bims-mepmim Biomed News
on Metabolites in pathological microenvironments and immunometabolism
Issue of 2024–02–18
27 papers selected by
Erika Mariana Palmieri, NIH/NCI Laboratory of Cancer ImmunoMetabolism
  1. Cysteine induces mitochondrial reductive stress in glioblastoma through hydrogen peroxide production.
  2. Macrophages Under the Influence of Tumor Mesothelin Weaken Host Defenses against Pancreatic Cancer Metastasis.
  3. SLC25A39 links mitochondrial GSH sensing with iron metabolism.
  4. GLUT1-mediated glucose import in B cells is critical for anaplerotic balance and humoral immunity.
  5. Chronic exercise improves hepatic acylcarnitine handling.
  6. Sonic hedgehog-heat shock protein 90β axis promotes the development of nonalcoholic steatohepatitis in mice.
  7. Targeting de novo lipogenesis to mitigate kidney disease.
  8. Efferocytosis reprograms the tumor microenvironment to promote pancreatic cancer liver metastasis.
  9. DGAT2 inhibition blocks SREBP-1 cleavage and improves hepatic steatosis by increasing phosphatidylethanolamine in the ER.
  10. Tissue niche occupancy determines the contribution of fetal- versus bone-marrow-derived macrophages to IgG effector functions.
  11. SLC25A51 decouples the mitochondrial NAD+/NADH ratio to control proliferation of AML cells.
  12. PPARα Agonism Enhances Immune Response to Radiotherapy while Dietary Oleic Acid Results in Counteraction.
  13. Dietary elaidic acid boosts tumoral antigen presentation and cancer immunity via ACSL5.
  14. Ketogenic diet-produced β-hydroxybutyric acid accumulates brain GABA and increases GABA/glutamate ratio to inhibit epilepsy.
  15. Induction of stearoyl-CoA desaturase confers cell density-dependent ferroptosis resistance in melanoma.
  16. Targeting metabolic sensing switch GPR84 on macrophages for cancer immunotherapy.
  17. Phospholipids with two polyunsaturated fatty acyl tails promote ferroptosis.
  18. The cell biology of ferroptosis.
  19. Nitric oxide in vascular biology: elegance in complexity.
  20. THBS1+ myeloid cells expand in SLD hepatocellular carcinoma and contribute to immunosuppression and unfavorable prognosis through TREM1.
  21. Proline restores mitochondrial function and reverses aging hallmarks in senescent cells.
  22. Structure of human phagocyte NADPH oxidase in the activated state.
  23. Neurogranin expression regulates mitochondrial function and redox balance in endothelial cells.
  24. A GPCR-neuropeptide axis dampens hyperactive neutrophils by promoting an alternative-like polarization during bacterial infection.
  25. Dynamic changes in the mouse hepatic lipidome following warm ischemia reperfusion injury.
  26. EFHD2 suppresses intestinal inflammation by blocking intestinal epithelial cell TNFR1 internalization and cell death.
  27. Methyltransferase Setd2 prevents T cell-mediated autoimmune diseases via phospholipid remodeling.
  1. Proc Natl Acad Sci U S A. 2024 Feb 20. 121(8): e2317343121
    Cysteine induces mitochondrial reductive stress in glioblastoma through hydrogen peroxide production.
    Evan K Noch, Laura Palma, Isaiah Yim, Nayah Bullen, Daniel Barnett, Alexander Walsh, Bhavneet Bhinder, Elisa Benedetti, Jan Krumsiek, Justin Gurvitch, Sumaiyah Khwaja, Daphne Atlas, Olivier Elemento, Lewis C Cantley.
      Glucose and amino acid metabolism are critical for glioblastoma (GBM) growth, but little is known about the specific metabolic alterations in GBM that are targetable with FDA-approved compounds. To investigate tumor metabolism signatures unique to GBM, we interrogated The Cancer Genome Atlas for alterations in glucose and amino acid signatures in GBM relative to other human cancers and found that GBM exhibits the highest levels of cysteine and methionine pathway gene expression of 32 human cancers. Treatment of patient-derived GBM cells with the FDA-approved single cysteine compound N-acetylcysteine (NAC) reduced GBM cell growth and mitochondrial oxygen consumption, which was worsened by glucose starvation. Normal brain cells and other cancer cells showed no response to NAC. Mechanistic experiments revealed that cysteine compounds induce rapid mitochondrial H2O2 production and reductive stress in GBM cells, an effect blocked by oxidized glutathione, thioredoxin, and redox enzyme overexpression. From analysis of the clinical proteomic tumor analysis consortium (CPTAC) database, we found that GBM cells exhibit lower expression of mitochondrial redox enzymes than four other cancers whose proteomic data are available in CPTAC. Knockdown of mitochondrial thioredoxin-2 in lung cancer cells induced NAC susceptibility, indicating the importance of mitochondrial redox enzyme expression in mitigating reductive stress. Intraperitoneal treatment of mice bearing orthotopic GBM xenografts with a two-cysteine peptide induced H2O2 in brain tumors in vivo. These findings indicate that GBM is uniquely susceptible to NAC-driven reductive stress and could synergize with glucose-lowering treatments for GBM.
    Keywords:  cysteine; glioblastoma; hydrogen peroxide; mitochondrial metabolism; reductive stress
    DOI:  https://doi.org/10.1073/pnas.2317343121
  2. Cancer Res. 2024 Feb 15. 84(4): 513-514
    Macrophages Under the Influence of Tumor Mesothelin Weaken Host Defenses against Pancreatic Cancer Metastasis.
    Christine Alewine.
      Although pancreatic cancer is a systemic disease that metastasizes early in its course, the signaling systems that promote this behavior remain incompletely understood. In this issue of Cancer Research, Luckett and colleagues identify a paracrine signaling pathway between cancer cells and macrophages that promotes pancreatic cancer metastasis. The authors used immunocompetent murine pancreatic cancer models with high versus low metastatic potential, genetic knockout and complementation strategies, and The Cancer Genome Atlas human data to demonstrate that tumor-secreted mesothelin repolarizes tumor and lung macrophages to a tumor-supportive phenotype. The repolarized macrophages increase secretion of VEGF and S100A9, raising local concentrations. In turn, VEGF enhances colony formation of cancer cells, while S100A9 promotes the recruitment of neutrophils to the lungs and the formation of neutrophil extracellular traps that support tumor metastasis. Together, these findings reveal a systemic signaling pathway that promotes pancreatic cancer metastasis by co-opting macrophages typically protective against cancer to instead promote its spread. See related article by Luckett et al., p. 527.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-23-4036
  3. Mol Cell. 2024 Feb 15. pii: S1097-2765(23)01083-3. [Epub ahead of print]84(4): 616-618
    SLC25A39 links mitochondrial GSH sensing with iron metabolism.
    Xiong Chen, Boyi Gan.
      Two recent studies by Liu et al.1 in Science and Shi et al.2 in this issue of Molecular Cell identify a mitochondrial GSH-sensing mechanism that couples SLC25A39-mediated GSH import to iron metabolism, advancing our understanding of nutrient sensing within organelles.
    DOI:  https://doi.org/10.1016/j.molcel.2023.12.037
  4. Cell Rep. 2024 Feb 08. pii: S2211-1247(24)00067-6. [Epub ahead of print]43(2): 113739
    GLUT1-mediated glucose import in B cells is critical for anaplerotic balance and humoral immunity.
    Theresa E H Bierling, Amelie Gumann, Shannon R Ottmann, Sebastian R Schulz, Leonie Weckwerth, Jana Thomas, Arne Gessner, Magdalena Wichert, Frederic Kuwert, Franziska Rost, Manuela Hauke, Tatjana Freudenreich, Dirk Mielenz, Hans-Martin Jäck, Katharina Pracht.
      Glucose uptake increases during B cell activation and antibody-secreting cell (ASC) differentiation, but conflicting findings prevent a clear metabolic profile at different stages of B cell activation. Deletion of the glucose transporter type 1 (GLUT1) gene in mature B cells (GLUT1-cKO) results in normal B cell development, but it reduces germinal center B cells and ASCs. GLUT1-cKO mice show decreased antigen-specific antibody titers after vaccination. In vitro, GLUT1-deficient B cells show impaired activation, whereas established plasmablasts abolish glycolysis, relying on mitochondrial activity and fatty acids. Transcriptomics and metabolomics reveal an altered anaplerotic balance in GLUT1-deficient ASCs. Despite attempts to compensate for glucose deprivation by increasing mitochondrial mass and gene expression associated with glycolysis, the tricarboxylic acid cycle, and hexosamine synthesis, GLUT1-deficient ASCs lack the metabolites for energy production and mitochondrial respiration, limiting protein synthesis. We identify GLUT1 as a critical metabolic player defining the germinal center response and humoral immunity.
    Keywords:  CP: Immunology; CP: Metabolism; GLUT1; adaptive immune response; antibody-secreting cell; glucose transporter type 1; glycolysis; metabolism; mitochondrial respiration; plasma cell; plasmablast
    DOI:  https://doi.org/10.1016/j.celrep.2024.113739
  5. iScience. 2024 Mar 15. 27(3): 109083
    Chronic exercise improves hepatic acylcarnitine handling.
    Diego Hernández-Saavedra, J Matthew Hinkley, Lisa A Baer, Kelsey M Pinckard, Pablo Vidal, Shinsuke Nirengi, Andrea M Brennan, Emily Y Chen, Niven R Narain, Valerie Bussberg, Vladimir V Tolstikov, Michael A Kiebish, Christina Markunas, Olga Ilkayeva, Bret H Goodpaster, Christopher B Newgard, Laurie J Goodyear, Paul M Coen, Kristin I Stanford.
      Exercise mediates tissue metabolic function through direct and indirect adaptations to acylcarnitine (AC) metabolism, but the exact mechanisms are unclear. We found that circulating medium-chain acylcarnitines (AC) (C12-C16) are lower in active/endurance trained human subjects compared to sedentary controls, and this is correlated with elevated cardiorespiratory fitness and reduced adiposity. In mice, exercise reduced serum AC and increased liver AC, and this was accompanied by a marked increase in expression of genes involved in hepatic AC metabolism and mitochondrial β-oxidation. Primary hepatocytes from high-fat fed, exercise trained mice had increased basal respiration compared to hepatocytes from high-fat fed sedentary mice, which may be attributed to increased Ca2+ cycling and lipid uptake into mitochondria. The addition of specific medium- and long-chain AC to sedentary hepatocytes increased mitochondrial respiration, mirroring the exercise phenotype. These data indicate that AC redistribution is an exercise-induced mechanism to improve hepatic function and metabolism.
    Keywords:  Cell biology; Health sciences; Physiology
    DOI:  https://doi.org/10.1016/j.isci.2024.109083
  6. Nat Commun. 2024 Feb 12. 15(1): 1280
    Sonic hedgehog-heat shock protein 90β axis promotes the development of nonalcoholic steatohepatitis in mice.
    Weitao Zhang, Junfeng Lu, Lianshun Feng, Hanyue Xue, Shiyang Shen, Shuiqing Lai, PingPing Li, Ping Li, Jian Kuang, Zhiwei Yang, Xiaojun Xu.
      Sonic hedgehog (SHH) and heat shock protein 90β (HSP90β) have been implicated in nonalcoholic steatohepatitis (NASH) but their molecular mechanisms of action remain elusive. We find that HSP90β is a key SHH downstream molecule for promoting NASH process. In hepatocytes, SHH reduces HSP90β ubiquitylation through deubiquitylase USP31, thus preventing HSP90β degradation and promoting hepatic lipid synthesis. HSP90β significantly increases in NASH mouse model, leading to secretion of exosomes enriched with miR-28-5p. miR-28-5p directly targetes and decreases Rap1b levels, which in turn promotes NF-κB transcriptional activity in macrophages and stimulates the expression of inflammatory factors. Genetic deletion, pharmacological inhibition of the SHH-HSP90β axis, or delivery of miR-28-5p to macrophages in the male mice liver, impairs NASH symptomatic development. Importantly, there is a markedly higher abundance of miR-28-5p in NASH patient sera. Taken together, the SHH-HSP90β-miR-28-5p axis offers promising therapeutic targets against NASH, and serum miR-28-5p may serve as a NASH diagnostic biomarker.
    DOI:  https://doi.org/10.1038/s41467-024-45520-8
  7. J Clin Invest. 2024 Feb 15. pii: e178125. [Epub ahead of print]134(4):
    Targeting de novo lipogenesis to mitigate kidney disease.
    Haikuo Li, Benjamin D Humphreys.
      Ten percent of the population worldwide suffers from chronic kidney disease (CKD), but the mechanisms driving CKD pathology are incompletely understood. While dysregulated lipid metabolism is one hallmark of CKD, the pathogenesis of cellular lipid accumulation remains unclear. In this issue of the JCI, Mukhi et al. Identify acyl-CoA synthetase short-chain family 2 (ACSS2) as a disease risk gene and demonstrate a role for ACSS2 in de novo lipogenesis (DNL). Notably, genetic or pharmacological inhibition of DNL protected against kidney disease progression in mice. These findings warrant evaluation of DNL inhibition with respect to efficacy and safety in people with CKD.
    DOI:  https://doi.org/10.1172/JCI178125
  8. Nat Cancer. 2024 Feb 14.
    Efferocytosis reprograms the tumor microenvironment to promote pancreatic cancer liver metastasis.
    Yuliana Astuti, Meirion Raymant, Valeria Quaranta, Kim Clarke, Maidinaimu Abudula, Olivia Smith, Gaia Bellomo, Vatshala Chandran-Gorner, Craig Nourse, Christopher Halloran, Paula Ghaneh, Daniel Palmer, Robert P Jones, Fiona Campbell, Jeffrey W Pollard, Jennifer P Morton, Ainhoa Mielgo, Michael C Schmid.
      Pancreatic ductal adenocarcinoma is a highly metastatic disease and macrophages support liver metastases. Efferocytosis, or engulfment of apoptotic cells by macrophages, is an essential process in tissue homeostasis and wound healing, but its role in metastasis is less well understood. Here, we found that the colonization of the hepatic metastatic site is accompanied by low-grade tissue injury and that efferocytosis-mediated clearance of parenchymal dead cells promotes macrophage reprogramming and liver metastasis. Mechanistically, progranulin expression in macrophages is necessary for efficient efferocytosis by controlling lysosomal acidification via cystic fibrosis transmembrane conductance regulator and the degradation of lysosomal cargo, resulting in LXRα/RXRα-mediated macrophage conversion and upregulation of arginase 1. Pharmacological blockade of efferocytosis or macrophage-specific genetic depletion of progranulin impairs macrophage conversion, improves CD8+ T cell functions, and reduces liver metastasis. Our findings reveal how hard-wired functions of macrophages in tissue repair contribute to liver metastasis and identify potential targets for prevention of pancreatic ductal adenocarcinoma liver metastasis.
    DOI:  https://doi.org/10.1038/s43018-024-00731-2
  9. Cell Metab. 2024 Feb 01. pii: S1550-4131(24)00011-1. [Epub ahead of print]
    DGAT2 inhibition blocks SREBP-1 cleavage and improves hepatic steatosis by increasing phosphatidylethanolamine in the ER.
    Shunxing Rong, Mingfeng Xia, Goncalo Vale, Simeng Wang, Chai-Wan Kim, Shili Li, Jeffrey G McDonald, Arun Radhakrishnan, Jay D Horton.
      Diacylglycerol acyltransferase 2 (DGAT2) catalyzes the final step of triglyceride (TG) synthesis. DGAT2 deletion in mice lowers liver TGs, and DGAT2 inhibitors are under investigation for the treatment of fatty liver disease. Here, we show that DGAT2 inhibition also suppressed SREBP-1 cleavage, reduced fatty acid synthesis, and lowered TG accumulation and secretion from liver. DGAT2 inhibition increased phosphatidylethanolamine (PE) levels in the endoplasmic reticulum (ER) and inhibited SREBP-1 cleavage, while DGAT2 overexpression lowered ER PE concentrations and increased SREBP-1 cleavage in vivo. ER enrichment with PE blocked SREBP-1 cleavage independent of Insigs, which are ER proteins that normally retain SREBPs in the ER. Thus, inhibition of DGAT2 shunted diacylglycerol into phospholipid synthesis, increasing the PE content of the ER, resulting in reduced SREBP-1 cleavage and less hepatic steatosis. This study reveals a new mechanism that regulates SREBP-1 activation and lipogenesis that is independent of sterols and SREBP-2 in liver.
    Keywords:  DGAT2; PE; SREBPs; diacylglycerol acyltransferase 2; hepatic steatosis; lipogenesis; phosphatidylethanolamine
    DOI:  https://doi.org/10.1016/j.cmet.2024.01.011
  10. Cell Rep. 2024 Feb 13. pii: S2211-1247(24)00085-8. [Epub ahead of print]43(2): 113757
    Tissue niche occupancy determines the contribution of fetal- versus bone-marrow-derived macrophages to IgG effector functions.
    Miriam Wöhner, Sarah Brechtelsbauer, Niklas Friedrich, Christof Vorsatz, Johanna Bulang, Chunguang Liang, Lena Schorr, Alain Beschin, Martin Guilliams, Jeffrey Ravetch, Falk Nimmerjahn, Markus Biburger.
      Understanding the mechanisms underlying cytotoxic immunoglobulin G (IgG) activity is critical for improving therapeutic antibody activity and inhibiting autoantibody-mediated tissue pathology. While prior research highlights the important role of the mononuclear phagocytic system for removing opsonized target cells, it remains unclear which monocyte or macrophage subsets stemming from fetal or post-natal bone-marrow (BM)-associated definitive hematopoiesis are involved in target cell depletion. By using a titrated irradiation approach as well as Kupffer-cell-specific deletion of activated Fcγ receptor signaling, we establish conditions under which the contribution of BM-derived monocytes versus yolk-sac-derived liver-resident macrophages to cytotoxic IgG activity can be studied. Our results demonstrate that liver-resident macrophages originating from either fetal or adult hematopoiesis play a central role in IgG-mediated depletion of opsonized target cells from the peripheral blood under steady-state conditions, highlighting the impact of the tissue niche and not macrophage origin for cytotoxic antibody activity.
    Keywords:  CP: Immunology; Fcγ receptors; IgG; Kupffer cells; antibody dependent cellular cytotoxicity; autoantibody; cytotoxic antibody; macrophages; monocytes; phagocytosis
    DOI:  https://doi.org/10.1016/j.celrep.2024.113757
  11. Cell Metab. 2024 Feb 13. pii: S1550-4131(24)00013-5. [Epub ahead of print]
    SLC25A51 decouples the mitochondrial NAD+/NADH ratio to control proliferation of AML cells.
    Mu-Jie Lu, Jonathan Busquets, Valeria Impedovo, Crystal N Wilson, Hsin-Ru Chan, Yu-Tai Chang, William Matsui, Stefano Tiziani, Xiaolu A Cambronne.
      SLC25A51 selectively imports oxidized NAD+ into the mitochondrial matrix and is required for sustaining cell respiration. We observed elevated expression of SLC25A51 that correlated with poorer outcomes in patients with acute myeloid leukemia (AML), and we sought to determine the role SLC25A51 may serve in this disease. We found that lowering SLC25A51 levels led to increased apoptosis and prolonged survival in orthotopic xenograft models. Metabolic flux analyses indicated that depletion of SLC25A51 shunted flux away from mitochondrial oxidative pathways, notably without increased glycolytic flux. Depletion of SLC25A51 combined with 5-azacytidine treatment limits expansion of AML cells in vivo. Together, the data indicate that AML cells upregulate SLC25A51 to decouple mitochondrial NAD+/NADH for a proliferative advantage by supporting oxidative reactions from a variety of fuels. Thus, SLC25A51 represents a critical regulator that can be exploited by cancer cells and may be a vulnerability for refractory AML.
    Keywords:  AML; MCART1; SLC25A51; glutamine utilization; oxidative mitochondria; tumor metabolism
    DOI:  https://doi.org/10.1016/j.cmet.2024.01.013
  12. Clin Cancer Res. 2024 Feb 16.
    PPARα Agonism Enhances Immune Response to Radiotherapy while Dietary Oleic Acid Results in Counteraction.
    Richard Blake Ross, Jacob Gadwa, Justin Yu, Laurel B Darragh, Michael W Knitz, Diemmy Nguyen, Nicholas A Olimpo, Khalid N M Abdelazeem, Alexander Nguyen, Sophia Corbo, Benjamin Van Court, Jessica Beynor, Brooke Neupert, Anthony J Saviola, Angelo D'Alessandro, Sana D Karam.
       INTRODUCTION: Head and neck cancer (HNC) improvements are stagnant, even with advances in immunotherapy. Our previous clinical trial data show altered fatty acid (FA) metabolism correlates with outcome. We hypothesized that pharmacologic and dietary modulation of FA catabolism will impact therapeutic efficacy.
    METHODS: We performed in vivo and in vitro experiments employing PPARα agonism with fenofibrate (FF) or high oleic acid diets (OAD) with radiotherapy, generating metabolomic, proteomic, stable isotope tracing, extracellular flux analysis, and flow cytometric data to investigate these alterations.
    RESULTS: FF improved anti-tumor efficacy of high dose per fraction radiotherapy in HNC murine models, while the OAD reversed this effect. FF treated mice on the control diet had evidence of increased FA catabolism. Stable isotope tracing showed less glycolytic utilization by ex vivo CD8+ T cells. Improved efficacy correlated with intratumoral alterations in eicosanoid metabolism and downregulated mTOR and CD36.
    CONCLUSION: Metabolic intervention with increased FA catabolism improves efficacy of HNC therapy and enhance anti-tumoral immune response.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-23-3433
  13. Cell Metab. 2024 Feb 08. pii: S1550-4131(24)00012-3. [Epub ahead of print]
    Dietary elaidic acid boosts tumoral antigen presentation and cancer immunity via ACSL5.
    Yongfeng Lai, Yuan Gao, Junhong Lin, Fangfang Liu, Liguo Yang, Jie Zhou, Ying Xue, Yan Li, Zhenzhen Chang, Jing Li, Tengfei Chao, Jing Chen, Xiang Cheng, Xianfu Gao, Xiong Li, Fujia Lu, Qian Chu, Weimin Wang.
      Immunomodulatory effects of long-chain fatty acids (LCFAs) and their activating enzyme, acyl-coenzyme A (CoA) synthetase long-chain family (ACSL), in the tumor microenvironment remain largely unknown. Here, we find that ACSL5 functions as an immune-dependent tumor suppressor. ACSL5 expression sensitizes tumors to PD-1 blockade therapy in vivo and the cytotoxicity mediated by CD8+ T cells in vitro via regulation of major histocompatibility complex class I (MHC-I)-mediated antigen presentation. Through screening potential substrates for ACSL5, we further identify that elaidic acid (EA), a trans LCFA that has long been considered harmful to human health, phenocopies to enhance MHC-I expression. EA supplementation can suppress tumor growth and sensitize PD-1 blockade therapy. Clinically, ACSL5 expression is positively associated with improved survival in patients with lung cancer, and plasma EA level is also predictive for immunotherapy efficiency. Our findings provide a foundation for enhancing immunotherapy through either targeting ACSL5 or metabolic reprogramming of antigen presentation via dietary EA supplementation.
    Keywords:  ACSL5; CD8(+) T cell; MHC class I; NLRC5; antigen presentation; checkpoint blockade; elaidic acid; immunotherapy; long-chain fatty acids
    DOI:  https://doi.org/10.1016/j.cmet.2024.01.012
  14. Cell Discov. 2024 Feb 13. 10(1): 17
    Ketogenic diet-produced β-hydroxybutyric acid accumulates brain GABA and increases GABA/glutamate ratio to inhibit epilepsy.
    Ya-Nan Qiao, Lei Li, Song-Hua Hu, Yuan-Xin Yang, Zhen-Zhen Ma, Lin Huang, Yan-Peng An, Yi-Yuan Yuan, Yan Lin, Wei Xu, Yao Li, Peng-Cheng Lin, Jing Cao, Jian-Yuan Zhao, Shi-Min Zhao.
      Ketogenic diet (KD) alleviates refractory epilepsy and reduces seizures in children. However, the metabolic/cell biologic mechanisms by which the KD exerts its antiepileptic efficacy remain elusive. Herein, we report that KD-produced β-hydroxybutyric acid (BHB) augments brain gamma-aminobutyric acid (GABA) and the GABA/glutamate ratio to inhibit epilepsy. The KD ameliorated pentetrazol-induced epilepsy in mice. Mechanistically, KD-produced BHB, but not other ketone bodies, inhibited HDAC1/HDAC2, increased H3K27 acetylation, and transcriptionally upregulated SIRT4 and glutamate decarboxylase 1 (GAD1). BHB-induced SIRT4 de-carbamylated and inactivated glutamate dehydrogenase to preserve glutamate for GABA synthesis, and GAD1 upregulation increased mouse brain GABA/glutamate ratio to inhibit neuron excitation. BHB administration in mice inhibited epilepsy induced by pentetrazol. BHB-mediated relief of epilepsy required high GABA level and GABA/glutamate ratio. These results identified BHB as the major antiepileptic metabolite of the KD and suggested that BHB may serve as an alternative and less toxic antiepileptic agent than KD.
    DOI:  https://doi.org/10.1038/s41421-023-00636-x
  15. J Cell Biochem. 2024 Feb 16.
    Induction of stearoyl-CoA desaturase confers cell density-dependent ferroptosis resistance in melanoma.
    Hitomi Shirahama, Yuri Tani, Satomi Tsukahara, Yuka Okamoto, Akiko Hasebe, Tomomiki Noda, Shuji Ando, Masaru Ushijima, Masaaki Matsuura, Akihiro Tomida.
      Ferroptosis is a form of regulated cell death that is induced by inhibiting glutathione peroxidase 4 (GPX4), which eliminates lipid peroxidation. Ferroptosis induction is influenced by the cell environment. However, the cellular states altering ferroptosis susceptibility remain largely unknown. We found that melanoma cell lines became resistant to ferroptosis as cell density increased. Comparative transcriptome and metabolome analyses revealed that cell density-dependent ferroptosis resistance was coupled with a shift toward a lipogenic phenotype accompanied by strong induction of stearoyl-CoA desaturase (SCD). Database analysis of gene dependency across hundreds of cancer cell lines uncovered a negative correlation between GPX4 and SCD dependency. Importantly, SCD inhibition, either pharmacologically or through genetic knockout, sensitized melanoma cells to GPX4 inhibition, thereby attenuating ferroptosis resistance in cells at high density. Our findings indicate that transition to an SCD-inducing, lipogenic cell state produces density-dependent resistance to ferroptosis, which may provide a therapeutic strategy against melanoma.
    Keywords:  ferroptosis; glutathione peroxidase 4; melanoma; stearoyl-CoA desaturase
    DOI:  https://doi.org/10.1002/jcb.30542
  16. Cancer Immunol Immunother. 2024 Feb 13. 73(3): 52
    Targeting metabolic sensing switch GPR84 on macrophages for cancer immunotherapy.
    Jianying Li, Anjun Ma, Ruohan Zhang, Yao Chen, Chelsea Bolyard, Bao Zhao, Cankun Wang, Thera Pich, Wantong Li, Nuo Sun, Qin Ma, Haitao Wen, Steven K Clinton, William E Carson, Zihai Li, Gang Xin.
       INTRODUCTION: As one of the major components of the tumor microenvironment, tumor-associated macrophages (TAMs) possess profound inhibitory activity against T cells and facilitate tumor escape from immune checkpoint blockade therapy. Converting this pro-tumorigenic toward the anti-tumorigenic phenotype thus is an important strategy for enhancing adaptive immunity against cancer. However, a plethora of mechanisms have been described for pro-tumorigenic differentiation in cancer, metabolic switches to program the anti-tumorigenic property of TAMs are elusive.
    MATERIALS AND METHODS: From an unbiased analysis of single-cell transcriptome data from multiple tumor models, we discovered that anti-tumorigenic TAMs uniquely express elevated levels of a specific fatty acid receptor, G-protein-coupled receptor 84 (GPR84). Genetic ablation of GPR84 in mice leads to impaired pro-inflammatory polarization of macrophages, while enhancing their anti-inflammatory phenotype. By contrast, GPR84 activation by its agonist, 6-n-octylaminouracil (6-OAU), potentiates pro-inflammatory phenotype via the enhanced STAT1 pathway. Moreover, 6-OAU treatment significantly retards tumor growth and increases the anti-tumor efficacy of anti-PD-1 therapy.
    CONCLUSION: Overall, we report a previously unappreciated fatty acid receptor, GPR84, that serves as an important metabolic sensing switch for orchestrating anti-tumorigenic macrophage polarization. Pharmacological agonists of GPR84 hold promise to reshape and reverse the immunosuppressive TME, and thereby restore responsiveness of cancer to overcome resistance to immune checkpoint blockade.
    Keywords:  Cancer immunotherapy; Immunometabolsim; Tumor-associated macrophage
    DOI:  https://doi.org/10.1007/s00262-023-03603-3
  17. Cell. 2024 Feb 08. pii: S0092-8674(24)00067-9. [Epub ahead of print]
    Phospholipids with two polyunsaturated fatty acyl tails promote ferroptosis.
    Baiyu Qiu, Fereshteh Zandkarimi, Carla T Bezjian, Eduard Reznik, Rajesh Kumar Soni, Wei Gu, Xuejun Jiang, Brent R Stockwell.
      Phospholipids containing a single polyunsaturated fatty acyl tail (PL-PUFA1s) are considered the driving force behind ferroptosis, whereas phospholipids with diacyl-PUFA tails (PL-PUFA2s) have been rarely characterized. Dietary lipids modulate ferroptosis, but the mechanisms governing lipid metabolism and ferroptosis sensitivity are not well understood. Our research revealed a significant accumulation of diacyl-PUFA phosphatidylcholines (PC-PUFA2s) following fatty acid or phospholipid treatments, correlating with cancer cell sensitivity to ferroptosis. Depletion of PC-PUFA2s occurred in aging and Huntington's disease brain tissue, linking it to ferroptosis. Notably, PC-PUFA2s interacted with the mitochondrial electron transport chain, generating reactive oxygen species (ROS) for initiating lipid peroxidation. Mitochondria-targeted antioxidants protected cells from PC-PUFA2-induced mitochondrial ROS (mtROS), lipid peroxidation, and cell death. These findings reveal a critical role for PC-PUFA2s in controlling mitochondria homeostasis and ferroptosis in various contexts and explain the ferroptosis-modulating mechanisms of free fatty acids. PC-PUFA2s may serve as diagnostic and therapeutic targets for modulating ferroptosis.
    Keywords:  PUFA; ROS; complex I; diacyl-PUFA phosphatidylcholine; electron transport chain; ferroptosis; lipids; mitochondria; phospholipid; polyunsaturated fatty acid
    DOI:  https://doi.org/10.1016/j.cell.2024.01.030
  18. Nat Rev Mol Cell Biol. 2024 Feb 16.
    The cell biology of ferroptosis.
    Scott J Dixon, James A Olzmann.
      Ferroptosis is a non-apoptotic cell death mechanism characterized by iron-dependent membrane lipid peroxidation. Here, we review what is known about the cellular mechanisms mediating the execution and regulation of ferroptosis. We first consider how the accumulation of membrane lipid peroxides leads to the execution of ferroptosis by altering ion transport across the plasma membrane. We then discuss how metabolites and enzymes that are distributed in different compartments and organelles throughout the cell can regulate sensitivity to ferroptosis by impinging upon iron, lipid and redox metabolism. Indeed, metabolic pathways that reside in the mitochondria, endoplasmic reticulum, lipid droplets, peroxisomes and other organelles all contribute to the regulation of ferroptosis sensitivity. We note how the regulation of ferroptosis sensitivity by these different organelles and pathways seems to vary between different cells and death-inducing conditions. We also highlight transcriptional master regulators that integrate the functions of different pathways and organelles to modulate ferroptosis sensitivity globally. Throughout this Review, we highlight open questions and areas in which progress is needed to better understand the cell biology of ferroptosis.
    DOI:  https://doi.org/10.1038/s41580-024-00703-5
  19. J Clin Invest. 2024 Feb 15. pii: e176747. [Epub ahead of print]134(4):
    Nitric oxide in vascular biology: elegance in complexity.
    Joseph Loscalzo.
      
    DOI:  https://doi.org/10.1172/JCI176747
  20. Cell Rep. 2024 Feb 12. pii: S2211-1247(24)00101-3. [Epub ahead of print] 113773
    THBS1+ myeloid cells expand in SLD hepatocellular carcinoma and contribute to immunosuppression and unfavorable prognosis through TREM1.
    Julie Giraud, Domitille Chalopin, Eloïse Ramel, Thomas Boyer, Atika Zouine, Marie-Alix Derieppe, Nicolas Larmonier, Olivier Adotevi, Brigitte Le Bail, Jean-Frédéric Blanc, Christophe Laurent, Laurence Chiche, Marc Derive, Macha Nikolski, Maya Saleh.
      Hepatocellular carcinoma (HCC) is an inflammation-associated cancer arising from viral or non-viral etiologies including steatotic liver diseases (SLDs). Expansion of immunosuppressive myeloid cells is a hallmark of inflammation and cancer, but their heterogeneity in HCC is not fully resolved and might underlie immunotherapy resistance. Here, we present a high-resolution atlas of innate immune cells from patients with HCC that unravels an SLD-associated contexture characterized by influx of inflammatory and immunosuppressive myeloid cells, including a discrete population of THBS1+ regulatory myeloid (Mreg) cells expressing monocyte- and neutrophil-affiliated genes. THBS1+ Mreg cells expand in SLD-associated HCC, populate fibrotic lesions, and are associated with poor prognosis. THBS1+ Mreg cells are CD163+ but distinguished from macrophages by high expression of triggering receptor expressed on myeloid cells 1 (TREM1), which contributes to their immunosuppressive activity and promotes HCC tumor growth in vivo. Our data support myeloid subset-targeted immunotherapies to treat HCC.
    Keywords:  CP: Cancer; TREM1; hepatocellular carcinoma; immunotherapy; inflammation; innate immunity; liver cancer; metabolism; myeloid cells; steatohepatitis
    DOI:  https://doi.org/10.1016/j.celrep.2024.113773
  21. Cell Rep. 2024 Feb 12. pii: S2211-1247(24)00066-4. [Epub ahead of print]43(2): 113738
    Proline restores mitochondrial function and reverses aging hallmarks in senescent cells.
    Debanik Choudhury, Na Rong, Hamsa Vardini Senthil Kumar, Sydney Swedick, Ronel Z Samuel, Pihu Mehrotra, John Toftegaard, Nika Rajabian, Ramkumar Thiyagarajan, Ashis K Podder, Yulun Wu, Shahryar Shahini, Kenneth L Seldeen, Bruce Troen, Pedro Lei, Stelios T Andreadis.
      Mitochondrial dysfunction is a hallmark of cellular senescence, with the loss of mitochondrial function identified as a potential causal factor contributing to senescence-associated decline in cellular functions. Our recent findings revealed that ectopic expression of the pluripotency transcription factor NANOG rejuvenates dysfunctional mitochondria of senescent cells by rewiring metabolic pathways. In this study, we report that NANOG restores the expression of key enzymes, PYCR1 and PYCR2, in the proline biosynthesis pathway. Additionally, senescent mesenchymal stem cells manifest severe mitochondrial respiratory impairment, which is alleviated through proline supplementation. Proline induces mitophagy by activating AMP-activated protein kinase α and upregulating Parkin expression, enhancing mitochondrial clearance and ultimately restoring cell metabolism. Notably, proline treatment also mitigates several aging hallmarks, including DNA damage, senescence-associated β-galactosidase, inflammatory cytokine expressions, and impaired myogenic differentiation capacity. Overall, this study highlights the role of proline in mitophagy and its potential in reversing senescence-associated mitochondrial dysfunction and aging hallmarks.
    Keywords:  AMPKα; CP: Cell biology; CP: Metabolism; Parkin; aging; amino acid; autophagy; mitochondria; mitophagy; proline; senescence
    DOI:  https://doi.org/10.1016/j.celrep.2024.113738
  22. Nature. 2024 Feb 14.
    Structure of human phagocyte NADPH oxidase in the activated state.
    Xiaoyu Liu, Yiting Shi, Rui Liu, Kangcheng Song, Lei Chen.
      Phagocyte NADPH oxidase, a protein complex with a core made up of NOX2 and p22 subunits, is responsible for transferring electrons from intracellular NADPH to extracellular oxygen1. This process generates superoxide anions that are vital for killing pathogens1. The activation of phagocyte NADPH oxidase requires membrane translocation and the binding of several cytosolic factors2. However, the exact mechanism by which cytosolic factors bind to and activate NOX2 is not well understood. Here we present the structure of the human NOX2-p22 complex activated by fragments of three cytosolic factors: p47, p67 and Rac1. The structure reveals that the p67-Rac1 complex clamps onto the dehydrogenase domain of NOX2 and induces its contraction, which stabilizes the binding of NADPH and results in a reduction of the distance between the NADPH-binding domain and the flavin adenine dinucleotide (FAD)-binding domain. Furthermore, the dehydrogenase domain docks onto the bottom of the transmembrane domain of NOX2, which reduces the distance between FAD and the inner haem. These structural rearrangements might facilitate the efficient transfer of electrons between the redox centres in NOX2 and lead to the activation of phagocyte NADPH oxidase.
    DOI:  https://doi.org/10.1038/s41586-024-07056-1
  23. Redox Biol. 2024 Feb 11. pii: S2213-2317(24)00061-2. [Epub ahead of print]70 103085
    Neurogranin expression regulates mitochondrial function and redox balance in endothelial cells.
    Ashton N Jorgensen, Nabil A Rashdan, K N Shashanka Rao, Luisa F Delgadillo, Gopi K Kolluru, David M Krzywanski, Christopher B Pattillo, Christopher G Kevil, Hyung W Nam.
      Endothelial dysfunction and endothelial activation are common early events in vascular diseases and can arise from mitochondrial dysfunction. Neurogranin (Ng) is a 17kD protein well known to regulate intracellular Ca2+-calmodulin (CaM) complex signaling, and its dysfunction is significantly implicated in brain aging and neurodegenerative diseases. We found that Ng is also expressed in human aortic endothelial cells (HAECs), and depleting Ng promotes Ca2+-CaM complex-dependent endothelial activation and redox imbalances. Endothelial-specific Ng knockout (Cre-CDH5-Ngf/f) mice demonstrate a significant delay in the flow-mediated dilation (FMD) response. Therefore, it is critical to characterize how endothelial Ng expression regulates reactive oxygen species (ROS) generation and affects cardiovascular disease. Label-free quantification proteomics identified that mitochondrial dysfunction and the oxidative phosphorylation pathway are significantly changed in the aorta of Cre-CDH5-Ngf/f mice. We found that a significant amount of Ng is expressed in the mitochondrial fraction of HAECs using western blotting and colocalized with the mitochondrial marker, COX IV, using immunofluorescence staining. Seahorse assay demonstrated that a lack of Ng decreases mitochondrial respiration. Treatment with MitoEbselen significantly restores the oxygen consumption rate in Ng knockdown cells. With the RoGFP-Orp1 approach, we identified that Ng knockdown increases mitochondrial-specific hydrogen peroxide (H2O2) production, and MitoEbselen treatment significantly reduced mitochondrial ROS (mtROS) levels in Ng knockdown cells. These results suggest that Ng plays a significant role in mtROS production. We discovered that MitoEbselen treatment also rescues decreased eNOS expression and nitric oxide (NO) levels in Ng knockdown cells, which implicates the critical role of Ng in mtROS-NO balance in the endothelial cells.
    Keywords:  Hydrogen peroxide; MitoEbselen; Mitochondria; Neurogranin; Reactive oxygen species
    DOI:  https://doi.org/10.1016/j.redox.2024.103085
  24. Immunity. 2024 Feb 13. pii: S1074-7613(24)00028-1. [Epub ahead of print]57(2): 333-348.e6
    A GPCR-neuropeptide axis dampens hyperactive neutrophils by promoting an alternative-like polarization during bacterial infection.
    Naina Gour, Hwan Mee Yong, Aishwarya Magesh, Aishwarya Atakkatan, Felipe Andrade, Stephane Lajoie, Xinzhong Dong.
      The notion that neutrophils exist as a homogeneous population is being replaced with the knowledge that neutrophils adopt different functional states. Neutrophils can have a pro-inflammatory phenotype or an anti-inflammatory state, but how these states are regulated remains unclear. Here, we demonstrated that the neutrophil-expressed G-protein-coupled receptor (GPCR) Mrgpra1 is a negative regulator of neutrophil bactericidal functions. Mrgpra1-mediated signaling was driven by its ligand, neuropeptide FF (NPFF), which dictated the balance between pro- and anti-inflammatory programming. Specifically, the Mrgpra1-NPFF axis counter-regulated interferon (IFN) γ-mediated neutrophil polarization during acute lung infection by favoring an alternative-like polarization, suggesting that it may act to balance overzealous neutrophilic responses. Distinct, cross-regulated populations of neutrophils were the primary source of NPFF and IFNγ during infection. As a subset of neutrophils at steady state expressed NPFF, these findings could have broad implications in various infectious and inflammatory diseases. Therefore, a neutrophil-intrinsic pathway determines their cellular fate, function, and magnitude of infection.
    Keywords:  IFNγ; Mrgpra1 GPCR; NPFF; lung infection; neuropeptide FF; neutrophil polarization; neutrophils
    DOI:  https://doi.org/10.1016/j.immuni.2024.01.003
  25. Sci Rep. 2024 02 13. 14(1): 3584
    Dynamic changes in the mouse hepatic lipidome following warm ischemia reperfusion injury.
    Kim H H Liss, Muhammad Mousa, Shria Bucha, Andrew Lutkewitte, Jeremy Allegood, L Ashley Cowart, Brian N Finck.
      Liver failure secondary to metabolic dysfunction-associated steatotic liver disease (MASLD) has become the most common cause for liver transplantation in many parts of the world. Moreover, the prevalence of MASLD not only increases the demand for liver transplantation, but also limits the supply of suitable donor organs because steatosis predisposes grafts to ischemia-reperfusion injury (IRI). There are currently no pharmacological interventions to limit hepatic IRI because the mechanisms by which steatosis leads to increased injury are unclear. To identify potential novel mediators of IRI, we used liquid chromatography and mass spectrometry to assess temporal changes in the hepatic lipidome in steatotic and non-steatotic livers after warm IRI in mice. Our untargeted analyses revealed distinct differences between the steatotic and non-steatotic response to IRI and highlighted dynamic changes in lipid composition with marked changes in glycerophospholipids. These findings enhance our knowledge of the lipidomic changes that occur following IRI and provide a foundation for future mechanistic studies. A better understanding of the mechanisms underlying such changes will lead to novel therapeutic strategies to combat IRI.
    DOI:  https://doi.org/10.1038/s41598-024-54122-9
  26. Nat Commun. 2024 Feb 12. 15(1): 1282
    EFHD2 suppresses intestinal inflammation by blocking intestinal epithelial cell TNFR1 internalization and cell death.
    Jiacheng Wu, Xiaoqing Xu, Jiaqi Duan, Yangyang Chai, Jiaying Song, Dongsheng Gong, Bingjing Wang, Ye Hu, Taotao Han, Yuanyuan Ding, Yin Liu, Jingnan Li, Xuetao Cao.
      TNF acts as one pathogenic driver for inducing intestinal epithelial cell (IEC) death and substantial intestinal inflammation. How the IEC death is regulated to physiologically prevent intestinal inflammation needs further investigation. Here, we report that EF-hand domain-containing protein D2 (EFHD2), highly expressed in normal intestine tissues but decreased in intestinal biopsy samples of ulcerative colitis patients, protects intestinal epithelium from TNF-induced IEC apoptosis. EFHD2 inhibits TNF-induced apoptosis in primary IECs and intestinal organoids (enteroids). Mice deficient of Efhd2 in IECs exhibit excessive IEC death and exacerbated experimental colitis. Mechanistically, EFHD2 interacts with Cofilin and suppresses Cofilin phosphorylation, thus blocking TNF receptor I (TNFR1) internalization to inhibit IEC apoptosis and consequently protecting intestine from inflammation. Our findings deepen the understanding of EFHD2 as the key regulator of membrane receptor trafficking, providing insight into death receptor signals and autoinflammatory diseases.
    DOI:  https://doi.org/10.1038/s41467-024-45539-x
  27. Proc Natl Acad Sci U S A. 2024 Feb 20. 121(8): e2314561121
    Methyltransferase Setd2 prevents T cell-mediated autoimmune diseases via phospholipid remodeling.
    Yali Chen, Kun Chen, Ha Zhu, Hua Qin, Juan Liu, Xuetao Cao.
      Coordinated metabolic reprogramming and epigenetic remodeling are critical for modulating T cell function and differentiation. However, how the epigenetic modification controls Th17/Treg cell balance via metabolic reprogramming remains obscure. Here, we find that Setd2, a histone H3K36 trimethyltransferase, suppresses Th17 development but promotes iTreg cell polarization via phospholipid remodeling. Mechanistically, Setd2 up-regulates transcriptional expression of lysophosphatidylcholine acyltransferase 4 (Lpcat4) via directly catalyzing H3K36me3 of Lpcat4 gene promoter in T cells. Lpcat4-mediated phosphatidylcholine PC(16:0,18:2) generation in turn limits endoplasmic reticulum stress and oxidative stress. These changes decrease HIF-1α transcriptional activity and thus suppress Th17 but enhance Treg development. Consistent with this regulatory paradigm, T cell deficiency of Setd2 aggravates neuroinflammation and demyelination in experimental autoimmune encephalomyelitis due to imbalanced Th17/Treg cell differentiation. Overall, our data reveal that Setd2 acts as an epigenetic brake for T cell-mediated autoimmunity through phospholipid remodeling, suggesting potential targets for treating neuroinflammatory diseases.
    Keywords:  Setd2; autoimmunity; lysophosphatidylcholine acyltransferase 4; phosphatidylcholine
    DOI:  https://doi.org/10.1073/pnas.2314561121
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