bims-mepmim Biomed News
on Metabolites in pathological microenvironments and immunometabolism
Issue of 2023–09–03
nineteen papers selected by
Erika Mariana Palmieri, NIH/NCI Laboratory of Cancer ImmunoMetabolism
  1. Adipocytes reprogram cancer cell metabolism by diverting glucose towards glycerol-3-phosphate thereby promoting metastasis.
  2. Formate promotes invasion and metastasis in reliance on lipid metabolism.
  3. Lysosomal cystine governs ferroptosis sensitivity in cancer via cysteine stress response.
  4. A defect in mitochondrial fatty acid synthesis impairs iron metabolism and causes elevated ceramide levels.
  5. Preserved respiratory chain capacity and physiology in mice with profoundly reduced levels of mitochondrial respirasomes.
  6. A yeast vacuolar pH 'heartbeat' coordinates amino acid metabolism and the cell cycle.
  7. Acute activation of adipocyte lipolysis reveals dynamic lipid remodeling of the hepatic lipidome.
  8. SIRT3 Regulates Clearance of Apoptotic Cardiomyocytes by Deacetylating Frataxin.
  9. GPRC5C Drives Branched-Chain Amino Acid Metabolism in Leukemogenesis.
  10. Cell cycle-linked vacuolar pH dynamics regulate amino acid homeostasis and cell growth.
  11. Iron-responsive element of Divalent metal transporter 1 (Dmt1) controls Notch-mediated cell fates.
  12. p16High senescence restricts cellular plasticity during somatic cell reprogramming.
  13. Deep and fast label-free Dynamic Organellar Mapping.
  14. Identification of an alternative triglyceride biosynthesis pathway.
  15. The interplay between dietary fatty acids and gut microbiota influences host metabolism and hepatic steatosis.
  16. Coxiella co-opts the Glutathione Peroxidase 4 to protect the host cell from oxidative stress-induced cell death.
  17. Cystine/glutamate antiporter System xc- deficiency impairs insulin secretion in mice.
  18. Red blood cell eNOS: a major player in regulating cardiovascular health.
  19. Induction of mitochondrial recycling reverts age-associated decline of the hematopoietic and immune systems.
  1. Nat Metab. 2023 Aug 31.
    Adipocytes reprogram cancer cell metabolism by diverting glucose towards glycerol-3-phosphate thereby promoting metastasis.
    Abir Mukherjee, Divya Bezwada, Francesco Greco, Malu Zandbergen, Tong Shen, Chun-Yi Chiang, Medine Tasdemir, Johannes Fahrmann, Dmitry Grapov, Michael R La Frano, Hieu S Vu, Brandon Faubert, John W Newman, Liam A McDonnell, Luigi Nezi, Oliver Fiehn, Ralph J DeBerardinis, Ernst Lengyel.
      In the tumor microenvironment, adipocytes function as an alternate fuel source for cancer cells. However, whether adipocytes influence macromolecular biosynthesis in cancer cells is unknown. Here we systematically characterized the bidirectional interaction between primary human adipocytes and ovarian cancer (OvCa) cells using multi-platform metabolomics, imaging mass spectrometry, isotope tracing and gene expression analysis. We report that, in OvCa cells co-cultured with adipocytes and in metastatic tumors, a part of the glucose from glycolysis is utilized for the biosynthesis of glycerol-3-phosphate (G3P). Normoxic HIF1α protein regulates the altered flow of glucose-derived carbons in cancer cells, resulting in increased glycerophospholipids and triacylglycerol synthesis. The knockdown of HIF1α or G3P acyltransferase 3 (a regulatory enzyme of glycerophospholipid synthesis) reduced metastasis in xenograft models of OvCa. In summary, we show that, in an adipose-rich tumor microenvironment, cancer cells generate G3P as a precursor for critical membrane and signaling components, thereby promoting metastasis. Targeting biosynthetic processes specific to adipose-rich tumor microenvironments might be an effective strategy against metastasis.
    DOI:  https://doi.org/10.1038/s42255-023-00879-8
  2. Cell Rep. 2023 Aug 30. pii: S2211-1247(23)01045-8. [Epub ahead of print]42(9): 113034
    Formate promotes invasion and metastasis in reliance on lipid metabolism.
    Catherine Delbrouck, Nicole Kiweler, Oleg Chen, Vitaly I Pozdeev, Lara Haase, Laura Neises, Anaïs Oudin, Aymeric Fouquier d'Hérouël, Ruolin Shen, Lisa Schlicker, Rashi Halder, Antoine Lesur, Anne Schuster, Nadja I Lorenz, Christian Jaeger, Maureen Feucherolles, Gilles Frache, Martyna Szpakowska, Andy Chevigne, Michael W Ronellenfitsch, Etienne Moussay, Marie Piraud, Alexander Skupin, Almut Schulze, Simone P Niclou, Elisabeth Letellier, Johannes Meiser.
      Metabolic rewiring is essential for cancer onset and progression. We previously showed that one-carbon metabolism-dependent formate production often exceeds the anabolic demand of cancer cells, resulting in formate overflow. Furthermore, we showed that increased extracellular formate concentrations promote the in vitro invasiveness of glioblastoma cells. Here, we substantiate these initial observations with ex vivo and in vivo experiments. We also show that exposure to exogeneous formate can prime cancer cells toward a pro-invasive phenotype leading to increased metastasis formation in vivo. Our results suggest that the increased local formate concentration within the tumor microenvironment can be one factor to promote metastases. Additionally, we describe a mechanistic interplay between formate-dependent increased invasiveness and adaptations of lipid metabolism and matrix metalloproteinase activity. Our findings consolidate the role of formate as pro-invasive metabolite and warrant further research to better understand the interplay between formate and lipid metabolism.
    Keywords:  CP: Cancer; CP: Metabolism; cancer metastasis; formate overflow; invasion; one-carbon metabolism
    DOI:  https://doi.org/10.1016/j.celrep.2023.113034
  3. Mol Cell. 2023 Aug 24. pii: S1097-2765(23)00640-8. [Epub ahead of print]
    Lysosomal cystine governs ferroptosis sensitivity in cancer via cysteine stress response.
    Robert V Swanda, Quanquan Ji, Xincheng Wu, Jingyue Yan, Leiming Dong, Yuanhui Mao, Saori Uematsu, Yizhou Dong, Shu-Bing Qian.
      The amino acid cysteine and its oxidized dimeric form cystine are commonly believed to be synonymous in metabolic functions. Cyst(e)ine depletion not only induces amino acid response but also triggers ferroptosis, a non-apoptotic cell death. Here, we report that unlike general amino acid starvation, cyst(e)ine deprivation triggers ATF4 induction at the transcriptional level. Unexpectedly, it is the shortage of lysosomal cystine, but not the cytosolic cysteine, that elicits the adaptative ATF4 response. The lysosome-nucleus signaling pathway involves the aryl hydrocarbon receptor (AhR) that senses lysosomal cystine via the kynurenine pathway. A blockade of lysosomal cystine efflux attenuates ATF4 induction and sensitizes ferroptosis. To potentiate ferroptosis in cancer, we develop a synthetic mRNA reagent, CysRx, that converts cytosolic cysteine to lysosomal cystine. CysRx maximizes cancer cell ferroptosis and effectively suppresses tumor growth in vivo. Thus, intracellular nutrient reprogramming has the potential to induce selective ferroptosis in cancer without systematic starvation.
    Keywords:  AhR; cancer therapy; cysteine; cystine; ferroptosis; lysosome; mRNA; nutrient stress
    DOI:  https://doi.org/10.1016/j.molcel.2023.08.004
  4. Nat Metab. 2023 Aug 31.
    A defect in mitochondrial fatty acid synthesis impairs iron metabolism and causes elevated ceramide levels.
    Undiagnosed Diseases Network
      In most eukaryotic cells, fatty acid synthesis (FAS) occurs in the cytoplasm and in mitochondria. However, the relative contribution of mitochondrial FAS (mtFAS) to the cellular lipidome is not well defined. Here we show that loss of function of Drosophila mitochondrial enoyl coenzyme A reductase (Mecr), which is the enzyme required for the last step of mtFAS, causes lethality, while neuronal loss of Mecr leads to progressive neurodegeneration. We observe a defect in Fe-S cluster biogenesis and increased iron levels in flies lacking mecr, leading to elevated ceramide levels. Reducing the levels of either iron or ceramide suppresses the neurodegenerative phenotypes, indicating an interplay between ceramide and iron metabolism. Mutations in human MECR cause pediatric-onset neurodegeneration, and we show that human-derived fibroblasts display similar elevated ceramide levels and impaired iron homeostasis. In summary, this study identifies a role of mecr/MECR in ceramide and iron metabolism, providing a mechanistic link between mtFAS and neurodegeneration.
    DOI:  https://doi.org/10.1038/s42255-023-00873-0
  5. Cell Metab. 2023 Aug 22. pii: S1550-4131(23)00289-9. [Epub ahead of print]
    Preserved respiratory chain capacity and physiology in mice with profoundly reduced levels of mitochondrial respirasomes.
    Dusanka Milenkovic, Jelena Misic, Johannes F Hevler, Thibaut Molinié, Injae Chung, Ilian Atanassov, Xinping Li, Roberta Filograna, Andrea Mesaros, Arnaud Mourier, Albert J R Heck, Judy Hirst, Nils-Göran Larsson.
      The mammalian respiratory chain complexes I, III2, and IV (CI, CIII2, and CIV) are critical for cellular bioenergetics and form a stable assembly, the respirasome (CI-CIII2-CIV), that is biochemically and structurally well documented. The role of the respirasome in bioenergetics and the regulation of metabolism is subject to intense debate and is difficult to study because the individual respiratory chain complexes coexist together with high levels of respirasomes. To critically investigate the in vivo role of the respirasome, we generated homozygous knockin mice that have normal levels of respiratory chain complexes but profoundly decreased levels of respirasomes. Surprisingly, the mutant mice are healthy, with preserved respiratory chain capacity and normal exercise performance. Our findings show that high levels of respirasomes are dispensable for maintaining bioenergetics and physiology in mice but raise questions about their alternate functions, such as those relating to the regulation of protein stability and prevention of age-associated protein aggregation.
    Keywords:  OXPHOS; mitochondria; mitochondrial respirasomes; supercomplexes
    DOI:  https://doi.org/10.1016/j.cmet.2023.07.015
  6. Nat Metab. 2023 Aug 28.
    A yeast vacuolar pH 'heartbeat' coordinates amino acid metabolism and the cell cycle.
    Patricia M Kane.
      
    DOI:  https://doi.org/10.1038/s42255-023-00875-y
  7. J Lipid Res. 2023 Aug 26. pii: S0022-2275(23)00107-4. [Epub ahead of print] 100434
    Acute activation of adipocyte lipolysis reveals dynamic lipid remodeling of the hepatic lipidome.
    Sicheng Zhang, Kevin J Williams, Amandine Verlande-Ferrero, Alvin P Chan, Gino B Su, Erin E Kershaw, James E Cox, John Alan Maschek, Suzanne N Shapira, Heather R Christofk, Thomas Q de Aguiar Vallim, Selma Masri, Claudio J Villanueva.
      Adipose tissue is the site of long-term energy storage. During the fasting state, exercise, and cold exposure, the white adipose tissue mobilizes energy for peripheral tissues through lipolysis. The mobilization of lipids from white adipose tissue to the liver can lead to excess triglyceride accumulation and fatty liver disease. Although the white adipose tissue is known to release free fatty acids, a comprehensive analysis of lipids mobilized from white adipocytes in vivo has not been completed. In these studies, we provide a comprehensive quantitative analysis of the adipocyte secreted lipidome and show that there is inter-organ crosstalk with liver. Our analysis identifies multiple lipid classes released by adipocytes in response to activation of lipolysis. Time-dependent analysis of the serum lipidome, showed that free fatty acids increase within 30 minutes of β3-adrenergic receptor activation, and subsequently decrease, followed by a rise in serum triglycerides, liver triglycerides, and several ceramide species. The triglyceride composition of liver is enriched for linoleic acid despite higher concentrations of palmitate in the blood. To further validate that these findings were a specific consequence of lipolysis, we generated mice with conditional deletion of ATGL exclusively in adipocytes. This loss of in vivo adipocyte lipolysis prevented the rise in serum free fatty acids and hepatic triglycerides. Furthermore, conditioned media from adipocytes promotes lipid remodeling in hepatocytes with concomitant changes in genes/pathways mediating lipid utilization. Together these data highlight critical role of adipocyte lipolysis in inter-organ crosstalk between adipocytes and liver.
    Keywords:  Adipocytes; Adipose tissue triglyceride lipase; Ceramides; Fasting; Lipase; Lipid droplets; Lipidomics; Lipids; Liver; Triglycerides
    DOI:  https://doi.org/10.1016/j.jlr.2023.100434
  8. Circ Res. 2023 Aug 30.
    SIRT3 Regulates Clearance of Apoptotic Cardiomyocytes by Deacetylating Frataxin.
    Jing Gao, Chenglin Huang, Linghui Kong, Wugang Zhou, Mengwei Sun, Tong Wei, Weili Shen.
       BACKGROUND: Efferocytosis is an activity of macrophages that is pivotal for the resolution of inflammation in hypertension. The precise mechanism by which macrophages coordinate efferocytosis and internalize apoptotic cardiomyocytes remains unknown. The aim of this study was to determine whether SIRT3 (sirtuin-3) is required for both apoptotic cardiomyocyte engulfment and anti-inflammatory responses during efferocytosis.
    METHODS: We generated myeloid SIRT3 knockout mice and knock-in mice carrying an acetylation-defective lysine to arginine K189R mutation (FXNK189R). The mice were given Ang II (angiotensin II) infusion for 7 days. We analyzed cardiac macrophages' mitochondrial iron levels, efferocytosis activity, and phenotype both in vivo and in vitro.
    RESULTS: We showed that SIRT3 deficiency exacerbated Ang II-induced downregulation of the efferocytosis receptor MerTK (c-Mer tyrosine kinase) and proinflammatory cytokine production, accompanied by disrupted mitochondrial iron homeostasis in cardiac macrophages. Quantitative acetylome analysis revealed that SIRT3 deacetylated FXN (frataxin) at lysine 189. Ang II attenuated SIRT3 activity and enhanced the acetylation level of FXN K189. Acetylated FXN further reduced the synthesis of ISCs (iron-sulfur clusters), resulting in mitochondrial iron accumulation. Phagocytic internalization of apoptotic cardiomyocytes increased myoglobin content, and derived iron ions promoted mitochondrial iron overload and lipid peroxidation. An iron chelator deferoxamine improved the levels of MerTK and efferocytosis, thereby attenuating proinflammatory macrophage activation. FXNK189R mice showed improved macrophage efferocytosis, reduced cardiac inflammation, and suppressed cardiac fibrosis.
    CONCLUSIONS: The SIRT3-FXN axis has the potential to resolve cardiac inflammation by increasing macrophage efferocytosis and anti-inflammatory activities.
    Keywords:  c-Mer tyrosine kinase; cytokines; ions; mutation; phenotype
    DOI:  https://doi.org/10.1161/CIRCRESAHA.123.323160
  9. Blood Adv. 2023 Aug 28. pii: bloodadvances.2023010460. [Epub ahead of print]
    GPRC5C Drives Branched-Chain Amino Acid Metabolism in Leukemogenesis.
    Yu Wei Zhang, Talia Velasco-Hernandez, Julian Mess, Maria-Eleni Lalioti, Mari Carmen Romero-Mulero, Nadine Obier, Nikolaos Karantzelis, Jasmin Rettkowski, Katharina Schönberger, Noémie Karabacz, Karin Jäcklein, Tatsuya Morishima, Juan Luis Trincado, Paola Romecin, Alba Martinez-Moreno, Hitoshi Takizawa, Khalid Shoumariyeh, Simon Renders, Robert Zeiser, Heike L Pahl, François Béliveau, Josée Hébert, Bernhard Lehnertz, Guy Sauvageau, Pablo Menendez, Nina Cabezas-Wallscheid.
      Leukemia stem cells (LSCs) share numerous features with healthy hematopoietic stem cells (HSCs). G-protein coupled receptor family C group 5 member C (GPRC5C) is a regulator of HSC dormancy. However, GPRC5C functionality in acute myeloid leukemia (AML) is yet to be determined. Within patient AML cohorts, high GPRC5C levels correlated with poorer survival. Ectopic Gprc5c expression increased AML aggression through activation of NF-κB, which resulted in an altered metabolic state with increased levels of intracellular branched-chain amino acids (BCAAs). This onco-metabolic profile was reversed upon loss of Gprc5c, which also abrogated the leukemia-initiating potential. Targeting the BCAA transporter SLC7A5 with JPH203 inhibited oxidative phosphorylation and elicited strong anti-leukemia effects, specifically in mouse and patient AML samples while sparing healthy bone marrow (BM) cells. This anti-leukemia effect was strengthened in the presence of venetoclax and azacitidine. Our results indicate that the GPRC5C-NF-κB-SLC7A5-BCAAs axis is a therapeutic target that can compromise leukemia stem cell function in AML.
    DOI:  https://doi.org/10.1182/bloodadvances.2023010460
  10. Nat Metab. 2023 Aug 28.
    Cell cycle-linked vacuolar pH dynamics regulate amino acid homeostasis and cell growth.
    Voytek Okreglak, Rachel Ling, Maria Ingaramo, Nathaniel H Thayer, Alfred Millett-Sikking, Daniel E Gottschling.
      Amino acid homeostasis is critical for many cellular processes. It is well established that amino acids are compartmentalized using pH gradients generated between organelles and the cytoplasm; however, the dynamics of this partitioning has not been explored. Here we develop a highly sensitive pH reporter and find that the major amino acid storage compartment in Saccharomyces cerevisiae, the lysosome-like vacuole, alkalinizes before cell division and re-acidifies as cells divide. The vacuolar pH dynamics require the uptake of extracellular amino acids and activity of TORC1, the v-ATPase and the cycling of the vacuolar specific lipid phosphatidylinositol 3,5-bisphosphate, which is regulated by the cyclin-dependent kinase Pho85 (CDK5 in mammals). Vacuolar pH regulation enables amino acid sequestration and mobilization from the organelle, which is important for mitochondrial function, ribosome homeostasis and cell size control. Collectively, our data provide a new paradigm for the use of dynamic pH-dependent amino acid compartmentalization during cell growth/division.
    DOI:  https://doi.org/10.1038/s42255-023-00872-1
  11. FEBS J. 2023 Aug 30.
    Iron-responsive element of Divalent metal transporter 1 (Dmt1) controls Notch-mediated cell fates.
    Judith Hounjet, Arjan J Groot, Jolanda P Piepers, Onno Kranenburg, Danny A Zwijnenburg, Francesca A Rapino, Jan B Koster, Kim R Kampen, Marc A Vooijs.
      Notch receptor activation is regulated by the intramembrane protease γ-secretase, which cleaves and liberates the Notch intracellular domain (Nicd) that regulates gene transcription. While γ-secretase cleavage is necessary, we demonstrate it is insufficient for Notch activation and requires vesicular trafficking. Here, we report Divalent metal transporter 1 (Dmt1, Slc11A2) as a novel and essential regulator of Notch signalling. Dmt1-deficient cells are defective in Notch signalling and have perturbed endolysosomal trafficking and function. Dmt1 encodes for two isoforms, with and without an iron response element (ire). We show that isoform-specific silencing of Dmt1-ire and Dmt1+ire have opposite consequences on Notch-dependent cell fates in cell lines and intestinal organoids. Loss of Dmt1-ire suppresses Notch activation and promotes differentiation, whereas loss of Dmt1+ire causes Notch activation and maintains stem-progenitor cell fates. Dmt1 isoform expression correlates with Notch and Wnt signalling in Apc-deficient intestinal organoids and human colorectal cancers. Consistently Dmt1-ire silencing induces Notch-dependent differentiation in colorectal cancer cells. These data identify Dmt1 isoforms as binary switches controlling Notch cell fate decisions in normal and tumour cells.
    Keywords:  Dmt1; Notch; ROS; intracellular vesicles; iron; pH; stem cell fate and differentiation
    DOI:  https://doi.org/10.1111/febs.16946
  12. Nat Cell Biol. 2023 Aug 31.
    p16High senescence restricts cellular plasticity during somatic cell reprogramming.
    Bogdan B Grigorash, Dominic van Essen, Guixian Liang, Laurent Grosse, Alexander Emelyanov, Zhixin Kang, Alexey Korablev, Benoît Kanzler, Clement Molina, Elsa Lopez, Oleg N Demidov, Carmen Garrido, Feng Liu, Simona Saccani, Dmitry V Bulavin.
      Despite advances in four-factor (4F)-induced reprogramming (4FR) in vitro and in vivo, how 4FR interconnects with senescence remains largely under investigated. Here, using genetic and chemical approaches to manipulate senescent cells, we show that removal of p16High cells resulted in the 4FR of somatic cells into totipotent-like stem cells. These cells expressed markers of both pluripotency and the two-cell embryonic state, readily formed implantation-competent blastoids and, following morula aggregation, contributed to embryonic and extraembryonic lineages. We identified senescence-dependent regulation of nicotinamide N-methyltransferase as a key mechanism controlling the S-adenosyl-L-methionine levels during 4FR that was required for expression of the two-cell genes and acquisition of an extraembryonic potential. Importantly, a partial 4F epigenetic reprogramming in old mice was able to reverse several markers of liver aging only in conjunction with the depletion of p16High cells. Our results show that the presence of p16High senescent cells limits cell plasticity, whereas their depletion can promote a totipotent-like state and histopathological tissue rejuvenation during 4F reprogramming.
    DOI:  https://doi.org/10.1038/s41556-023-01214-9
  13. Nat Commun. 2023 Aug 29. 14(1): 5252
    Deep and fast label-free Dynamic Organellar Mapping.
    Julia P Schessner, Vincent Albrecht, Alexandra K Davies, Pavel Sinitcyn, Georg H H Borner.
      The Dynamic Organellar Maps (DOMs) approach combines cell fractionation and shotgun-proteomics for global profiling analysis of protein subcellular localization. Here, we enhance the performance of DOMs through data-independent acquisition (DIA) mass spectrometry. DIA-DOMs achieve twice the depth of our previous workflow in the same mass spectrometry runtime, and substantially improve profiling precision and reproducibility. We leverage this gain to establish flexible map formats scaling from high-throughput analyses to extra-deep coverage. Furthermore, we introduce DOM-ABC, a powerful and user-friendly open-source software tool for analyzing profiling data. We apply DIA-DOMs to capture subcellular localization changes in response to starvation and disruption of lysosomal pH in HeLa cells, which identifies a subset of Golgi proteins that cycle through endosomes. An imaging time-course reveals different cycling patterns and confirms the quantitative predictive power of our translocation analysis. DIA-DOMs offer a superior workflow for label-free spatial proteomics as a systematic phenotype discovery tool.
    DOI:  https://doi.org/10.1038/s41467-023-41000-7
  14. Nature. 2023 Aug 30.
    Identification of an alternative triglyceride biosynthesis pathway.
    Gian-Luca McLelland, Marta Lopez-Osias, Cristy R C Verzijl, Brecht D Ellenbroek, Rafaela A Oliveira, Nicolaas J Boon, Marleen Dekker, Lisa G van den Hengel, Rahmen Ali, Hans Janssen, Ji-Ying Song, Paul Krimpenfort, Tim van Zutphen, Johan W Jonker, Thijn R Brummelkamp.
      Triacylglycerols (TAGs) are the main source of stored energy in the body, providing an important substrate pool for mitochondrial beta-oxidation. Imbalances in the amount of TAGs are associated with obesity, cardiac disease and various other pathologies1,2. In humans, TAGs are synthesized from excess, coenzyme A-conjugated fatty acids by diacylglycerol O-acyltransferases (DGAT1 and DGAT2)3. In other organisms, this activity is complemented by additional enzymes4, but whether such alternative pathways exist in humans remains unknown. Here we disrupt the DGAT pathway in haploid human cells and use iterative genetics to reveal an unrelated TAG-synthesizing system composed of a protein we called DIESL (also known as TMEM68, an acyltransferase of previously unknown function) and its regulator TMX1. Mechanistically, TMX1 binds to and controls DIESL at the endoplasmic reticulum, and loss of TMX1 leads to the unconstrained formation of DIESL-dependent lipid droplets. DIESL is an autonomous TAG synthase, and expression of human DIESL in Escherichia coli endows this organism with the ability to synthesize TAG. Although both DIESL and the DGATs function as diacylglycerol acyltransferases, they contribute to the cellular TAG pool under specific conditions. Functionally, DIESL synthesizes TAG at the expense of membrane phospholipids and maintains mitochondrial function during periods of extracellular lipid starvation. In mice, DIESL deficiency impedes rapid postnatal growth and affects energy homeostasis during changes in nutrient availability. We have therefore identified an alternative TAG biosynthetic pathway driven by DIESL under potent control by TMX1.
    DOI:  https://doi.org/10.1038/s41586-023-06497-4
  15. Nat Commun. 2023 Sep 01. 14(1): 5329
    The interplay between dietary fatty acids and gut microbiota influences host metabolism and hepatic steatosis.
    Marc Schoeler, Sandrine Ellero-Simatos, Till Birkner, Jordi Mayneris-Perxachs, Lisa Olsson, Harald Brolin, Ulrike Loeber, Jamie D Kraft, Arnaud Polizzi, Marian Martí-Navas, Josep Puig, Antonio Moschetta, Alexandra Montagner, Pierre Gourdy, Christophe Heymes, Hervé Guillou, Valentina Tremaroli, José Manuel Fernández-Real, Sofia K Forslund, Remy Burcelin, Robert Caesar.
      Dietary lipids can affect metabolic health through gut microbiota-mediated mechanisms, but the influence of lipid-microbiota interaction on liver steatosis is largely unknown. We investigate the impact of dietary lipids on human gut microbiota composition and the effects of microbiota-lipid interactions on steatosis in male mice. In humans, low intake of saturated fatty acids (SFA) is associated with increased microbial diversity independent of fiber intake. In mice, poorly absorbed dietary long-chain SFA, particularly stearic acid, induce a shift in bile acid profile and improved metabolism and steatosis. These benefits are dependent on the gut microbiota, as they are transmitted by microbial transfer. Diets enriched in polyunsaturated fatty acids are protective against steatosis but have minor influence on the microbiota. In summary, we find that diets enriched in poorly absorbed long-chain SFA modulate gut microbiota profiles independent of fiber intake, and this interaction is relevant to improve metabolism and decrease liver steatosis.
    DOI:  https://doi.org/10.1038/s41467-023-41074-3
  16. Proc Natl Acad Sci U S A. 2023 Sep 05. 120(36): e2308752120
    Coxiella co-opts the Glutathione Peroxidase 4 to protect the host cell from oxidative stress-induced cell death.
    Robson K Loterio, David R Thomas, Warrison Andrade, Yi Wei Lee, Leonardo L Santos, Danielle P A Mascarenhas, Thiago M Steiner, Jéssica Chiaratto, Laura F Fielden, Leticia Lopes, Lauren E Bird, Gustavo H Goldman, Diana Stojanovski, Nichollas E Scott, Dario S Zamboni, Hayley J Newton.
      The causative agent of human Q fever, Coxiella burnetii, is highly adapted to infect alveolar macrophages by inhibiting a range of host responses to infection. Despite the clinical and biological importance of this pathogen, the challenges related to genetic manipulation of both C. burnetii and macrophages have limited our knowledge of the mechanisms by which C. burnetii subverts macrophages functions. Here, we used the related bacterium Legionella pneumophila to perform a comprehensive screen of C. burnetii effectors that interfere with innate immune responses and host death using the greater wax moth Galleria mellonella and mouse bone marrow-derived macrophages. We identified MceF (Mitochondrial Coxiella effector protein F), a C. burnetii effector protein that localizes to mitochondria and contributes to host cell survival. MceF was shown to enhance mitochondrial function, delay membrane damage, and decrease mitochondrial ROS production induced by rotenone. Mechanistically, MceF recruits the host antioxidant protein Glutathione Peroxidase 4 (GPX4) to the mitochondria. The protective functions of MceF were absent in primary macrophages lacking GPX4, while overexpression of MceF in human cells protected against oxidative stress-induced cell death. C. burnetii lacking MceF was replication competent in mammalian cells but induced higher mortality in G. mellonella, indicating that MceF modulates the host response to infection. This study reveals an important C. burnetii strategy to subvert macrophage cell death and host immunity and demonstrates that modulation of the host antioxidant system is a viable strategy to promote the success of intracellular bacteria.
    Keywords:  Coxiella burnetii; Dot/Icm effector; GPX4; Legionella pneumophila; oxidative stress
    DOI:  https://doi.org/10.1073/pnas.2308752120
  17. Diabetologia. 2023 Aug 31.
    Cystine/glutamate antiporter System xc- deficiency impairs insulin secretion in mice.
    Axel de Baat, Daniel T Meier, Leila Rachid, Adriano Fontana, Marianne Böni-Schnetzler, Marc Y Donath.
       AIMS/HYPOTHESIS: Glutamate-induced cytotoxicity (excitotoxicity) has been detected in pancreatic beta cells. The cystine/glutamate antiporter System xc- exports glutamate to the extracellular space and is therefore implicated as driving excitotoxicity. As of yet, it has not been investigated whether System xc- contributes to pancreatic islet function.
    METHODS: This study describes the implications of deficiency of System xc- on glucose metabolism in both constitutive and myeloid cell-specific knockout mice using metabolic tests and diet-induced obesity. Pancreatic islets were isolated and analysed for beta cell function, glutathione levels and ER stress.
    RESULTS: Constitutive System xc- deficiency led to an approximately threefold decrease in glutathione levels in the pancreatic islets as well as cystine shortage characterised by upregulation of Chac1. This shortage further manifested as downregulation of beta cell identity genes and a tonic increase in endoplasmic reticulum stress markers, which resulted in diminished insulin secretion both in vitro and in vivo. Myeloid-specific deletion did not have a significant impact on metabolism or islet function.
    CONCLUSIONS/INTERPRETATION: These findings suggest that System xc- is required for glutathione maintenance and insulin production in beta cells and that the system is dispensable for islet macrophage function.
    Keywords:  Beta cell; CHAC1; Cysteine; Cystine; Glutathione; Insulin; Islet; SLC7A11; System xc–
    DOI:  https://doi.org/10.1007/s00125-023-05993-6
  18. Br J Pharmacol. 2023 Sep 01.
    Red blood cell eNOS: a major player in regulating cardiovascular health.
    Anthea LoBue, Sophia K Heuser, Marla Lindemann, Junjie Li, Masudur Rahman, Malte Kelm, Johannes Stegbauer, Miriam M Cortese-Krott.
      Red blood cells (RBCs) have traditionally been seen as simple carriers of gases and nutrients in the body. One important non-canonical function of RBCs in the cardiovascular system is the regulation of nitric oxide (NO) metabolism. It was shown that RBCs can scavenge NO, transport NO metabolites, and produce NO in hypoxic conditions, thereby inducing hypoxic vasodilation. RBCs also express an endothelial nitric oxide synthase (eNOS). However, its physiological significance has been controversial for many years. This review article provides a comprehensive overview of the experimental research on RBC eNOS signaling in vivo. These data show that RBC eNOS signaling modulates intracellular NO production and NO-heme levels, as well as extracellular paracrine NO metabolite signaling, which contributes to regulating peripheral vascular resistance, blood pressure, and cardioprotection. Additionally, this article explores the potential intracellular molecular mechanisms and the implications of RBC eNOS in cardiovascular health and disease.
    DOI:  https://doi.org/10.1111/bph.16230
  19. Nat Aging. 2023 Aug 31.
    Induction of mitochondrial recycling reverts age-associated decline of the hematopoietic and immune systems.
    Mukul Girotra, Yi-Hsuan Chiang, Melanie Charmoy, Pierpaolo Ginefra, Helen Carrasco Hope, Charles Bataclan, Yi-Ru Yu, Frederica Schyrr, Fabien Franco, Hartmut Geiger, Stephane Cherix, Ping-Chih Ho, Olaia Naveiras, Johan Auwerx, Werner Held, Nicola Vannini.
      Aging compromises hematopoietic and immune system functions, making older adults especially susceptible to hematopoietic failure, infections and tumor development, and thus representing an important medical target for a broad range of diseases. During aging, hematopoietic stem cells (HSCs) lose their blood reconstitution capability and commit preferentially toward the myeloid lineage (myeloid bias)1,2. These processes are accompanied by an aberrant accumulation of mitochondria in HSCs3. The administration of the mitochondrial modulator urolithin A corrects mitochondrial function in HSCs and completely restores the blood reconstitution capability of 'old' HSCs. Moreover, urolithin A-supplemented food restores lymphoid compartments, boosts HSC function and improves the immune response against viral infection in old mice. Altogether our results demonstrate that boosting mitochondrial recycling reverts the aging phenotype in the hematopoietic and immune systems.
    DOI:  https://doi.org/10.1038/s43587-023-00473-3
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