exercising humans. Performing steady-state respirometry with isolated mitochondria we found that oxygen limitation of respiration reduced electron flow and oxidative phosphorylation, lowered the mitochondrial membrane potential difference, and decreased mitochondrial calcium influx. Similarly, in myotubes under functional hypoxia mitochondrial calcium uptake decreased in response to sarcoplasmic reticulum calcium release for contraction. In both myotubes and human skeletal muscle this blunted mitochondrial adaptive responses and remodeling upon contractions. Our results suggest that by regulating calcium uptake the mitochondrial electron transfer system is a hub for coordinating cellular adaption under functional hypoxia.
    Keywords:  Coenzyme Q; Exercise; Membrane potential; Respirometry; Skeletal muscle
    DOI:  https://doi.org/10.1016/j.redox.2024.103037
  5. EMBO J. 2024 Feb 28.
    Metabolic rewiring of macrophages by epidermal-derived lactate promotes sterile inflammation in the murine skin.
    Uttkarsh Ayyangar, Aneesh Karkhanis, Heather Tay, Aliya Farissa Binte Afandi, Oindrila Bhattacharjee, Lalitha Ks, Sze Han Lee, James Chan, Srikala Raghavan.
      Dysregulated macrophage responses and changes in tissue metabolism are hallmarks of chronic inflammation in the skin. However, the metabolic cues that direct and support macrophage functions in the skin are poorly understood. Here, we show that during sterile skin inflammation, the epidermis and macrophages uniquely depend on glycolysis and the TCA cycle, respectively. This compartmentalisation is initiated by ROS-induced HIF-1α stabilization leading to enhanced glycolysis in the epidermis. The end-product of glycolysis, lactate, is then exported by epithelial cells and utilized by the dermal macrophages to induce their M2-like fates through NF-κB pathway activation. In addition, we show that psoriatic skin disorder is also driven by such lactate metabolite-mediated crosstalk between the epidermis and macrophages. Notably, small-molecule inhibitors of lactate transport in this setting attenuate sterile inflammation and psoriasis disease burden, and suppress M2-like fate acquisition in dermal macrophages. Our study identifies an essential role for the metabolite lactate in regulating macrophage responses to inflammation, which may be effectively targeted to treat inflammatory skin disorders such as psoriasis.
    Keywords:  Epithelial-immune Crosstalk; Lactate Metabolism; Metabolic Compartmentation; Psoriasis; Sterile Inflammation
    DOI:  https://doi.org/10.1038/s44318-024-00039-y
  6. Cancer Res. 2024 Feb 28.
    β-catenin Activation Reprograms Ammonia Metabolism to Promote Senescence Resistance in Hepatocellular Carcinoma.
    Ye Wang, Chunxiao Cheng, Yanjun Lu, Zhaowu Lian, Qi Liu, Yanchao Xu, Yunzheng Li, Huan Li, Laizhu Zhang, Xiang Jiang, Binghua Li, Decai Yu.
      Hepatocellular carcinoma (HCC) is a typical tumor that undergoes metabolic reprogramming, differing from normal liver tissue in glucose, lipid, nucleic acid, and amino acid metabolism. While ammonia is a toxic metabolic byproduct, it has also been recently recognized as a signaling molecule to activate lipid metabolism, and it can be a nitrogen source for biosynthesis to support tumorigenesis. In this study, we revealed that β-catenin activation increases ammonia production in HCC mainly by stimulating glutaminolysis. β-catenin/LEF1 activated the transcription of the glutamate dehydrogenase GLUD1, which then promoted ammonia utilization to enhance the production of glutamate, aspartate, and proline as evidenced by 15NH4Cl metabolic flux. β-catenin/TCF4 induced the transcription of SLC4A11, an ammonia transporter, to excrete excess ammonia. SLC4A11 was upregulated in HCC tumor tissues, and high SLC4A11 expression was associated with poor prognosis and advanced disease stages. Loss of SLC4A11 induced HCC cell senescence in vitro by blocking ammonia excretion and reduced β-catenin-driven tumor growth in vivo. Furthermore, elevated levels of plasma ammonia promoted the progression of β-catenin mutant HCC, which was impeded by SLC4A11 deficiency. Downregulation of SLC4A11 led to ammonia accumulation in tumor interstitial fluid (TIF) and decreased plasma ammonia levels in HCC with activated β-catenin. Altogether, this study indicates that β-catenin activation reprograms ammonia metabolism and that blocking ammonia excretion by targeting SLC4A11 could be a promising approach to induce senescence in β-catenin mutant HCC.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-23-0673
  7. Nat Metab. 2024 Feb 27.
    Histone butyrylation in the mouse intestine is mediated by the microbiota and associated with regulation of gene expression.
    Leah A Gates, Bernardo Sgarbi Reis, Peder J Lund, Matthew R Paul, Marylene Leboeuf, Annaelle M Djomo, Zara Nadeem, Mariana Lopes, Francisca N Vitorino, Gokhan Unlu, Thomas S Carroll, Kivanç Birsoy, Benjamin A Garcia, Daniel Mucida, C David Allis.
      Post-translational modifications (PTMs) on histones are a key source of regulation on chromatin through impacting cellular processes, including gene expression1. These PTMs often arise from metabolites and are thus impacted by metabolism and environmental cues2-7. One class of metabolically regulated PTMs are histone acylations, which include histone acetylation, butyrylation, crotonylation and propionylation3,8. As these PTMs can be derived from short-chain fatty acids, which are generated by the commensal microbiota in the intestinal lumen9-11, we aimed to define how microbes impact the host intestinal chromatin landscape, mainly in female mice. Here we show that in addition to acetylation, intestinal epithelial cells from the caecum and distal mouse intestine also harbour high levels of butyrylation and propionylation on lysines 9 and 27 of histone H3. We demonstrate that these acylations are regulated by the microbiota and that histone butyrylation is additionally regulated by the metabolite tributyrin. Tributyrin-regulated gene programmes are correlated with histone butyrylation, which is associated with active gene-regulatory elements and levels of gene expression. Together, our study uncovers a regulatory layer of how the microbiota and metabolites influence the intestinal epithelium through chromatin, demonstrating a physiological setting in which histone acylations are dynamically regulated and associated with gene regulation.
    DOI:  https://doi.org/10.1038/s42255-024-00992-2
  8. Nat Cell Biol. 2024 Mar 01.
    Cancer-associated fibroblast-derived acetate promotes pancreatic cancer development by altering polyamine metabolism via the ACSS2-SP1-SAT1 axis.
    Divya Murthy, Kuldeep S Attri, Surendra K Shukla, Ravi Thakur, Nina V Chaika, Chunbo He, Dezhen Wang, Kanupriya Jha, Aneesha Dasgupta, Ryan J King, Scott E Mulder, Joshua Souchek, Teklab Gebregiworgis, Vikant Rai, Rohit Patel, Tuo Hu, Sandeep Rana, Sai Sundeep Kollala, Camila Pacheco, Paul M Grandgenett, Fang Yu, Vikas Kumar, Audrey J Lazenby, Adrian R Black, Susanna Ulhannan, Ajay Jain, Barish H Edil, David L Klinkebiel, Robert Powers, Amarnath Natarajan, Michael A Hollingsworth, Kamiya Mehla, Quan Ly, Sarika Chaudhary, Rosa F Hwang, Kathryn E Wellen, Pankaj K Singh.
      The ability of tumour cells to thrive in harsh microenvironments depends on the utilization of nutrients available in the milieu. Here we show that pancreatic cancer-associated fibroblasts (CAFs) regulate tumour cell metabolism through the secretion of acetate, which can be blocked by silencing ATP citrate lyase (ACLY) in CAFs. We further show that acetyl-CoA synthetase short-chain family member 2 (ACSS2) channels the exogenous acetate to regulate the dynamic cancer epigenome and transcriptome, thereby facilitating cancer cell survival in an acidic microenvironment. Comparative H3K27ac ChIP-seq and RNA-seq analyses revealed alterations in polyamine homeostasis through regulation of SAT1 gene expression and enrichment of the SP1-responsive signature. We identified acetate/ACSS2-mediated acetylation of SP1 at the lysine 19 residue that increased SP1 protein stability and transcriptional activity. Genetic or pharmacologic inhibition of the ACSS2-SP1-SAT1 axis diminished the tumour burden in mouse models. These results reveal that the metabolic flexibility imparted by the stroma-derived acetate enabled cancer cell survival under acidosis via the ACSS2-SP1-SAT1 axis.
    DOI:  https://doi.org/10.1038/s41556-024-01372-4
  9. Nat Commun. 2024 Feb 26. 15(1): 1752
    Intestinal stroma guides monocyte differentiation to macrophages through GM-CSF.
    Egle Kvedaraite, Magda Lourda, Natalia Mouratidou, Tim Düking, Avinash Padhi, Kirsten Moll, Paulo Czarnewski, Indranil Sinha, Ioanna Xagoraris, Efthymia Kokkinou, Anastasios Damdimopoulos, Whitney Weigel, Olga Hartwig, Telma E Santos, Tea Soini, Aline Van Acker, Nelly Rahkonen, Malin Flodström Tullberg, Emma Ringqvist, Marcus Buggert, Carl Jorns, Ulrik Lindforss, Caroline Nordenvall, Christopher T Stamper, David Unnersjö-Jess, Mira Akber, Ruta Nadisauskaite, Jessica Jansson, Niels Vandamme, Chiara Sorini, Marijke Elise Grundeken, Helena Rolandsdotter, George Rassidakis, Eduardo J Villablanca, Maja Ideström, Stefan Eulitz, Henrik Arnell, Jenny Mjösberg, Jan-Inge Henter, Mattias Svensson.
      Stromal cells support epithelial cell and immune cell homeostasis and play an important role in inflammatory bowel disease (IBD) pathogenesis. Here, we quantify the stromal response to inflammation in pediatric IBD and reveal subset-specific inflammatory responses across colon segments and intestinal layers. Using data from a murine dynamic gut injury model and human ex vivo transcriptomic, protein and spatial analyses, we report that PDGFRA+CD142-/low fibroblasts and monocytes/macrophages co-localize in the intestine. In primary human fibroblast-monocyte co-cultures, intestinal PDGFRA+CD142-/low fibroblasts foster monocyte transition to CCR2+CD206+ macrophages through granulocyte-macrophage colony-stimulating factor (GM-CSF). Monocyte-derived CCR2+CD206+ cells from co-cultures have a phenotype similar to intestinal CCR2+CD206+ macrophages from newly diagnosed pediatric IBD patients, with high levels of PD-L1 and low levels of GM-CSF receptor. The study describes subset-specific changes in stromal responses to inflammation and suggests that the intestinal stroma guides intestinal macrophage differentiation.
    DOI:  https://doi.org/10.1038/s41467-024-46076-3
  10. Nat Commun. 2024 Feb 28. 15(1): 1799
    A spatial map of hepatic mitochondria uncovers functional heterogeneity shaped by nutrient-sensing signaling.
    Sun Woo Sophie Kang, Rory P Cunningham, Colin B Miller, Lauryn A Brown, Constance M Cultraro, Adam Harned, Kedar Narayan, Jonathan Hernandez, Lisa M Jenkins, Alexei Lobanov, Maggie Cam, Natalie Porat-Shliom.
      In the liver, mitochondria are exposed to different concentrations of nutrients due to their spatial positioning across the periportal and pericentral axis. How the mitochondria sense and integrate these signals to respond and maintain homeostasis is not known. Here, we combine intravital microscopy, spatial proteomics, and functional assessment to investigate mitochondrial heterogeneity in the context of liver zonation. We find that periportal and pericentral mitochondria are morphologically and functionally distinct; beta-oxidation is elevated in periportal regions, while lipid synthesis is predominant in the pericentral mitochondria. In addition, comparative phosphoproteomics reveals spatially distinct patterns of mitochondrial composition and potential regulation via phosphorylation. Acute pharmacological modulation of nutrient sensing through AMPK and mTOR shifts mitochondrial phenotypes in the periportal and pericentral regions, linking nutrient gradients across the lobule and mitochondrial heterogeneity. This study highlights the role of protein phosphorylation in mitochondrial structure, function, and overall homeostasis in hepatic metabolic zonation. These findings have important implications for liver physiology and disease.
    DOI:  https://doi.org/10.1038/s41467-024-45751-9
  11. FASEB J. 2024 Feb 29. 38(4): e23486
    Mitochondrial function and reactive oxygen species production during human sperm capacitation: Unraveling key players.
    Pilar Irigoyen, Santiago Mansilla, Laura Castro, Adriana Cassina, Rossana Sapiro.
      Sperm capacitation is a critical process for male fertility. It involves a series of biochemical and physiological changes that occur in the female reproductive tract, rendering the sperm competent for successful fertilization. The precise mechanisms and, specifically, the role of mitochondria, in sperm capacitation remain incompletely understood. Previously, we revealed that in mouse sperm mitochondrial activity (e.g., oxygen consumption, membrane potential, ATP/ADP exchange, and mitochondrial Ca2+ ) increases during capacitation. Herein, we studied mitochondrial function by high-resolution respirometry (HRR) and reactive oxygen species production in capacitated (CAP) and non-capacitated (NC) human spermatozoa. We found that in capacitated sperm from normozoospermic donors, the respiratory control ratio increased by 36%, accompanied by a double oxygen consumption rate (OCR) in the presence of antimycin A. Extracellular hydrogen peroxide (H2 O2 ) detection was three times higher in CAP than in NC sperm cells. To confirm that H2 O2 production depends on mitochondrial superoxide ( O2·-$$ {\mathrm{O}}_2^{\cdotp -} $$ ) formation, we evaluated mitochondrial aconitase (ACO2) amount, activity, and role in the metabolic flux from the sperm tricarboxylic acid cycle. We estimated that CAP cells produce, on average by individual, (59 ± 22)% more O2·-$$ {\mathrm{O}}_2^{\cdotp -} $$ in the steady-state compared to NC cells. Finally, we analyzed two targets of oxidative stress: lipid peroxidation by western blot against 4-hydroxynonenal and succinate dehydrogenase (SDH) activity by HRR. We did not observe modifications in lipoperoxidation nor the activity of SDH, suggesting that during capacitation, the increase in mitochondrial H2 O2 production does not damage sperm and it is necessary for the normal CAP process.
    Keywords:  aconitase 2; male fertility; mitochondrial activity; reactive oxygen species; respirometry assay; sperm capacitation
    DOI:  https://doi.org/10.1096/fj.202301957RR
  12. Cell Rep. 2024 Feb 26. pii: S2211-1247(24)00163-3. [Epub ahead of print]43(3): 113835
    IL-37 dampens immunosuppressive functions of MDSCs via metabolic reprogramming in the tumor microenvironment.
    Yu Mei, Ying Zhu, Kylie Su Mei Yong, Zuhairah Binte Hanafi, Huanle Gong, Yonghao Liu, Huey Yee Teo, Muslima Hussain, Yuan Song, Qingfeng Chen, Haiyan Liu.
      Interleukin-37 (IL-37) has been shown to inhibit tumor growth in various cancer types. However, the immune regulatory function of IL-37 in the tumor microenvironment is unclear. Here, we established a human leukocyte antigen-I (HLA-I)-matched humanized patient-derived xenograft hepatocellular carcinoma (HCC) model and three murine orthotopic HCC models to study the function of IL-37 in the tumor microenvironment. We found that IL-37 inhibited HCC growth and promoted T cell activation. Further study revealed that IL-37 impaired the immunosuppressive capacity of myeloid-derived suppressor cells (MDSCs). Pretreatment of MDSCs with IL-37 before adoptive transfer attenuated their tumor-promoting function in HCC tumor-bearing mice. Moreover, IL-37 promoted both glycolysis and oxidative phosphorylation in MDSCs, resulting in the upregulation of ATP release, which impaired the immunosuppressive capacity of MDSCs. Collectively, we demonstrated that IL-37 inhibited tumor development through dampening MDSCs' immunosuppressive capacity in the tumor microenvironment via metabolic reprogramming, making it a promising target for future cancer immunotherapy.
    Keywords:  ATP; CP: Cancer; CP: Immunology; Interleukin-37; hepatocellular carcinoma; metabolism; myeloid-derived suppressor cells
    DOI:  https://doi.org/10.1016/j.celrep.2024.113835
  13. J Clin Invest. 2024 Mar 01. pii: e174806. [Epub ahead of print]134(5):
    PIEZO1 is a distal nephron mechanosensor and is required for flow-induced K+ secretion.
    Rolando Carrisoza-Gaytan, Stephanie M Mutchler, Francisco Carattino, Joanne Soong, Marianela G Dalghi, Peng Wu, WenHui Wang, Gerard Apodaca, Lisa M Satlin, Thomas R Kleyman.
      Ca2+-activated BK channels in renal intercalated cells (ICs) mediate luminal flow-induced K+ secretion (FIKS), but how ICs sense increased flow remains uncertain. We examined whether PIEZO1, a mechanosensitive Ca2+-permeable channel expressed in the basolateral membranes of ICs, is required for FIKS. In isolated cortical collecting ducts (CCDs), the mechanosensitive cation-selective channel inhibitor GsMTx4 dampened flow-induced increases in intracellular Ca2+ concentration ([Ca2+]i), whereas the PIEZO1 activator Yoda1 increased [Ca2+]i and BK channel activity. CCDs from mice fed a high-K+ (HK) diet exhibited a greater Yoda1-dependent increase in [Ca2+]i than CCDs from mice fed a control K+ diet. ICs in CCDs isolated from mice with a targeted gene deletion of Piezo1 in ICs (IC-Piezo1-KO) exhibited a blunted [Ca2+]i response to Yoda1 or increased flow, with an associated loss of FIKS in CCDs. Male IC-Piezo1-KO mice selectively exhibited an increased blood [K+] in response to an oral K+ bolus and blunted urinary K+ excretion following a volume challenge. Whole-cell expression of BKα subunit was reduced in ICs of IC-Piezo1-KO mice fed an HK diet. We conclude that PIEZO1 mediates flow-induced basolateral Ca2+ entry into ICs, is upregulated in the CCD in response to an HK diet, and is necessary for FIKS.
    Keywords:  Calcium channels; Cell biology; Epithelial transport of ions and water; Nephrology; Potassium channels
    DOI:  https://doi.org/10.1172/JCI174806
  14. J Lipid Res. 2024 Feb 26. pii: S0022-2275(24)00030-0. [Epub ahead of print] 100525
    Mining cholesterol genes from thousands of mouse livers identifies Aldolase C as a regulator of cholesterol biosynthesis.
    James A Votava, Steven V John, Zhonggang Li, Shuyang Chen, Jing Fan, Brian W Parks.
      The availability of genome-wide transcriptomic and proteomic datasets is ever-increasing and often not used beyond initial publication. Here, we applied module-based co-expression network analysis to a comprehensive catalog of 35 mouse genome-wide liver expression datasets (encompassing more than 3800 mice) with the goal of identifying and validating unknown genes involved in cholesterol metabolism. From these 35 datasets, we identified a conserved module of genes enriched with cholesterol biosynthetic genes. Using a systematic approach across the 35 datasets, we identified three genes (Rdh11, Echdc1, and Aldoc) with no known role in cholesterol metabolism. We then performed functional validation studies and show that each gene is capable of regulating cholesterol metabolism. For the glycolytic gene, Aldoc, we demonstrate that it contributes to de novo cholesterol biosynthesis and regulates cholesterol and triglyceride levels in mice. As Aldoc is located within a genome-wide significant GWAS locus for human plasma cholesterol levels, our studies establish Aldoc as a causal gene within this locus. Through our work, we develop a framework for leveraging mouse genome-wide liver datasets for identifying and validating genes involved in cholesterol metabolism.
    Keywords:  ALDOC; Cholesterol; ECHDC1; Lipid metabolism; RDH11; Triglycerides; WGCNA
    DOI:  https://doi.org/10.1016/j.jlr.2024.100525
  15. iScience. 2024 Mar 15. 27(3): 109122
    Hematologic DNMT3A reduction and high-fat diet synergize to promote weight gain and tissue inflammation.
    Jaime M Reyes, Ayala Tovy, Linda Zhang, Angelina S Bortoletto, Carina Rosas, Chun-Wei Chen, Sarah M Waldvogel, Anna G Guzman, Rogelio Aguilar, Sinjini Gupta, Ling Liu, Matthew T Buckley, Kalyani R Patel, Andrea N Marcogliese, Yumei Li, Choladda V Curry, Thomas Rando, Anne Brunet, Ronald J Parchem, Rachel E Rau, Margaret A Goodell.
      During aging, blood cell production becomes dominated by a limited number of variant hematopoietic stem cell (HSC) clones. Differentiated progeny of variant HSCs are thought to mediate the detrimental effects of such clonal hematopoiesis on organismal health, but the mechanisms are poorly understood. While somatic mutations in DNA methyltransferase 3A (DNMT3A) frequently drive clonal dominance, the aging milieu also likely contributes. Here, we examined in mice the interaction between high-fat diet (HFD) and reduced DNMT3A in hematopoietic cells; strikingly, this combination led to weight gain. HFD amplified pro-inflammatory pathways and upregulated inflammation-associated genes in mutant cells along a pro-myeloid trajectory. Aberrant DNA methylation during myeloid differentiation and in response to HFD led to pro-inflammatory activation and maintenance of stemness genes. These findings suggest that reduced DNMT3A in hematopoietic cells contributes to weight gain, inflammation, and metabolic dysfunction, highlighting a role for DNMT3A loss in the development of metabolic disorders.
    Keywords:  Epigenetics; Immunology; Physiology; Stem cells research; Transcriptomics
    DOI:  https://doi.org/10.1016/j.isci.2024.109122
  16. Cell Death Discov. 2024 Mar 01. 10(1): 108
    Coculture with macrophages alters ferroptosis susceptibility of triple-negative cancer cells.
    Hiroto Konishi, Yuya Haga, Moe Okumura, Hirofumi Tsujino, Kazuma Higashisaka, Yasuo Tsutsumi.
      Various treatment options, such as molecular targeted drugs and immune checkpoint blockades, are available for patients with cancer. However, some cancer types are refractory to molecular targeted therapies or acquire drug resistance after long-term treatment. Thus, ferroptosis, a newly defined type of programmed cell death caused by the iron-dependent accumulation of lipid peroxidation, has gained attention as a novel cancer treatment strategy. Understanding cell-cell interactions in the tumor microenvironment is important for the clinical application of ferroptosis inducers. However, the effects of cell-cell interactions on ferroptosis sensitivity remain unclear. Thus, we aimed to evaluate the effects of macrophage-cancer cell interactions on ferroptosis induction. Coculture experiments showed that conditioned medium prepared from macrophages did not alter the ferroptosis sensitivity of cancer cells. By contrast, coculture via transwell, which enables cell-cell interactions through secretion, increased the sensitivity of cancer cells to ferroptosis inducers. Additionally, direct coculture increased the susceptibility of cancer cells to RSL3-induced ferroptosis. Mechanistically, coculture with macrophages upregulated the levels of intracellular ferrous ions and lipid peroxidation in cancer cells. These findings provide novel insights into the mechanisms by which cell-cell interactions influence ferroptosis induction and application of ferroptosis inducers as a cancer treatment option.
    DOI:  https://doi.org/10.1038/s41420-024-01884-w
  17. Proc Natl Acad Sci U S A. 2024 Mar 05. 121(10): e2318771121
    Mitochondrial uncoupling proteins protect human airway epithelial ciliated cells from oxidative damage.
    Akansha Jain, Bo Ram Kim, Wenjie Yu, Thomas O Moninger, Philip H Karp, Brett A Wagner, Michael J Welsh.
      Apical cilia on epithelial cells defend the lung by propelling pathogens and particulates out of the respiratory airways. Ciliated cells produce ATP that powers cilia beating by densely grouping mitochondria just beneath the apical membrane. However, this efficient localization comes at a cost because electrons leaked during oxidative phosphorylation react with molecular oxygen to form superoxide, and thus, the cluster of mitochondria creates a hotspot for oxidant production. The relatively high oxygen concentration overlying airway epithelia further intensifies the risk of generating superoxide. Thus, airway ciliated cells face a unique challenge of producing harmful levels of oxidants. However, surprisingly, highly ciliated epithelia produce less reactive oxygen species (ROS) than epithelia with few ciliated cells. Compared to other airway cell types, ciliated cells express high levels of mitochondrial uncoupling proteins, UCP2 and UCP5. These proteins decrease mitochondrial protonmotive force and thereby reduce production of ROS. As a result, lipid peroxidation, a marker of oxidant injury, decreases. However, mitochondrial uncoupling proteins exact a price for decreasing oxidant production; they decrease the fraction of mitochondrial respiration that generates ATP. These findings indicate that ciliated cells sacrifice mitochondrial efficiency in exchange for safety from damaging oxidation. Employing uncoupling proteins to prevent oxidant production, instead of relying solely on antioxidants to decrease postproduction oxidant levels, may offer an advantage for targeting a local area of intense ROS generation.
    Keywords:  lung; metabolism; motile cilia; oxygen; reactive oxygen species
    DOI:  https://doi.org/10.1073/pnas.2318771121
  18. Cell Chem Biol. 2024 Feb 26. pii: S2451-9456(24)00075-8. [Epub ahead of print]
    Metabolic rewiring and communication in cancer immunity.
    Nicole M Chapman, Hongbo Chi.
      The immune system shapes tumor development and progression. Although immunotherapy has transformed cancer treatment, its overall efficacy remains limited, underscoring the need to uncover mechanisms to improve therapeutic effects. Metabolism-associated processes, including intracellular metabolic reprogramming and intercellular metabolic crosstalk, are emerging as instructive signals for anti-tumor immunity. Here, we first summarize the roles of intracellular metabolic pathways in controlling immune cell function in the tumor microenvironment. How intercellular metabolic communication regulates anti-tumor immunity, and the impact of metabolites or nutrients on signaling events, are also discussed. We then describe how targeting metabolic pathways in tumor cells or intratumoral immune cells or via nutrient-based interventions may boost cancer immunotherapies. Finally, we conclude with discussions on profiling and functional perturbation methods of metabolic activity in intratumoral immune cells, and perspectives on future directions. Uncovering the mechanisms for metabolic rewiring and communication in the tumor microenvironment may enable development of novel cancer immunotherapies.
    DOI:  https://doi.org/10.1016/j.chembiol.2024.02.001
  19. Nat Commun. 2024 Feb 26. 15(1): 1764
    MarShie: a clearing protocol for 3D analysis of single cells throughout the bone marrow at subcellular resolution.
    Till Fabian Mertens, Alina Tabea Liebheit, Johanna Ehl, Ralf Köhler, Asylkhan Rakhymzhan, Andrew Woehler, Lukas Katthän, Gernot Ebel, Wjatscheslaw Liublin, Ana Kasapi, Antigoni Triantafyllopoulou, Tim Julius Schulz, Raluca Aura Niesner, Anja Erika Hauser.
      Analyzing immune cell interactions in the bone marrow is vital for understanding hematopoiesis and bone homeostasis. Three-dimensional analysis of the complete, intact bone marrow within the cortex of whole long bones remains a challenge, especially at subcellular resolution. We present a method that stabilizes the marrow and provides subcellular resolution of fluorescent signals throughout the murine femur, enabling identification and spatial characterization of hematopoietic and stromal cell subsets. By combining a pre-processing algorithm for stripe artifact removal with a machine-learning approach, we demonstrate reliable cell segmentation down to the deepest bone marrow regions. This reveals age-related changes in the marrow. It highlights the interaction between CX3CR1+ cells and the vascular system in homeostasis, in contrast to other myeloid cell types, and reveals their spatial characteristics after injury. The broad applicability of this method will contribute to a better understanding of bone marrow biology.
    DOI:  https://doi.org/10.1038/s41467-024-45827-6
  20. Nat Commun. 2024 Feb 26. 15(1): 1750
    S-nitrosothiol homeostasis maintained by ADH5 facilitates STING-dependent host defense against pathogens.
    Mutian Jia, Li Chai, Jie Wang, Mengge Wang, Danhui Qin, Hui Song, Yue Fu, Chunyuan Zhao, Chengjiang Gao, Jihui Jia, Wei Zhao.
      Oxidative (or respiratory) burst confers host defense against pathogens by generating reactive species, including reactive nitrogen species (RNS). The microbial infection-induced excessive RNS damages many biological molecules via S-nitrosothiol (SNO) accumulation. However, the mechanism by which the host enables innate immunity activation during oxidative burst remains largely unknown. Here, we demonstrate that S-nitrosoglutathione (GSNO), the main endogenous SNO, attenuates innate immune responses against herpes simplex virus-1 (HSV-1) and Listeria monocytogenes infections. Mechanistically, GSNO induces the S-nitrosylation of stimulator of interferon genes (STING) at Cys257, inhibiting its binding to the second messenger cyclic guanosine monophosphate-adenosine monophosphate (cGAMP). Alcohol dehydrogenase 5 (ADH5), the key enzyme that metabolizes GSNO to decrease cellular SNOs, facilitates STING activation by inhibiting S-nitrosylation. Concordantly, Adh5 deficiency show defective STING-dependent immune responses upon microbial challenge and facilitates viral replication. Thus, cellular oxidative burst-induced RNS attenuates the STING-mediated innate immune responses to microbial infection, while ADH5 licenses STING activation by maintaining cellular SNO homeostasis.
    DOI:  https://doi.org/10.1038/s41467-024-46212-z
  21. Nat Cell Biol. 2024 Mar 01.
    Targeting stromal metabolism in pancreatic ductal adenocarcinoma.
    Miao Yin, Qun-Ying Lei.
      
    DOI:  https://doi.org/10.1038/s41556-023-01330-6
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