bims-mepmim Biomed News
on Metabolites in pathological microenvironments and immunometabolism
Issue of 2024–07–28
thirty-six papers selected by
Erika Mariana Palmieri, NIH/NCI Laboratory of Cancer ImmunoMetabolism
  1. Metabolic Regulation in the Induction of Trained Immunity.
  2. Citrate metabolism controls the senescent microenvironment via the remodeling of pro-inflammatory enhancers.
  3. Atf3-mediated metabolic reprogramming in hepatic macrophage orchestrates metabolic dysfunction-associated steatohepatitis.
  4. The ATP-exporting channel Pannexin 1 promotes CD8+ T cell effector and memory responses.
  5. 100 years of the Warburg effect: A cancer metabolism endeavor.
  6. Complex roles for mitochondrial complexes in microglia.
  7. Metastatic breast cancer cells are metabolically reprogrammed to maintain redox homeostasis during metastasis.
  8. Metabolic Messengers: itaconate.
  9. Decrease in UCP1 by sustained high lipid promotes NK cell necroptosis to exacerbate nonalcoholic liver fibrosis.
  10. Challenges of Spatially Resolved Metabolism in Cancer Research.
  11. A small intestinal bile acid modulates the gut microbiome to improve host metabolic phenotypes following bariatric surgery.
  12. NADPH oxidase in B cells and macrophages protects against murine lupus by regulation of TLR7.
  13. Senescent cancer-associated fibroblasts in pancreatic adenocarcinoma restrict CD8+ T cell activation and limit responsiveness to immunotherapy in mice.
  14. Enhancing mitochondrial pyruvate metabolism ameliorates ischemic reperfusion injury in the heart.
  15. Investigation of a fluorescent reporter microenvironment niche labeling strategy in experimental brain metastasis.
  16. m6A-Mediated Induction of 7-Dehydrocholesterol Reductase Stimulates Cholesterol Synthesis and cAMP Signaling to Promote Bladder Cancer Metastasis.
  17. Microglia mitochondrial complex I deficiency during development induces glial dysfunction and early lethality.
  18. Spatial lipidomics reveals zone-specific hepatic lipid alteration and remodeling in Metabolic dysfunction-associated steatohepatitis.
  19. An NAD+-dependent metabolic checkpoint regulates hematopoietic stem cell activation and aging.
  20. Mitochondrial respiration in microglia is essential for response to demyelinating injury but not proliferation.
  21. Ammonia transporter RhBG initiates downstream signaling and functional responses by activating NFκB.
  22. Signaling by Neutrophil G Protein-Coupled Receptors that Regulate the Release of Superoxide Anions.
  23. Alterations of ceramide synthesis induce PD-L1 internalization and signaling to regulate tumor metastasis and immunotherapy response.
  24. Cross-species single-cell RNA sequencing reveals divergent phenotypes and activation states of adaptive immunity in human carotid and experimental murine atherosclerosis.
  25. Ferroptosis is a targetable detrimental factor in metabolic dysfunction-associated steatotic liver disease.
  26. Cardiolipin remodeling maintains the inner mitochondrial membrane in cells with saturated lipidomes.
  27. Non-invasive mapping of brown adipose tissue activity with magnetic resonance imaging.
  28. Glutathione synthesis in the mouse liver supports lipid abundance through NRF2 repression.
  29. The TCR assigns naive T cells to a preferred lymph node.
  30. Timing and location dictate monocyte fate and their transition to tumor-associated macrophages.
  31. Lysozyme 1 Inflamed CCR2+ Macrophages Promote Obesity-Induced Cardiac Dysfunction.
  32. LACTB suppresses liver cancer progression through regulation of ferroptosis.
  33. ALDH5A1/miR-210 axis plays a key role in reprogramming cellular metabolism and has a significant correlation with glioblastoma patient survival.
  34. Protocol for the characterization of the pancreatic tumor microenvironment using organoid-derived mouse models and single-nuclei RNA sequencing.
  35. Targeted degradation of extracellular mitochondrial aspartyl-tRNA synthetase modulates immune responses.
  36. Sweetening mitochondria: Hexokinase shields mitochondria from fission when glucose is low.
  1. Semin Immunopathol. 2024 Jul 25. 46(3-4): 7
    Metabolic Regulation in the Induction of Trained Immunity.
    Anaisa V Ferreira, Jorge Domínguez-Andrés, Laura M Merlo Pich, Leo A B Joosten, Mihai G Netea.
      The innate immune system exhibits features of memory, termed trained immunity, which promote faster and more robust responsiveness to heterologous challenges. Innate immune memory is sustained through epigenetic modifications, affecting gene accessibility, and promoting a tailored gene transcription for an enhanced immune response. Alterations in the epigenetic landscape are intertwined with metabolic rewiring. Here, we review the metabolic pathways that underscore the induction and maintenance of trained immunity, including glycolysis, oxidative phosphorylation, the tricarboxylic acid cycle, and amino acid and lipid metabolism. The intricate interplay of these pathways is pivotal for establishing innate immune memory in distinct cellular compartments. We explore in particular the case of resident lung alveolar macrophages. We propose that leveraging the memory of the innate immune system may present therapeutic potential. Specifically, targeting the metabolic programs of innate immune cells is an emerging strategy for clinical interventions, either to boost immune responses in immunosuppressed conditions or to mitigate maladaptive activation in hyperinflammatory diseases.
    Keywords:  Epigenetics; Metabolism; Therapy; Trained immunity
    DOI:  https://doi.org/10.1007/s00281-024-01015-8
  2. Cell Rep. 2024 Jul 17. pii: S2211-1247(24)00825-8. [Epub ahead of print] 114496
    Citrate metabolism controls the senescent microenvironment via the remodeling of pro-inflammatory enhancers.
    Kan Etoh, Hirotaka Araki, Tomoaki Koga, Yuko Hino, Kanji Kuribayashi, Shinjiro Hino, Mitsuyoshi Nakao.
      The senescent microenvironment and aged cells per se contribute to tissue remodeling, chronic inflammation, and age-associated dysfunction. However, the metabolic and epigenomic bases of the senescence-associated secretory phenotype (SASP) remain largely unknown. Here, we show that ATP-citrate lyase (ACLY), a key enzyme in acetyl-coenzyme A (CoA) synthesis, is essential for the pro-inflammatory SASP, independent of persistent growth arrest in senescent cells. Citrate-derived acetyl-CoA facilitates the action of SASP gene enhancers. ACLY-dependent de novo enhancers augment the recruitment of the chromatin reader BRD4, which causes SASP activation. Consistently, specific inhibitions of the ACLY-BRD4 axis suppress the STAT1-mediated interferon response, creating the pro-inflammatory microenvironment in senescent cells and tissues. Our results demonstrate that ACLY-dependent citrate metabolism represents a selective target for controlling SASP designed to promote healthy aging.
    Keywords:  ACLY; CP: Cell biology; CP: Metabolism; H3K27 acetylation; SASP; acetyl-CoA; citrate metabolism; senescence; senostatics
    DOI:  https://doi.org/10.1016/j.celrep.2024.114496
  3. Sci Adv. 2024 Jul 26. 10(30): eado3141
    Atf3-mediated metabolic reprogramming in hepatic macrophage orchestrates metabolic dysfunction-associated steatohepatitis.
    Shuwei Hu, Rui Li, Dongxu Gong, Pei Hu, Jitu Xu, Yingjie Ai, Xiaojie Zhao, Chencheng Hu, Minghuan Xu, Chenxi Liu, Shuyu Chen, Jie Fan, Zhonghua Zhao, Zhigang Zhang, Huijuan Wu, Yanyong Xu.
      Metabolic dysfunction-associated steatohepatitis (MASH) is regulated by complex interplay between the macrophages and surrounding cells in the liver. Here, we show that Atf3 regulates glucose-fatty acid cycle in macrophages attenuates hepatocyte steatosis, and fibrogenesis in hepatic stellate cells (HSCs). Overexpression of Atf3 in macrophages protects against the development of MASH in Western diet-fed mice, whereas Atf3 ablation has the opposite effect. Mechanistically, Atf3 improves the reduction of fatty acid oxidation induced by glucose via forkhead box O1 (FoxO1) and Cd36. Atf3 inhibits FoxO1 activity via blocking Hdac1-mediated FoxO1 deacetylation at K242, K245, and K262 and increases Zdhhc4/5-mediated CD36 palmitoylation at C3, C7, C464, and C466; furthermore, macrophage Atf3 decreases hepatocytes lipogenesis and HSCs activation via retinol binding protein 4 (Rbp4). Anti-Rbp4 can prevent MASH progression that is induced by Atf3 deficiency in macrophages. This study identifies Atf3 as a regulator of glucose-fatty acid cycle. Targeting macrophage Atf3 or Rbp4 may be a plausible therapeutic strategy for MASH.
    DOI:  https://doi.org/10.1126/sciadv.ado3141
  4. iScience. 2024 Jul 19. 27(7): 110290
    The ATP-exporting channel Pannexin 1 promotes CD8+ T cell effector and memory responses.
    Trupti Vardam-Kaur, Alma Banuelos, Maria Gabaldon-Parish, Bruna Gois Macedo, Caio Loureiro Salgado, Kelsey Marie Wanhainen, Maggie Hanqi Zhou, Sarah van Dijk, Igor Santiago-Carvalho, Angad S Beniwal, Chloe L Leff, Changwei Peng, Nhan L Tran, Stephen C Jameson, Henrique Borges da Silva.
      Sensing of extracellular ATP (eATP) controls CD8+ T cell function. Their accumulation can occur through export by specialized molecules, such as the release channel Pannexin 1 (Panx1). Whether Panx1 controls CD8+ T cell immune responses in vivo, however, has not been previously addressed. Here, we report that T-cell-specific Panx1 is needed for CD8+ T cell responses to viral infections and cancer. We found that CD8-specific Panx1 promotes both effector and memory CD8+ T cell responses. Panx1 favors initial effector CD8+ T cell activation through extracellular ATP (eATP) export and subsequent P2RX4 activation, which helps promote full effector differentiation through extracellular lactate accumulation and its subsequent recycling. In contrast, Panx1 promotes memory CD8+ T cell survival primarily through ATP export and subsequent P2RX7 engagement, leading to improved mitochondrial metabolism. In summary, Panx1-mediated eATP export regulates effector and memory CD8+ T cells through distinct purinergic receptors and different metabolic and signaling pathways.
    Keywords:  Biochemistry; Biological sciences; Immune response; Immune system; Immunology; Natural sciences
    DOI:  https://doi.org/10.1016/j.isci.2024.110290
  5. Cell. 2024 Jul 25. pii: S0092-8674(24)00700-1. [Epub ahead of print]187(15): 3824-3828
    100 years of the Warburg effect: A cancer metabolism endeavor.
    Sarah-Maria Fendt.
      If you are a scientist and you only know one thing about tumor metabolism, it's likely the Warburg effect. But who was Otto Warburg, and how did his discoveries regarding the metabolism of tumors shape our current thinking about the metabolic needs of cancer cells?
    DOI:  https://doi.org/10.1016/j.cell.2024.06.026
  6. Nat Metab. 2024 Jul 24.
    Complex roles for mitochondrial complexes in microglia.
    Rosa C Paolicelli, Stefano Pluchino.
      
    DOI:  https://doi.org/10.1038/s42255-024-01095-8
  7. Redox Biol. 2024 Jul 20. pii: S2213-2317(24)00254-4. [Epub ahead of print]75 103276
    Metastatic breast cancer cells are metabolically reprogrammed to maintain redox homeostasis during metastasis.
    Marco Biondini, Camille Lehuédé, Sébastien Tabariès, Matthew G Annis, Alain Pacis, Eric H Ma, Christine Tam, Brian E Hsu, Yannick Audet-Delage, Afnan Abu-Thuraia, Charlotte Girondel, Valerie Sabourin, Stephanie P Totten, Mariana de Sá Tavares Russo, Gaëlle Bridon, Daina Avizonis, Marie-Christine Guiot, Julie St-Pierre, Josie Ursini-Siegel, Russell Jones, Peter M Siegel.
      Metabolic rewiring is essential for tumor growth and progression to metastatic disease, yet little is known regarding how cancer cells modify their acquired metabolic programs in response to different metastatic microenvironments. We have previously shown that liver-metastatic breast cancer cells adopt an intrinsic metabolic program characterized by increased HIF-1α activity and dependence on glycolysis. Here, we confirm by in vivo stable isotope tracing analysis (SITA) that liver-metastatic breast cancer cells retain a glycolytic profile when grown as mammary tumors or liver metastases. However, hepatic metastases exhibit unique metabolic adaptations including elevated expression of genes involved in glutathione (GSH) biosynthesis and reactive oxygen species (ROS) detoxification when compared to mammary tumors. Accordingly, breast-cancer-liver-metastases exhibited enhanced de novo GSH synthesis. Confirming their increased capacity to mitigate ROS-mediated damage, liver metastases display reduced levels of 8-Oxo-2'-deoxyguanosine. Depletion of the catalytic subunit of the rate-limiting enzyme in glutathione biosynthesis, glutamate-cysteine ligase (GCLC), strongly reduced the capacity of breast cancer cells to form liver metastases, supporting the importance of these distinct metabolic adaptations. Loss of GCLC also affected the early steps of the metastatic cascade, leading to decreased numbers of circulating tumor cells (CTCs) and impaired metastasis to the liver and the lungs. Altogether, our results indicate that GSH metabolism could be targeted to prevent the dissemination of breast cancer cells.
    Keywords:  Breast cancer; GCLC; Glutathione; Glycolysis; HIF-1α; Liver metastasis; Metabolism; Oxidative stress
    DOI:  https://doi.org/10.1016/j.redox.2024.103276
  8. Nat Metab. 2024 Jul 26.
    Metabolic Messengers: itaconate.
    A F McGettrick, L A Bourner, F C Dorsey, L A J O'Neill.
      The metabolite itaconate has emerged as an important immunoregulator with roles in antibacterial defence, inhibition of inflammation and, more recently, as an inhibitory factor in obesity. Itaconate is one of the most upregulated metabolites in inflammatory macrophages. It is produced owing to the disturbance of the tricarboxylic acid cycle and the diversion of aconitate to itaconate via the enzyme aconitate decarboxylase 1. In immunology, initial studies concentrated on the role of itaconate in inflammatory macrophages where it was shown to be inhibitory, but this has expanded as the impact of itaconate on other cell types is starting to emerge. This review focuses on itaconate as a key immunoregulatory metabolite and describes its diverse mechanisms of action and its many impacts on the immune and inflammatory responses and in cancer. We also examine the clinical relevance of this immunometabolite and its therapeutic potential for immune and inflammatory diseases.
    DOI:  https://doi.org/10.1038/s42255-024-01092-x
  9. Cell Death Dis. 2024 Jul 20. 15(7): 518
    Decrease in UCP1 by sustained high lipid promotes NK cell necroptosis to exacerbate nonalcoholic liver fibrosis.
    Min Gu, Yu Zhang, Zhijie Lin, Xiangyu Hu, Yaqin Zhu, Weiming Xiao, Xiaoqin Jia, Weiwei Chen, Guotao Lu, Weijuan Gong.
      Uncoupling protein 1 (UCP1) catalyzes the leak of protons across the mitochondrial inner membrane for thermogenesis. Compromised NK cell activity is involved in the occurrence of nonalcoholic liver fibrosis. Here, decreased UCP1 in NK cells was identified in patients with advanced nonalcoholic fatty liver disease. Although no obvious changes were observed in the NK cells of physiologic UCP1-/- mice (8-10 weeks old), impaired NK cell bioactivity was shown in methionine-choline-diet (MCD)-fed UCP1-/- mice and involved in the acerbation of nonalcoholic steatohepatitis (NASH) progress to liver fibrosis. Moreover, UCP1-deficient NK cells were responsible for the aggravation of liver fibrosis, as confirmed in MCD-fed UCP1flox/flox-NCR1cre mice. Acerbation of liver fibrosis was also seen in wild-type mice when their endogenous NK cells were replaced with UCP1-/- NK cells. Transcriptions of mitophagy-associated molecules in UCP1-/- NK cells were enhanced according to RNA-seq. Electron microscopic results showed mitochondrial injuries and autophagic vesicles in MCD-fed NKWT cells, PA-treated NKWT cells, or physiologic NKKO cells. However, the co-existence of UCP1 deficiency and high lipid can synergistically induce NK cell necroptosis via DRP1S616 accompanied with reduced mitophagy. Finally, The UCP1 in NK cells was downregulated when treated by sustained high PA (600 μM) via the PPARγ/ATF2 axis. Thus, persistent high-lipid treatment not only decreases UCP1 expression but also combines with reduced UCP1 to promote NK cell necroptosis, and it is involved in NASH progression to fibrosis.
    DOI:  https://doi.org/10.1038/s41419-024-06910-4
  10. Metabolites. 2024 Jul 11. pii: 383. [Epub ahead of print]14(7):
    Challenges of Spatially Resolved Metabolism in Cancer Research.
    Andrew N Lane, Richard M Higashi, Teresa W-M Fan.
      Stable isotope-resolved metabolomics comprises a critical set of technologies that can be applied to a wide variety of systems, from isolated cells to whole organisms, to define metabolic pathway usage and responses to perturbations such as drugs or mutations, as well as providing the basis for flux analysis. As the diversity of stable isotope-enriched compounds is very high, and with newer approaches to multiplexing, the coverage of metabolism is now very extensive. However, as the complexity of the model increases, including more kinds of interacting cell types and interorgan communication, the analytical complexity also increases. Further, as studies move further into spatially resolved biology, new technical problems have to be overcome owing to the small number of analytes present in the confines of a single cell or cell compartment. Here, we review the overall goals and solutions made possible by stable isotope tracing and their applications to models of increasing complexity. Finally, we discuss progress and outstanding difficulties in high-resolution spatially resolved tracer-based metabolic studies.
    Keywords:  cancer metabolism; experimental models; spatially resolved metabolism; stable isotope-resolved metabolomics
    DOI:  https://doi.org/10.3390/metabo14070383
  11. Cell Host Microbe. 2024 Jul 17. pii: S1931-3128(24)00232-4. [Epub ahead of print]
    A small intestinal bile acid modulates the gut microbiome to improve host metabolic phenotypes following bariatric surgery.
    Yingjia Chen, Snehal N Chaudhari, David A Harris, Cullen F Roberts, Andrei Moscalu, Vasundhara Mathur, Lei Zhao, Ali Tavakkoli, A Sloan Devlin, Eric G Sheu.
      Bariatric surgical procedures such as sleeve gastrectomy (SG) provide effective type 2 diabetes (T2D) remission in human patients. Previous work demonstrated that gastrointestinal levels of the bacterial metabolite lithocholic acid (LCA) are decreased after SG in mice and humans. Here, we show that LCA worsens glucose tolerance and impairs whole-body metabolism. We also show that taurodeoxycholic acid (TDCA), which is the only bile acid whose concentration increases in the murine small intestine post-SG, suppresses the bacterial bile acid-inducible (bai) operon and production of LCA both in vitro and in vivo. Treatment of diet-induced obese mice with TDCA reduces LCA levels and leads to microbiome-dependent improvements in glucose handling. Moreover, TDCA abundance is decreased in small intestinal tissue from T2D patients. This work reveals that TDCA is an endogenous inhibitor of LCA production and suggests that TDCA may contribute to the glucoregulatory effects of bariatric surgery.
    Keywords:  bariatric surgery; bile acid-inducible operon; bile acids; lithocholic acid; metabolism; small intestine; taurodeoxycholic acid; type 2 diabetes
    DOI:  https://doi.org/10.1016/j.chom.2024.06.014
  12. JCI Insight. 2024 Jul 23. pii: e178563. [Epub ahead of print]
    NADPH oxidase in B cells and macrophages protects against murine lupus by regulation of TLR7.
    Rachael A Gordon, Haylee A Cosgrove, Anthony Marinov, Sebastien Gingras, Jeremy S Tilstra, Allison M Campbell, Sheldon I Bastacky, Michael Kashgarian, Andras Perl, Kevin M Nickerson, Mark J Shlomchik.
      Loss of NADPH oxidase (NOX2) exacerbates systemic lupus erythematosus (SLE) in mice and humans, but the mechanisms underlying this effect remain unclear. To identify the cell lineages in which NOX2 deficiency drives SLE, we employed conditional knockout (KO) and chimera approaches to delete Cybb in several hematopoietic cell lineages of MRL.Faslpr lupus-prone mice. Deletion of Cybb in macrophages/monocytes exacerbated lupus nephritis, though not to the degree observed in the Cybb global KOs. Unexpectedly, the absence of Cybb in B cells resulted in profound glomerulonephritis and interstitial nephritis, rivaling that seen with global deletion. Further, we identified that NOX2 is a key regulator of TLR7, a driver of SLE pathology, both globally and specifically in B cells. This is mediated in part through suppression of TLR7-mediated NF-kB signaling in B cells. Thus, NOX2's immunomodulatory effect in SLE is orchestrated not only by its function in the myeloid compartment, but through a pivotal role in B cells by selectively inhibiting TLR7 signaling.
    Keywords:  Autoimmunity; Lupus
    DOI:  https://doi.org/10.1172/jci.insight.178563
  13. Nat Commun. 2024 Jul 22. 15(1): 6162
    Senescent cancer-associated fibroblasts in pancreatic adenocarcinoma restrict CD8+ T cell activation and limit responsiveness to immunotherapy in mice.
    Benjamin Assouline, Rachel Kahn, Lutfi Hodali, Reba Condiotti, Yarden Engel, Ela Elyada, Tzlil Mordechai-Heyn, Jason R Pitarresi, Dikla Atias, Eliana Steinberg, Tirza Bidany-Mizrahi, Esther Forkosh, Lior H Katz, Ofra Benny, Talia Golan, Matan Hofree, Sheila A Stewart, Karine A Atlan, Gideon Zamir, Ben Z Stanger, Michael Berger, Ittai Ben-Porath.
      Senescent cells within tumors and their stroma exert complex pro- and anti-tumorigenic functions. However, the identities and traits of these cells, and the potential for improving cancer therapy through their targeting, remain poorly characterized. Here, we identify a senescent subset within previously-defined cancer-associated fibroblasts (CAFs) in pancreatic ductal adenocarcinomas (PDAC) and in premalignant lesions in mice and humans. Senescent CAFs isolated from mouse and humans expressed elevated levels of immune-regulatory genes. Depletion of senescent CAFs, either genetically or using the Bcl-2 inhibitor ABT-199 (venetoclax), increased the proportion of activated CD8+ T cells in mouse pancreatic carcinomas, whereas induction of CAF senescence had the opposite effect. Combining ABT-199 with an immune checkpoint therapy regimen significantly reduced mouse tumor burden. These results indicate that senescent CAFs in PDAC stroma limit the numbers of activated cytotoxic CD8+ T cells, and suggest that their targeted elimination through senolytic treatment may enhance immunotherapy.
    DOI:  https://doi.org/10.1038/s41467-024-50441-7
  14. JCI Insight. 2024 Jul 25. pii: e180906. [Epub ahead of print]
    Enhancing mitochondrial pyruvate metabolism ameliorates ischemic reperfusion injury in the heart.
    Joseph R Visker, Ahmad A Cluntun, Jesse N Velasco-Silva, David R Eberhardt, Luis Cedeno-Rosario, Thirupura S Shankar, Rana Hamouche, Jing Ling, Hyoin Kwak, J Yanni Hillas, Ian Aist, Eleni Tseliou, Sutip Navankasattusas, Dipayan Chaudhuri, Gregory S Ducker, Stavros G Drakos, Jared Rutter.
      The clinical therapy for treating acute myocardial infarction is primary percutaneous coronary intervention (PPCI). PPCI is effective at reperfusing the heart, however the rapid re-introduction of blood can cause ischemia-reperfusion (I/R). Reperfusion injury is responsible for up to half of the final myocardial damage, but there are no pharmacological interventions to reduce I/R. We previously demonstrated that inhibiting monocarboxylate transporter 4 (MCT4) and re-directing pyruvate towards oxidation can blunt hypertrophy. We hypothesized this pathway might be important during I/R. Here, we establish that the pyruvate-lactate axis plays a role in determining myocardial salvage following injury. Post-I/R, the mitochondrial pyruvate carrier (MPC), required for pyruvate oxidation, is upregulated in the surviving myocardium. In cardiomyocytes lacking the MPC, there was increased cell death and less salvage after I/R, which was associated with an upregulation of MCT4. To determine the importance of pyruvate oxidation, we inhibited MCT4 with a small-molecule drug (VB124) at reperfusion. This strategy normalized reactive oxygen species (ROS), mitochondrial membrane potential (∆Ψ), and Ca2+, increased pyruvate entry to TCA cycle, increased oxygen consumption, improved myocardial salvage and functional outcomes following I/R. Our data suggests normalizing pyruvate-lactate metabolism by inhibiting MCT4 is a promising therapy to mitigate I/R injury.
    Keywords:  Carbohydrate metabolism; Cardiology; Cardiovascular disease; Metabolism; Mitochondria
    DOI:  https://doi.org/10.1172/jci.insight.180906
  15. iScience. 2024 Jul 19. 27(7): 110284
    Investigation of a fluorescent reporter microenvironment niche labeling strategy in experimental brain metastasis.
    Matteo Massara, Bastien Dolfi, Vladimir Wischnewski, Emma Nolan, Werner Held, Ilaria Malanchi, Johanna A Joyce.
      Brain metastases are the most common brain tumors in patients and are associated with poor prognosis. Investigating the colonization and outgrowth of brain metastases is challenging given the complexity of the organ, tissue sampling difficulty, and limited experimental models. To address this challenge, we employed a strategy to analyze the metastatic niche in established lesions, based on the release of a cell-penetrating mCherry tag from labeled tumor cells to neighboring niche cells, using different brain metastasis mouse models. We found that CD206+ macrophages were the most abundant cells taking up the mCherry label in established metastases. In vitro and in vivo experiments demonstrated that macrophages uptake and retain the canonical form of mCherry, even without the cell-penetrating portion of the tag. These results identify a specific macrophage subset in the brain that retains tumor-supplied fluorescent molecules, thereby complicating the long-term use of niche labeling strategies in established experimental brain metastasis.
    Keywords:  Cancer; Cell biology; Microenvironment
    DOI:  https://doi.org/10.1016/j.isci.2024.110284
  16. Cancer Res. 2024 Jul 24.
    m6A-Mediated Induction of 7-Dehydrocholesterol Reductase Stimulates Cholesterol Synthesis and cAMP Signaling to Promote Bladder Cancer Metastasis.
    Youmiao Zeng, Yongbo Luo, Keyuan Zhao, Sheng Liu, Kaiwen Wu, Yudong Wu, Kaixuan Du, Wenbang Pan, Yiheng Dai, Yuanhao Liu, Mengda Ren, Fengyan Tian, Lijie Zhou, Chaohui Gu.
      Dysregulation of cholesterol homeostasis occurs in multiple types of tumors and promotes cancer progression. Investigating the specific processes that induce abnormal cholesterol metabolism could identify therapeutic targets to improve cancer treatment. In this investigation, we observed upregulation of 7-dehydrocholesterol reductase (DHCR7), a vital enzyme involved in the synthesis of cholesterol, within bladder cancer (BC) tissues in comparison to normal tissues, which was correlated with increased BC metastasis. Increased expression of DHCR7 in BC was attributed to decreased mRNA degradation mediated by YTHDF2. Loss or inhibition of DHCR7 reduced BC cell invasion in vitro and metastasis in vivo. Mechanistically, DHCR7 promoted BC metastasis by activating the cAMP/PKA/FAK pathway. Specifically, DHCR7 increased cAMP levels by elevating cholesterol content in lipid rafts, thereby facilitating the transduction of signaling pathways mediated by cAMP receptors. DHCR7 additionally enhanced the cAMP signaling pathway by reducing the concentration of 7-DHC and promoting the transcription of the G protein-coupled receptor GIPR. Overall, these findings demonstrate that DHCR7 plays an important role in BC invasion and metastasis by modulating cholesterol synthesis and cAMP signaling. Furthermore, inhibition of DHCR7 shows promise as a viable therapeutic strategy for suppressing BC invasion and metastasis.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-23-3703
  17. Nat Metab. 2024 Jul 24.
    Microglia mitochondrial complex I deficiency during development induces glial dysfunction and early lethality.
    Bella Mora-Romero, Nicolas Capelo-Carrasco, Juan J Pérez-Moreno, María I Alvarez-Vergara, Laura Trujillo-Estrada, Carmen Romero-Molina, Emilio Martinez-Marquez, Noelia Morano-Catalan, Marisa Vizuete, Jose Lopez-Barneo, Jose L Nieto-Gonzalez, Pablo Garcia-Junco-Clemente, Javier Vitorica, Antonia Gutierrez, David Macias, Alicia E Rosales-Nieves, Alberto Pascual.
      Primary mitochondrial diseases (PMDs) are associated with pediatric neurological disorders and are traditionally related to oxidative phosphorylation system (OXPHOS) defects in neurons. Interestingly, both PMD mouse models and patients with PMD show gliosis, and pharmacological depletion of microglia, the innate immune cells of the brain, ameliorates multiple symptoms in a mouse model. Given that microglia activation correlates with the expression of OXPHOS genes, we studied whether OXPHOS deficits in microglia may contribute to PMDs. We first observed that the metabolic rewiring associated with microglia stimulation in vitro (via IL-33 or TAU treatment) was partially changed by complex I (CI) inhibition (via rotenone treatment). In vivo, we generated a mouse model deficient for CI activity in microglia (MGcCI). MGcCI microglia showed metabolic rewiring and gradual transcriptional activation, which led to hypertrophy and dysfunction in juvenile (1-month-old) and adult (3-month-old) stages, respectively. MGcCI mice presented widespread reactive astrocytes, a decrease of synaptic markers accompanied by an increased number of parvalbumin neurons, a behavioral deficit characterized by prolonged periods of immobility, loss of weight and premature death that was partially rescued by pharmacologic depletion of microglia. Our data demonstrate that microglia development depends on mitochondrial CI and suggest a direct microglial contribution to PMDs.
    DOI:  https://doi.org/10.1038/s42255-024-01081-0
  18. J Lipid Res. 2024 Jul 18. pii: S0022-2275(24)00104-4. [Epub ahead of print] 100599
    Spatial lipidomics reveals zone-specific hepatic lipid alteration and remodeling in Metabolic dysfunction-associated steatohepatitis.
    Patcharamon Seubnooch, Matteo Montani, Jean-Francois Dufour, Mojgan Masoodi.
      Alteration in lipid metabolism plays a pivotal role in developing metabolic dysfunction-associated steatohepatitis (MASH). However, our understanding of alteration in lipid metabolism across liver zonation in MASH remains limited. Within this study, we investigated MASH-associated zone-specific lipid metabolism in a diet and chemical-induced MASH mouse model. Spatial lipidomics using mass spectrometry imaging in a MASH mouse model revealed 130 lipids from various classes altered across liver zonation and exhibited zone-specific lipid signatures in MASH. Triacylglycerols, diacylglycerols, sphingolipids and ceramides showed distinct zone-specific changes and re-distribution from pericentral to periportal localisation in MASH. Saturated and monounsaturated fatty acids (FA) were the primary FA composition of increased lipids in MASH, while polyunsaturated FAs were the major FA composition of decreased lipids. We observed elevated fibrosis in the periportal region, which could be the result of observed metabolic alteration across zonation. Our study provides valuable insights into zone-specific hepatic lipid metabolism and demonstrates the significance of spatial lipidomics in understanding liver lipid metabolism. Identifying unique lipid distribution patterns may offer valuable insights into the pathophysiology of MASH and facilitate the discovery of diagnostic markers associated with liver zonation.
    Keywords:  Hepatic lipid zonation; Lipid distribution; Liver lipid metabolism; Liver zonation; MASH; MASLD; NAFLD; NASH; Steatotic liver disease
    DOI:  https://doi.org/10.1016/j.jlr.2024.100599
  19. Nat Aging. 2024 Jul 23.
    An NAD+-dependent metabolic checkpoint regulates hematopoietic stem cell activation and aging.
    Zehan Song, Sang Hee Park, Wei-Chieh Mu, Yufan Feng, Chih-Ling Wang, Yifei Wang, Marine Barthez, Ayane Maruichi, Jiayue Guo, Fanghan Yang, Anita Wong Lin, Kartoosh Heydari, Claudia C S Chini, Eduardo N Chini, Cholsoon Jang, Danica Chen.
      How hematopoietic stem cells (HSCs) maintain metabolic homeostasis to support tissue repair and regeneration throughout the lifespan is elusive. Here, we show that CD38, an NAD+-dependent metabolic enzyme, promotes HSC proliferation by inducing mitochondrial Ca2+ influx and mitochondrial metabolism in young mice. Conversely, aberrant CD38 upregulation during aging is a driver of HSC deterioration in aged mice due to dysregulated NAD+ metabolism and compromised mitochondrial stress management. The mitochondrial calcium uniporter, a mediator of mitochondrial Ca2+ influx, also supports HSC proliferation in young mice yet drives HSC decline in aged mice. Pharmacological inactivation of CD38 reverses HSC aging and the pathophysiological changes of the aging hematopoietic system in aged mice. Together, our study highlights an NAD+ metabolic checkpoint that balances mitochondrial activation to support HSC proliferation and mitochondrial stress management to enhance HSC self-renewal throughout the lifespan, and links aberrant Ca2+ signaling to HSC aging.
    DOI:  https://doi.org/10.1038/s43587-024-00670-8
  20. Nat Metab. 2024 Jul 24.
    Mitochondrial respiration in microglia is essential for response to demyelinating injury but not proliferation.
    Joshua S Stoolman, Rogan A Grant, Taylor A Poor, Samuel E Weinberg, Karis B D'Alessandro, Jerica Tan, Jennifer Yuan-Shih Hu, Megan E Zerrer, Walter A Wood, Madeline C Harding, Sahil Soni, Karen M Ridge, Paul T Schumacker, G R Scott Budinger, Navdeep S Chandel.
      Microglia are necessary for central nervous system (CNS) function during development and play roles in ageing, Alzheimer's disease and the response to demyelinating injury1-5. The mitochondrial respiratory chain (RC) is necessary for conventional T cell proliferation6 and macrophage-dependent immune responses7-10. However, whether mitochondrial RC is essential for microglia proliferation or function is not known. We conditionally deleted the mitochondrial complex III subunit Uqcrfs1 (Rieske iron-sulfur polypeptide 1) in the microglia of adult mice to assess the requirement of microglial RC for survival, proliferation and adult CNS function in vivo. Notably, mitochondrial RC function was not required for survival or proliferation of microglia in vivo. RNA sequencing analysis showed that loss of RC function in microglia caused changes in gene expression distinct from aged or disease-associated microglia. Microglia-specific loss of mitochondrial RC function is not sufficient to induce cognitive decline. Amyloid-β plaque coverage decreased and microglial interaction with amyloid-β plaques increased in the hippocampus of 5xFAD mice with mitochondrial RC-deficient microglia. Microglia-specific loss of mitochondrial RC function did impair remyelination following an acute, reversible demyelinating event. Thus, mitochondrial respiration in microglia is dispensable for proliferation but is essential to maintain a proper response to CNS demyelinating injury.
    DOI:  https://doi.org/10.1038/s42255-024-01080-1
  21. Proc Natl Acad Sci U S A. 2024 Jul 30. 121(31): e2314760121
    Ammonia transporter RhBG initiates downstream signaling and functional responses by activating NFκB.
    Saurabh Mishra, Nicole Welch, Shashi Shekhar Singh, Khuraijam Dhanachandra Singh, Annette Bellar, Avinash Kumar, Lars N Deutz, Maxmillian D Hanlon, Sashi Kant, Sumitava Dastidar, Hailee Patel, Vandana Agrawal, Amy H Attaway, Ryan Musich, George R Stark, Francesco Saverio Tedesco, George A Truskey, I David Weiner, Sadashiva S Karnik, Srinivasan Dasarathy.
      Transceptors, solute transporters that facilitate intracellular entry of molecules and also initiate intracellular signaling events, have been primarily studied in lower-order species. Ammonia, a cytotoxic endogenous metabolite, is converted to urea in hepatocytes for urinary excretion in mammals. During hyperammonemia, when hepatic metabolism is impaired, nonureagenic ammonia disposal occurs primarily in skeletal muscle. Increased ammonia uptake in skeletal muscle is mediated by a membrane-bound, 12 transmembrane domain solute transporter, Rhesus blood group-associated B glycoprotein (RhBG). We show that in addition to its transport function, RhBG interacts with myeloid differentiation primary response-88 (MyD88) to initiate an intracellular signaling cascade that culminates in activation of NFκB. We also show that ammonia-induced MyD88 signaling is independent of the canonical toll-like receptor-initiated mechanism of MyD88-dependent NFκB activation. In silico, in vitro, and in situ experiments show that the conserved cytosolic J-domain of the RhBG protein interacts with the Toll-interleukin-1 receptor (TIR) domain of MyD88. In skeletal muscle from human patients, human-induced pluripotent stem cell-derived myotubes, and myobundles show an interaction of RhBG-MyD88 during hyperammonemia. Using complementary experimental and multiomics analyses in murine myotubes and mice with muscle-specific RhBG or MyD88 deletion, we show that the RhBG-MyD88 interaction is essential for the activation of NFkB but not ammonia transport. Our studies show a paradigm of substrate-dependent regulation of transceptor function with the potential for modulation of cellular responses in mammalian systems by decoupling transport and signaling functions of transceptors.
    Keywords:  NFkB; hyperammonemia; skeletal muscle; solute transporter; transceptor
    DOI:  https://doi.org/10.1073/pnas.2314760121
  22. J Leukoc Biol. 2024 Jul 26. pii: qiae165. [Epub ahead of print]
    Signaling by Neutrophil G Protein-Coupled Receptors that Regulate the Release of Superoxide Anions.
    Claes Dahlgren, Huamei Forsman, Martina Sundqvist, Lena Björkman, Jonas Mårtensson.
      In human peripheral blood, the neutrophil granulocytes (neutrophils) are the most-abundant white blood cells. These professional phagocytes are rapidly recruited from the bloodstream to inflamed tissues by chemotactic factors that signal danger. Neutrophils, which express many receptors that are members of the large family of G protein-coupled receptors (GPCRs), are critical for the elimination of pathogens and inflammatory insults, as well as for the resolution of inflammation leading to tissue repair. Danger-signaling molecular patterns such as the N-formylated peptides that are formed during bacterial and mitochondrial protein synthesis and recognized by formyl peptide receptors (FPRs) and free fatty acids recognized by free fatty acid receptors (FFARs) regulate neutrophil functions. Short peptides and short chain fatty acids activate FPR1 and FFA2R, respectively, while longer peptides and fatty acids activate FPR2 and GPR84, respectively. The activation profiles of these receptors include the release of reactive oxygen species (ROS) generated by the NADPH oxidase. Activation of the oxidase and the production of ROS are processes that are regulated by proinflammatory mediators, including TNFα and GM-CSF. The receptors have signaling and functional similarities, although there are also important differences, not only between the two closely related neutrophil FPRs, but also between the FPRs and the FFARs. In neutrophils, these receptors never walk alone, and additional mechanistic insights into the regulation of the GPCRs and the novel regulatory mechanisms underlying the activation of NADPH oxidase advance our understanding of the role of receptor transactivation in the regulation of inflammatory reactions.
    Keywords:  GPCR; allosteric modulation; biased signaling; pattern recognition; receptor transactivation
    DOI:  https://doi.org/10.1093/jleuko/qiae165
  23. Cell Rep. 2024 Jul 23. pii: S2211-1247(24)00861-1. [Epub ahead of print]43(8): 114532
    Alterations of ceramide synthesis induce PD-L1 internalization and signaling to regulate tumor metastasis and immunotherapy response.
    Wyatt Wofford, Jisun Kim, Dosung Kim, Alhaji H Janneh, Han Gyul Lee, F Cansu Atilgan, Natalia Oleinik, Mohamed Faisal Kassir, Ozge Saatci, Paramita Chakraborty, Unal Metin Tokat, Salih Gencer, Breege Howley, Philip Howe, Shikhar Mehrotra, Ozgur Sahin, Besim Ogretmen.
      Programmed death ligand 1, PD-L1 (CD274), facilitates immune evasion and exerts pro-survival functions in cancer cells. Here, we report a mechanism whereby internalization of PD-L1 in response to alterations of bioactive lipid/ceramide metabolism by ceramide synthase 4 (CerS4) induces sonic hedgehog (Shh) and transforming growth factor β receptor signaling to enhance tumor metastasis in triple-negative breast cancers (TNBCs), exhibiting immunotherapy resistance. Mechanistically, data showed that internalized PD-L1 interacts with an RNA-binding protein, caprin-1, to stabilize Shh/TGFBR1/Wnt mRNAs to induce β-catenin signaling and TNBC growth/metastasis, consistent with increased infiltration of FoxP3+ regulatory T cells and resistance to immunotherapy. While mammary tumors developed in MMTV-PyMT/CerS4-/- were highly metastatic, targeting the Shh/PD-L1 axis using sonidegib and anti-PD-L1 antibody vastly decreased tumor growth and metastasis, consistent with the inhibition of PD-L1 internalization and Shh/Wnt signaling, restoring anti-tumor immune response. These data, validated in clinical samples and databases, provide a mechanism-based therapeutic strategy to improve immunotherapy responses in metastatic TNBCs.
    Keywords:  CP: Cancer; CP: Metabolism; CerS4; PD-L1; ceramide; immunotherapy; metastasis; sonic hedgehog; sphingolipid
    DOI:  https://doi.org/10.1016/j.celrep.2024.114532
  24. Cardiovasc Res. 2024 Jul 23. pii: cvae154. [Epub ahead of print]
    Cross-species single-cell RNA sequencing reveals divergent phenotypes and activation states of adaptive immunity in human carotid and experimental murine atherosclerosis.
    Hauke Horstmann, Nathaly Anto Michel, Xia Sheng, Sophie Hansen, Alexandra Lindau, Katharina Pfeil, Marbely C Fernández, Timoteo Marchini, Holger Winkels, Lucia Sol Mitre, Tijani Abogunloko, Xiaowei Li, Timothy Bon-Nawul Mwinyella, Mark Colin Gissler, Heiko Bugger, Timo Heidt, Konrad Buscher, Ingo Hilgendorf, Peter Stachon, Sven Piepenburg, Nicolas Verheyen, Thomas Rathner, Teresa Gerhardt, Patrick Malcolm Siegel, Wolfgang Kurt Oswald, Tina Cohnert, Alma Zernecke, Josef Madl, Peter Kohl, Amanda C Foks, Constantin von Zur Muehlen, Dirk Westermann, Andreas Zirlik, Dennis Wolf.
       BACKGROUND AND AIMS: The distinct functions of immune cells in atherosclerosis have been mostly defined by preclinical mouse studies. Contrastingly, the immune cell composition of human atherosclerotic plaques and their contribution to disease progression is only poorly understood. It remains uncertain whether genetic animal models allow for valuable translational approaches.
    METHODS AND RESULTS: Single cell RNA-sequencing (scRNA-seq) was performed to define the immune cell landscape in human carotid atherosclerotic plaques. The human immune cell repertoire demonstrated an unexpectedly high heterogeneity and was dominated by cells of the T-cell lineage, a finding confirmed by immunohistochemistry. Bioinformatical integration with 7 mouse scRNA-seq data sets from adventitial and atherosclerotic vascular tissue revealed a total of 51 identities of cell types and differentiation states, of which some were only poorly conserved between species and exclusively found in humans. Locations, frequencies, and transcriptional programs of immune cells in mouse models did not resemble the immune cell landscape in human carotid atherosclerosis. In contrast to standard mouse models of atherosclerosis, human plaque leukocytes were dominated by several T-cell phenotypes with transcriptional hallmarks of T-cell activation and memory formation, T-cell receptor-, and pro-inflammatory signaling. Only mice at the age of 22 months partially resembled the activated T-cell phenotype. In a validation cohort of 43 patients undergoing carotid endarterectomy, the abundance of activated immune cell subsets in the plaque defined by multi-color flow cytometry associated with the extend of clinical atherosclerosis.
    CONCLUSIONS: Integrative scRNA-seq reveals a substantial difference in the immune cell composition of murine and human carotid atherosclerosis - a finding that questions the translational value of standard mouse models for adaptive immune cell studies. Clinical associations suggest a specific role for T-cell driven (auto-) immunity in human plaque formation and -instability.
    Keywords:  Atherosclerosis; Immunity; Leukocytes; Prediction; Transcriptome; scRNA-seq
    DOI:  https://doi.org/10.1093/cvr/cvae154
  25. Cell Death Differ. 2024 Jul 26.
    Ferroptosis is a targetable detrimental factor in metabolic dysfunction-associated steatotic liver disease.
    Cédric Peleman, Stig Hellemans, Geraldine Veeckmans, Wout Arras, Hao Zheng, Ine Koeken, Emily Van San, Behrouz Hassannia, Magali Walravens, Edissa Kayirangwa, Nateneal Tamerat Beyene, Mikhaïl Alfons Van Herck, Winnok Harald De Vos, Isabel Pintelon, Luc van Nassauw, Baptiste Oosterlinck, Annemieke Smet, Lieve Vits, Eveline Dirinck, An Verrijken, Joris De Man, Annelies Van Eyck, Wilhelmus Josephus Kwanten, Luisa Vonghia, Ann Driessen, Koen Augustyns, Shinya Toyokuni, Benedicte De Winter, Christophe Van Steenkiste, Sven Francque, Tom Vanden Berghe.
      There is an unmet clinical need for pharmacologic treatment for metabolic dysfunction-associated steatotic liver disease (MASLD). Hepatocyte cell death is a hallmark of this highly prevalent chronic liver disease, but the dominant type of cell death remains uncertain. Here we report that ferroptosis, an iron-catalyzed mode of regulated cell death, contributes to MASLD. Unsupervised clustering in a cohort of biopsy-proven MASLD patients revealed a subgroup with hepatic ferroptosis signature and lower glutathione peroxidase 4 (GPX4) levels. Likewise, a subgroup with reduced ferroptosis defenses was discerned in public transcriptomics datasets. Four weeks of choline-deficient L-amino acid-defined high-fat diet (CDAHFD) induced MASLD with ferroptosis in mice. Gpx4 overexpression did not affect steatohepatitis, instead CDAHFD protected from morbidity due to hepatocyte-specific Gpx4 knockout. The ferroptosis inhibitor UAMC-3203 attenuated steatosis and alanine aminotransferase in CDAHFD and a second model, i.e., the high-fat high-fructose diet (HFHFD). The effect of monounsaturated and saturated fatty acids supplementation on ferroptosis susceptibility was assessed in human HepG2 cells. Fat-laden HepG2 showed a drop in ferroptosis defenses, increased phosphatidylglycerol with two polyunsaturated fatty acid (PUFA) lipid tails, and sustained ferroptosis sensitivity. In conclusion, this study identified hepatic ferroptosis as a detrimental factor in MASLD patients. Unexpectedly, non-PUFA supplementation to hepatocytes altered lipid bilayer composition to maintain ferroptosis sensitivity. Based on findings in in vivo models, ferroptosis inhibition represents a promising therapeutic target in MASLD.
    DOI:  https://doi.org/10.1038/s41418-024-01348-9
  26. J Lipid Res. 2024 Jul 20. pii: S0022-2275(24)00106-8. [Epub ahead of print] 100601
    Cardiolipin remodeling maintains the inner mitochondrial membrane in cells with saturated lipidomes.
    Kailash Venkatraman, Itay Budin.
      Cardiolipin (CL) is a unique, four-chain phospholipid synthesized in the inner mitochondrial membrane (IMM). The acyl chain composition of CL is regulated through a remodeling pathway, whose loss causes mitochondrial dysfunction in Barth syndrome (BTHS). Yeast has been used extensively as a model system to characterize CL metabolism, but mutants lacking its two remodeling enzymes, Cld1p and Taz1p, exhibit mild structural and respiratory phenotypes compared to mammalian cells. Here we show the essential role of CL remodeling in the structure and function of the IMM in yeast grown under reduced oxygenation. Microaerobic fermentation, which mimics natural yeast environments, caused the accumulation of saturated fatty acids and, under these conditions, remodeling mutants showed a loss of IMM ultrastructure. We extended this observation to HEK293 cells, where iPLA2 inhibition by Bromoenol lactone resulted in respiratory dysfunction and cristae loss upon mild treatment with exogenous saturated fatty acids. In microaerobic yeast, remodeling mutants accumulated unremodeled, saturated CL, but also displayed reduced total CL levels, highlighting the interplay between saturation and CL biosynthesis and breakdown. We identified the mitochondrial phospholipase A1 Ddl1p as a regulator of CL levels, and those of its precursors phosphatidylglycerol and phosphatidic acid, under these conditions. Loss of DDL1 partially rescued IMM structure in cells unable to initiate CL remodeling and had differing lipidomic effects depending on oxygenation. These results introduce a revised yeast model for investigating CL remodeling and suggest that its structural functions are dependent on the overall lipid environment in the mitochondrion.
    Keywords:  Barth Syndrome; Cardiolipin; Lipid saturation; Mitochondria; Phospholipids
    DOI:  https://doi.org/10.1016/j.jlr.2024.100601
  27. Nat Metab. 2024 Jul;6(7): 1367-1379
    Non-invasive mapping of brown adipose tissue activity with magnetic resonance imaging.
    Zimeng Cai, Qiaoling Zhong, Yanqiu Feng, Qian Wang, Zuoman Zhang, Cailv Wei, Zhinan Yin, Changhong Liang, Chong Wee Liew, Lawrence Kazak, Aaron M Cypess, Zaiyi Liu, Kejia Cai.
      Thermogenic brown adipose tissue (BAT) has a positive impact on whole-body metabolism. However, in vivo mapping of BAT activity typically relies on techniques involving ionizing radiation, such as [18F]fluorodeoxyglucose ([18F]FDG) positron emission tomography (PET) and computed tomography (CT). Here we report a noninvasive metabolic magnetic resonance imaging (MRI) approach based on creatine chemical exchange saturation transfer (Cr-CEST) contrast to assess in vivo BAT activity in rodents and humans. In male rats, a single dose of the β3-adrenoceptor agonist (CL 316,243) or norepinephrine, as well as cold exposure, triggered a robust elevation of the Cr-CEST MRI signal, which was consistent with the [18F]FDG PET and CT data and 1H nuclear magnetic resonance measurements of creatine concentration in BAT. We further show that Cr-CEST MRI detects cold-stimulated BAT activation in humans (both males and females) using a 3T clinical scanner, with data-matching results from [18F]FDG PET and CT measurements. This study establishes Cr-CEST MRI as a promising noninvasive and radiation-free approach for in vivo mapping of BAT activity.
    DOI:  https://doi.org/10.1038/s42255-024-01082-z
  28. Nat Commun. 2024 Jul 21. 15(1): 6152
    Glutathione synthesis in the mouse liver supports lipid abundance through NRF2 repression.
    Gloria Asantewaa, Emily T Tuttle, Nathan P Ward, Yun Pyo Kang, Yumi Kim, Madeline E Kavanagh, Nomeda Girnius, Ying Chen, Katherine Rodriguez, Fabio Hecht, Marco Zocchi, Leonid Smorodintsev-Schiller, TashJaé Q Scales, Kira Taylor, Fatemeh Alimohammadi, Renae P Duncan, Zachary R Sechrist, Diana Agostini-Vulaj, Xenia L Schafer, Hayley Chang, Zachary R Smith, Thomas N O'Connor, Sarah Whelan, Laura M Selfors, Jett Crowdis, G Kenneth Gray, Roderick T Bronson, Dirk Brenner, Alessandro Rufini, Robert T Dirksen, Aram F Hezel, Aaron R Huber, Joshua Munger, Benjamin F Cravatt, Vasilis Vasiliou, Calvin L Cole, Gina M DeNicola, Isaac S Harris.
      Cells rely on antioxidants to survive. The most abundant antioxidant is glutathione (GSH). The synthesis of GSH is non-redundantly controlled by the glutamate-cysteine ligase catalytic subunit (GCLC). GSH imbalance is implicated in many diseases, but the requirement for GSH in adult tissues is unclear. To interrogate this, we have developed a series of in vivo models to induce Gclc deletion in adult animals. We find that GSH is essential to lipid abundance in vivo. GSH levels are highest in liver tissue, which is also a hub for lipid production. While the loss of GSH does not cause liver failure, it decreases lipogenic enzyme expression, circulating triglyceride levels, and fat stores. Mechanistically, we find that GSH promotes lipid abundance by repressing NRF2, a transcription factor induced by oxidative stress. These studies identify GSH as a fulcrum in the liver's balance of redox buffering and triglyceride production.
    DOI:  https://doi.org/10.1038/s41467-024-50454-2
  29. Sci Adv. 2024 Jul 26. 10(30): eadl0796
    The TCR assigns naive T cells to a preferred lymph node.
    Peter C de Greef, Sospeter Ngoci Njeru, Claudia Benz, Simon Fillatreau, Bernard Malissen, Fabien Agenès, Rob J de Boer, Jörg Kirberg.
      Naive T cells recirculate between the spleen and lymph nodes where they mount immune responses when meeting dendritic cells presenting foreign antigen. As this may happen anywhere, naive T cells ought to visit all lymph nodes. Here, deep sequencing almost-complete TCR repertoires led to a comparison of different lymph nodes within and between individual mice. We find strong evidence for a deterministic CD4/CD8 lineage choice and a consistent spatial structure. Specifically, some T cells show a preference for one or multiple lymph nodes, suggesting that their TCR interacts with locally presented (self-)peptides. These findings are mirrored in TCR-transgenic mice showing localized CD69 expression, retention, and cell division. Thus, naive T cells intermittently sense antigenically dissimilar niches, which is expected to affect their homeostatic competition.
    DOI:  https://doi.org/10.1126/sciadv.adl0796
  30. Sci Immunol. 2024 Jul 26. 9(97): eadk3981
    Timing and location dictate monocyte fate and their transition to tumor-associated macrophages.
    Garett Dunsmore, Wei Guo, Ziyi Li, David Alejandro Bejarano, Rhea Pai, Katharine Yang, Immanuel Kwok, Leonard Tan, Melissa Ng, Carlos De La Calle Fabregat, Aline Yatim, Antoine Bougouin, Kevin Mulder, Jake Thomas, Javiera Villar, Mathilde Bied, Benoit Kloeckner, Charles-Antoine Dutertre, Grégoire Gessain, Svetoslav Chakarov, Zhaoyuan Liu, Jean-Yves Scoazec, Ana-Maria Lennon-Dumenil, Thomas Marichal, Catherine Sautès-Fridman, Wolf Herman Fridman, Ankur Sharma, Bing Su, Andreas Schlitzer, Lai Guan Ng, Camille Blériot, Florent Ginhoux.
      Tumor-associated macrophages (TAMs) are a heterogeneous population of cells whose phenotypes and functions are shaped by factors that are incompletely understood. Herein, we asked when and where TAMs arise from blood monocytes and how they evolve during tumor development. We initiated pancreatic ductal adenocarcinoma (PDAC) in inducible monocyte fate-mapping mice and combined single-cell transcriptomics and high-dimensional flow cytometry to profile the monocyte-to-TAM transition. We revealed that monocytes differentiate first into a transient intermediate population of TAMs that generates two longer-lived lineages of terminally differentiated TAMs with distinct gene expression profiles, phenotypes, and intratumoral localization. Transcriptome datasets and tumor samples from patients with PDAC evidenced parallel TAM populations in humans and their prognostic associations. These insights will support the design of new therapeutic strategies targeting TAMs in PDAC.
    DOI:  https://doi.org/10.1126/sciimmunol.adk3981
  31. Circ Res. 2024 Jul 26.
    Lysozyme 1 Inflamed CCR2+ Macrophages Promote Obesity-Induced Cardiac Dysfunction.
    Lai Zhang, Huian Han, Andi Xu, Adwait Sathe, Siying Fu, Jiaqi Zhao, Wenhan Cai, Yaqing Yang, Jinting Liu, Hui Bai, Jingjing Ben, Xudong Zhu, Xiaoyu Li, Qing Yang, Zidun Wang, Yayun Gu, Chao Xing, Gabriele G Schiattarella, Steven Yan Cheng, Hanwen Zhang, Qi Chen.
       BACKGROUND: Macrophages are key players in obesity-associated cardiovascular diseases, which are marked by inflammatory and immune alterations. However, the pathophysiological mechanisms underlying macrophage's role in obesity-induced cardiac inflammation are incompletely understood. Our study aimed to identify the key macrophage population involved in obesity-induced cardiac dysfunction and investigate the molecular mechanism that contributes to the inflammatory response.
    METHODS AND RESULTS: Though analyzing in-depth cardiac macrophage clusters identified by single macrophage RNA-sequencing, we find that the Ccr2 cluster undergoes a functional transition from homeostatic maintenance to proinflammation. Our data highlight specific changes in macrophage behavior during cardiac dysfunction under metabolic challenge. Consistently, inducible ablation of CCR2+CX3CR1+ macrophages by a dual recombinase-based lineage-tracing approach or selective deletion of macrophage C-C chemokine receptor 2 (CCR2) prevents obesity-induced cardiac dysfunction. At the mechanistic level, we demonstrate that the obesity-induced functional shift of CCR2-expressing macrophages is mediated by the CCR2/ATF3/lysozyme 1/NF-κB (nuclear factor kappa B) signaling. Finally, we uncover a noncanonical role for lysozyme 1 as a transcription activator, binding to the RelA promoter, driving NF-κB signaling, and strongly promoting inflammation and cardiac dysfunction in obesity.
    CONCLUSIONS: Our findings suggest that lysozyme 1 may represent a potential target for the diagnosis of obesity-induced inflammation and the treatment of obesity-induced heart disease.
    Keywords:  RNA; cardiovascular diseases; inflammation; macrophages; muramidase
    DOI:  https://doi.org/10.1161/CIRCRESAHA.124.324106
  32. Redox Biol. 2024 Jul 18. pii: S2213-2317(24)00248-9. [Epub ahead of print]75 103270
    LACTB suppresses liver cancer progression through regulation of ferroptosis.
    Kaixuan Zeng, Na Huang, Nanbin Liu, Xi Deng, Yanhua Mu, Xurui Zhang, Jian Zhang, Chongyu Zhang, Yong Li, Zongfang Li.
      Ferroptosis, driven by iron-dependent phospholipid peroxidation, is emerging as an intrinsic cancer defense mechanism. However, the regulatory networks involved in ferroptosis remain largely unknown. Here, we found that serine beta-lactamase-like protein (LACTB) inhibits liver cancer progression by regulating ferroptosis. LACTB is downregulated in liver cancer, and the ectopic expression of LACTB markedly inhibits cell viability, colony formation, and tumour growth. LACTB knockout exerts the opposite effects. Further investigation revealed that LACTB blocks HSPA8 transcription in a p53-dependent manner, resulting in the elevation of NCOA4-mediated ferritinophagy and inhibition of SLC7A11/GSH/GPX4 signalling, thereby triggering ferroptosis and suppressing liver cancer progression. Liver cancer cells with an endogenous mutation of p53 binding site in the HSPA8 promoter exhibited increased resistance to ferroptosis inducers, and the ferroptosis-promoting effect of LACTB was significantly weakened in these mutant cells. Importantly, LACTB is identified as a downstream target of lenvatinib, and adeno-associated virus-mediated overexpression and knockdown of LACTB notably enhance and attenuate the anti-tumour efficacy of lenvatinib in vivo, respectively. Taken together, our study reveals a novel action of LACTB and provides potential therapeutic strategies for enhancing the efficacy of lenvatinib in liver cancer.
    Keywords:  Ferroptosis; LACTB; Lenvatinib; Liver cancer
    DOI:  https://doi.org/10.1016/j.redox.2024.103270
  33. Cancer Cell Int. 2024 Jul 22. 24(1): 259
    ALDH5A1/miR-210 axis plays a key role in reprogramming cellular metabolism and has a significant correlation with glioblastoma patient survival.
    Indranil Mondal, Neelam Gupta, Vikas Sharma, Chitra Sarkar, Durga Prasad Mishra, Ritu Kulshreshtha.
       BACKGROUND: Glioblastoma (GBM) is the most aggressive among the tumors of the central nervous system (CNS), and has a dismal prognosis. Altered metabolism, especially the increased rate of aerobic glycolysis promotes rapid proliferation of GBM cells. Here, we investigated the role of aldehyde dehydrogenase 5 family member A1 (ALDH5A1), a mitochondrial enzyme in the aspect of GBM metabolism. We also studied the regulatory mechanisms of altered ALDH5A1 expression in GBM.
    APPROACH AND RESULTS: We show that ALDH5A1 is significantly downregulated in GBM patients in a grade dependent manner as compared to control brain and its low expression is associated with poor prognosis. It is significantly downregulated under hypoxia and is a direct target of the hypoxia induced microRNA: miR-210. Ectopic overexpression of ALDH5A1 in GBM cell lines U-87 MG and T98G markedly reduced their proliferation, 3D spheroid forming ability, and formation of reactive oxygen species (ROS). ALDH5A1 upregulation increased the oxygen consumption rate (OCR), and reduced the extracellular acidification rate (ECAR) of GBM cells while miR-210 overexpression showed the opposite. A significant downregulation in the transcript levels of LDHA, PDK1, and SLC2A1; coupled with lower glucose uptake and lactate production upon ALDH5A1 overexpression reveals that ALDH5A1 significantly reduces the glycolytic capacity of GBM cells. Total ATP generated in 24 h was more when miR-210 was overexpressed, while a slight decrease in ATP formation was observed upon ALDH5A1 upregulation. Interestingly, we also observed that ALDH5A1 expression is elevated and miR-210 levels are downregulated in IDH-mutant glioma as compared to its wild-type form.
    CONCLUSION: Overall, our findings suggest that miR-210 mediated downregulation of ALDH5A1 plays a critical role in tumor metabolism and helps maintaining a high glycolytic phenotype in GBM.
    Keywords:  Glioblastoma; Glycolysis; Hypoxia; Metabolism; OXPHOS; microRNA
    DOI:  https://doi.org/10.1186/s12935-024-03432-z
  34. STAR Protoc. 2024 Jul 24. pii: S2666-1667(24)00368-X. [Epub ahead of print]5(3): 103203
    Protocol for the characterization of the pancreatic tumor microenvironment using organoid-derived mouse models and single-nuclei RNA sequencing.
    Muntadher Jihad, Gianluca Mucciolo, Wenlong Li, Akanksha Anand, Joaquín Araos Henríquez, Sara Pinto Teles, Judhell S Manansala, Sally Ashworth, Eloise G Lloyd, Priscilla S W Cheng, Weike Luo, Ashley Sawle, Anna Piskorz, Giulia Biffi.
      Single-nuclei RNA sequencing (snRNA-seq) allows for obtaining gene expression profiles from frozen or hard-to-dissociate tissues at the single-nuclei level. Here, we describe a protocol to obtain snRNA-seq data of pancreatic tumors from orthotopically grafted organoid-derived mouse models. We provide details on the establishment of these mouse models, the isolation of single nuclei from pancreatic tumors, and the analysis of the snRNA-seq datasets. For complete details on the use and execution of this protocol, please refer to Mucciolo et al.1.
    Keywords:  Cancer; Genomics; Model Organisms; Organoids; RNAseq; Sequence analysis; Sequencing
    DOI:  https://doi.org/10.1016/j.xpro.2024.103203
  35. Nat Commun. 2024 Jul 22. 15(1): 6172
    Targeted degradation of extracellular mitochondrial aspartyl-tRNA synthetase modulates immune responses.
    Benjamin S Johnson, Daniela Farkas, Rabab El-Mergawy, Jessica A Adair, Ajit Elhance, Moemen Eltobgy, Francesca M Coan, Lexie Chafin, Jessica A Joseph, Alex Cornwell, Finny J Johns, Lorena Rosas, Mauricio Rojas, Laszlo Farkas, Joseph S Bednash, James D Londino, Prabir Ray, Anuradha Ray, Valerian Kagan, Janet S Lee, Bill B Chen, Rama K Mallampalli.
      The severity of bacterial pneumonia can be worsened by impaired innate immunity resulting in ineffective pathogen clearance. We describe a mitochondrial protein, aspartyl-tRNA synthetase (DARS2), which is released in circulation during bacterial pneumonia in humans and displays intrinsic innate immune properties and cellular repair properties. DARS2 interacts with a bacterial-induced ubiquitin E3 ligase subunit, FBXO24, which targets the synthetase for ubiquitylation and degradation, a process that is inhibited by DARS2 acetylation. During experimental pneumonia, Fbxo24 knockout mice exhibit elevated DARS2 levels with an increase in pulmonary cellular and cytokine levels. In silico modeling identified an FBXO24 inhibitory compound with immunostimulatory properties which extended DARS2 lifespan in cells. Here, we show a unique biological role for an extracellular, mitochondrially derived enzyme and its molecular control by the ubiquitin apparatus, which may serve as a mechanistic platform to enhance protective host immunity through small molecule discovery.
    DOI:  https://doi.org/10.1038/s41467-024-50031-7
  36. Mol Cell. 2024 Jul 25. pii: S1097-2765(24)00542-2. [Epub ahead of print]84(14): 2593-2595
    Sweetening mitochondria: Hexokinase shields mitochondria from fission when glucose is low.
    Antigoni Diokmetzidou, Luca Scorrano.
      In this issue of Molecular Cell, Pilic et al.1 show that hexokinase, the first enzyme of glycolysis, forms perimitochondrial rings that prevent mitochondrial fragmentation when ATP levels drop.
    DOI:  https://doi.org/10.1016/j.molcel.2024.06.035
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