bims-mepmim Biomed News
on Metabolites in pathological microenvironments and immunometabolism
Issue of 2023–10–22
24 papers selected by
Erika Mariana Palmieri, NIH/NCI Laboratory of Cancer ImmunoMetabolism
  1. Identification of hyperoxidized PRDX3 as a ferroptosis marker reveals ferroptotic damage in chronic liver diseases.
  2. Polyamine metabolism controls B-to-Z DNA transition to orchestrate DNA sensor cGAS activity.
  3. Endogenous renal adiponectin drives gluconeogenesis through enhancing pyruvate and fatty acid utilization.
  4. GPR84-mediated signal transduction effects metabolic function by promoting brown adipocyte activity.
  5. ABHD6 suppression promotes anti-inflammatory polarization of adipose tissue macrophages via 2-monoacylglycerol/PPAR signaling in obese mice.
  6. Mitochondria-lysosome-related organelles mediate mitochondrial clearance during cellular dedifferentiation.
  7. Hepatoviruses promote very-long-chain fatty acid and sphingolipid synthesis for viral RNA replication and quasi-enveloped virus release.
  8. Proline uptake promotes activation of lymphoid tissue inducer cells to maintain gut homeostasis.
  9. CD36 maintains lipid homeostasis via selective uptake of monounsaturated fatty acids during matrix detachment and tumor progression.
  10. Combined metabolomic and lipidomic analysis uncovers metabolic profile and biomarkers for papillary thyroid carcinoma.
  11. A1 is induced by pathogen ligands to limit myeloid cell death and NLRP3 inflammasome activation.
  12. Metabolic stratification of human breast tumors reveal subtypes of clinical and therapeutic relevance.
  13. Aspartyl-tRNA synthetase 2 orchestrates iron-sulfur metabolism in hematopoietic stem cells via fine-tuning alternative RNA splicing.
  14. Pyrroline-5-carboxylate reductase 1 reprograms proline metabolism to drive breast cancer stemness under psychological stress.
  15. Nutritional and metabolic control of germ cell fate through O-GlcNAc regulation.
  16. The cellular states and fates of shed intestinal cells.
  17. The GR-KLF15 axis promotes suppression of hepatic lipogenesis during fasting.
  18. High-resolution structural proteomics of mitochondria using the 'Build and Retrieve' methodology.
  19. The dimerized pentraxin-like domain of the adhesion G protein-coupled receptor 112 (ADGRG4) suggests function in sensing mechanical forces.
  20. Fatty Acids Increase GDF15 and Reduce Food Intake Through a GFRAL Signaling Axis.
  21. The murine retinal pigment epithelium requires peroxisomal β-oxidation to maintain lysosomal function and prevent dedifferentiation.
  22. Hematopoietic stem cells undergo a lymphoid to myeloid switch in early stages of emergency granulopoiesis.
  23. Tumor-resident Lactobacillus iners confer chemoradiation resistance through lactate-induced metabolic rewiring.
  24. A redox-based characterization of human immune cell subsets by polychromatic flow cytometry.
  1. Mol Cell. 2023 Oct 17. pii: S1097-2765(23)00752-9. [Epub ahead of print]
    Identification of hyperoxidized PRDX3 as a ferroptosis marker reveals ferroptotic damage in chronic liver diseases.
    Shaojie Cui, Anchal Ghai, Yaqin Deng, Shili Li, Ruihui Zhang, Christopher Egbulefu, Guosheng Liang, Samuel Achilefu, Jin Ye.
      Ferroptosis, a regulated cell death pathway driven by accumulation of phospholipid peroxides, has been challenging to identify in physiological conditions owing to the lack of a specific marker. Here, we identify hyperoxidized peroxiredoxin 3 (PRDX3) as a marker for ferroptosis both in vitro and in vivo. During ferroptosis, mitochondrial lipid peroxides trigger PRDX3 hyperoxidation, a posttranslational modification that converts a Cys thiol to sulfinic or sulfonic acid. Once hyperoxidized, PRDX3 translocates from mitochondria to plasma membranes, where it inhibits cystine uptake, thereby causing ferroptosis. Applying hyperoxidized PRDX3 as a marker, we determined that ferroptosis is responsible for death of hepatocytes in mouse models of both alcoholic and nonalcoholic fatty liver diseases, the most prevalent chronic liver disorders. Our study highlights the importance of ferroptosis in pathophysiological conditions and opens the possibility to treat these liver diseases with drugs that inhibit ferroptosis.
    Keywords:  AFLD; NAFLD; PRDX3; cell death marker; ferroptosis; hyperoxidation
    DOI:  https://doi.org/10.1016/j.molcel.2023.09.025
  2. Immunity. 2023 Oct 08. pii: S1074-7613(23)00417-X. [Epub ahead of print]
    Polyamine metabolism controls B-to-Z DNA transition to orchestrate DNA sensor cGAS activity.
    Chunyuan Zhao, Yunjin Ma, Minghui Zhang, Xiaoyan Gao, Wenbo Liang, Ying Qin, Yue Fu, Mutian Jia, Hui Song, Chengjiang Gao, Wei Zhao.
      Cyclic guanosine monophosphate (GMP)-AMP (cGAMP) synthase (cGAS) is a universal double-stranded DNA (dsDNA) sensor that recognizes foreign and self-DNA in the cytoplasm and initiates innate immune responses and has been implicated in various infectious and non-infectious contexts. cGAS binds to the backbone of dsDNA and generates the second messenger, cGAMP, which activates the stimulator of interferon genes (STING). Here, we show that the endogenous polyamines spermine and spermidine attenuated cGAS activity and innate immune responses. Mechanistically, spermine and spermidine induced the transition of B-form DNA to Z-form DNA (Z-DNA), thereby decreasing its binding affinity with cGAS. Spermidine/spermine N1-acetyltransferase 1 (SAT1), the rate-limiting enzyme in polyamine catabolism that decreases the cellular concentrations of spermine and spermidine, enhanced cGAS activation by inhibiting cellular Z-DNA accumulation; SAT1 deficiency promoted herpes simplex virus 1 (HSV-1) replication in vivo. The results indicate that spermine and spermidine induce dsDNA to adopt the Z-form conformation and that SAT1-mediated polyamine metabolism orchestrates cGAS activity.
    Keywords:  B-DNA; Z-DNA; cGAS; innate immunity; polyamine metabolism; spermidine; spermine; type I IFNs
    DOI:  https://doi.org/10.1016/j.immuni.2023.09.012
  3. Nat Commun. 2023 Oct 17. 14(1): 6531
    Endogenous renal adiponectin drives gluconeogenesis through enhancing pyruvate and fatty acid utilization.
    Toshiharu Onodera, May-Yun Wang, Joseph M Rutkowski, Stanislaw Deja, Shiuhwei Chen, Michael S Balzer, Dae-Seok Kim, Xuenan Sun, Yu A An, Bianca C Field, Charlotte Lee, Ei-Ichi Matsuo, Monika Mizerska, Ina Sanjana, Naoto Fujiwara, Christine M Kusminski, Ruth Gordillo, Laurent Gautron, Denise K Marciano, Ming Chang Hu, Shawn C Burgess, Katalin Susztak, Orson W Moe, Philipp E Scherer.
      Adiponectin is a secretory protein, primarily produced in adipocytes. However, low but detectable expression of adiponectin can be observed in cell types beyond adipocytes, particularly in kidney tubular cells, but its local renal role is unknown. We assessed the impact of renal adiponectin by utilizing male inducible kidney tubular cell-specific adiponectin overexpression or knockout mice. Kidney-specific adiponectin overexpression induces a doubling of phosphoenolpyruvate carboxylase expression and enhanced pyruvate-mediated glucose production, tricarboxylic acid cycle intermediates and an upregulation of fatty acid oxidation (FAO). Inhibition of FAO reduces the adiponectin-induced enhancement of glucose production, highlighting the role of FAO in the induction of renal gluconeogenesis. In contrast, mice lacking adiponectin in the kidney exhibit enhanced glucose tolerance, lower utilization and greater accumulation of lipid species. Hence, renal adiponectin is an inducer of gluconeogenesis by driving enhanced local FAO and further underlines the important systemic contribution of renal gluconeogenesis.
    DOI:  https://doi.org/10.1038/s41467-023-42188-4
  4. J Clin Invest. 2023 Oct 19. pii: e168992. [Epub ahead of print]
    GPR84-mediated signal transduction effects metabolic function by promoting brown adipocyte activity.
    Xuenan Sun, Yu A An, Vivian A Paschoal, Camila O De Souza, May-Yun Wang, Lavanya Vishvanath, Lorena Ma Bueno, Ayanna S Cobb, Joseph A Nieto Carrion, Madison E Ibe, Chao Li, Harrison A Kidd, Shiuhwei Chen, Wenhong Li, Rana K Gupta, Da Young Oh.
      The G protein-coupled receptor 84 (GPR84), a medium-chain fatty acid receptor, has garnered attention because of its potential involvement in a range of metabolic conditions. However, the precise mechanisms underlying this effect remain elusive. Our study has shed light on the pivotal role of GPR84, revealing its robust expression and functional significance within the brown adipose tissue (BAT). Mice lacking GPR84 exhibited increased lipid accumulation in BAT, rendering them more susceptible to cold exposure, and displaying reduced BAT activity compared to their wild-type counterparts. Our in vitro experiments with primary brown adipocytes from GPR84 knockout mice revealed diminished expression of thermogenic genes and reduced O2 consumption. Furthermore, the application of the GPR84 agonist 6-OAU counteracted these effects, effectively reinstating the brown adipocyte activity. These compelling in vivo and in vitro findings converge to highlight mitochondrial dysfunction as the primary cause of BAT anomalies in GPR84 knockout mice. The activation of GPR84 induced an increase in intracellular Ca2+ levels, which intricately influences mitochondrial respiration. By modulating mitochondrial Ca2+ levels and respiration, GPR84 has emerged as a potent molecule involved in BAT activity. These findings suggested that GPR84 is a potential therapeutic target for invigorating BAT and ameliorating metabolic disorders.
    Keywords:  Adipose tissue; Calcium; Cell Biology; Metabolism; Molecular biology
    DOI:  https://doi.org/10.1172/JCI168992
  5. Mol Metab. 2023 Oct 12. pii: S2212-8778(23)00156-4. [Epub ahead of print] 101822
    ABHD6 suppression promotes anti-inflammatory polarization of adipose tissue macrophages via 2-monoacylglycerol/PPAR signaling in obese mice.
    P Poursharifi, C Schmitt, I Chenier, Y H Leung, A K Oppong, Y Bai, L-L Klein, A Al-Mass, R Lussier, M Abu-Farha, J Abubaker, F Al-Mulla, M-L Peyot, S R M Madiraju, M Prentki.
       OBJECTIVE: Pro-inflammatory polarization of adipose tissue macrophages (ATMs) plays a critical role in the pathogenesis of obesity-associated chronic inflammation. However, little is known about the role of lipids in the regulation of ATMs polarity and inflammation in response to metabolic stress. Deletion of α/β-hydrolase domain-containing 6 (ABHD6), a monoacylglycerol (MAG) hydrolase, has been shown to protect against diet-induced obesity and insulin resistance.
    METHODS AND RESULTS: Here we investigated the immunometabolic role of macrophage ABHD6 in response to nutrient excess. Whole-body ABHD6 KO mice on high-fat diet showed lower susceptibility to systemic diet-induced inflammation. Moreover, in the setting of overnutrition, stromal vascular cells from gonadal fat of KO vs. control mice contained lower number of M1 macrophages and exhibited enhanced levels of metabolically activated macrophages (MMe) and M2 markers, oxygen consumption, and interleukin-6 (IL-6) release. Likewise, under in vitro nutri-stress condition, pharmacological inhibition of ABHD6 in MMe-polarized macrophages attenuated the expression and release of pro-inflammatory cytokines and M1 markers and induced the upregulation of lipid metabolism genes. ABHD6-inhibited MMe macrophages showed elevated levels of peroxisome proliferator-activated receptors (PPARs) and 2-MAG species. Notably, among different MAG species, only 2-MAG treatment led to increased levels of PPAR target genes in MMe macrophages.
    CONCLUSIONS: Collectively, our findings identify ABHD6 as a key component of pro-inflammatory macrophage activation in response to excess nutrition and implicate an endogenous macrophage lipolysis/2-MAG/PPARs cascade, as a lipid signaling and immunometabolic pathway, which favors the anti-inflammatory polarization of ATMs in obesity.
    Keywords:  Immunometabolism; Inflammation; Lipid metabolism; Macrophage; Monoacylglycerol; α/β-hydrolase domain-containing 6
    DOI:  https://doi.org/10.1016/j.molmet.2023.101822
  6. Cell Rep. 2023 Oct 19. pii: S2211-1247(23)01303-7. [Epub ahead of print]42(10): 113291
    Mitochondria-lysosome-related organelles mediate mitochondrial clearance during cellular dedifferentiation.
    Xiaowen Ma, Sharon Manley, Hui Qian, Yuan Li, Chen Zhang, Kevin Li, Benjamin Ding, Fengli Guo, Allen Chen, Xing Zhang, Meilian Liu, Meihua Hao, Benjamin Kugler, E Matthew Morris, John Thyfault, Ling Yang, Hiromi Sesaki, Hong-Min Ni, Heidi McBride, Wen-Xing Ding.
      Dysfunctional mitochondria are removed via multiple pathways, such as mitophagy, a selective autophagy process. Here, we identify an intracellular hybrid mitochondria-lysosome organelle (termed the mitochondria-lysosome-related organelle [MLRO]), which regulates mitochondrial homeostasis independent of canonical mitophagy during hepatocyte dedifferentiation. The MLRO is an electron-dense organelle that has either a single or double membrane with both mitochondria and lysosome markers. Mechanistically, the MLRO is likely formed from the fusion of mitochondria-derived vesicles (MDVs) with lysosomes through a PARKIN-, ATG5-, and DRP1-independent process, which is negatively regulated by transcription factor EB (TFEB) and associated with mitochondrial protein degradation and hepatocyte dedifferentiation. The MLRO, which is galectin-3 positive, is reminiscent of damaged lysosome and could be cleared by overexpression of TFEB, resulting in attenuation of hepatocyte dedifferentiation. Together, results from this study suggest that the MLRO may act as an alternative mechanism for mitochondrial quality control independent of canonical autophagy/mitophagy involved in cell dedifferentiation.
    Keywords:  ATG5; CP: Cell biology; DRP1; autophagy; hepatocytes; lysosome; mitophagy
    DOI:  https://doi.org/10.1016/j.celrep.2023.113291
  7. Sci Adv. 2023 Oct 20. 9(42): eadj4198
    Hepatoviruses promote very-long-chain fatty acid and sphingolipid synthesis for viral RNA replication and quasi-enveloped virus release.
    Tomoyuki Shiota, Zhucui Li, Guan-Yuan Chen, Kevin L McKnight, Takayoshi Shirasaki, Bryan Yonish, Heyjeong Kim, Ethan J Fritch, Timothy P Sheahan, Masamichi Muramatsu, Maryna Kapustina, Craig E Cameron, You Li, Qibin Zhang, Stanley M Lemon.
      Virus-induced changes in host lipid metabolism are an important but poorly understood aspect of viral pathogenesis. By combining nontargeted lipidomics analyses of infected cells and purified extracellular quasi-enveloped virions with high-throughput RNA sequencing and genetic depletion studies, we show that hepatitis A virus, an hepatotropic picornavirus, broadly manipulates the host cell lipid environment, enhancing synthesis of ceramides and other sphingolipids and transcriptionally activating acyl-coenzyme A synthetases and fatty acid elongases to import and activate long-chain fatty acids for entry into the fatty acid elongation cycle. Phospholipids with very-long-chain acyl tails (>C22) are essential for genome replication, whereas increases in sphingolipids support assembly and release of quasi-enveloped virions wrapped in membranes highly enriched for sphingomyelin and very-long-chain ceramides. Our data provide insight into how a pathogenic virus alters lipid flux in infected hepatocytes and demonstrate a distinction between lipid species required for viral RNA synthesis versus nonlytic quasi-enveloped virus release.
    DOI:  https://doi.org/10.1126/sciadv.adj4198
  8. Nat Metab. 2023 Oct 19.
    Proline uptake promotes activation of lymphoid tissue inducer cells to maintain gut homeostasis.
    Di Wu, Zongxian Li, Yime Zhang, Yinlian Zhang, Guanqun Ren, Yanyu Zeng, Huiying Liu, Weiqiang Guan, Xingyu Zhao, Peng Li, Luni Hu, Zhiyuan Hou, Jingjing Gong, Jun Li, Wenfei Jin, Zeping Hu, Changtao Jiang, Houhua Li, Chao Zhong.
      Metabolic regulation is integral to the proper functioning of innate lymphoid cells, yet the underlying mechanisms remain elusive. Here, we show that disruption of exogenous proline uptake, either through dietary restriction or by deficiency of the proline transporter Slc6a7, in lymphoid tissue inducer (LTi) cells, impairs LTi activation and aggravates dextran sodium sulfate-induced colitis in mice. With an integrative transcriptomic and metabolomic analysis, we profile the metabolic characteristics of various innate lymphoid cell subsets and reveal a notable enrichment of proline metabolism in LTi cells. Mechanistically, defective proline uptake diminishes the generation of reactive oxygen species, previously known to facilitate LTi activation. Additionally, LTi cells deficient in Slc6a7 display downregulation of Cebpb and Kdm6b, resulting in compromised transcriptional and epigenetic regulation of interleukin-22. Furthermore, our study uncovers the therapeutic potential of proline supplementation in alleviating colitis. Therefore, these findings shed light on the role of proline in facilitating LTi activation and ultimately contributing to gut homeostasis.
    DOI:  https://doi.org/10.1038/s42255-023-00908-6
  9. Cell Metab. 2023 Oct 10. pii: S1550-4131(23)00368-6. [Epub ahead of print]
    CD36 maintains lipid homeostasis via selective uptake of monounsaturated fatty acids during matrix detachment and tumor progression.
    Alexander R Terry, Veronique Nogueira, Hyunsoo Rho, Gopalakrishnan Ramakrishnan, Jing Li, Soeun Kang, Koralege C Pathmasiri, Sameer Ahmed Bhat, Liping Jiang, Shafi Kuchay, Stephanie M Cologna, Nissim Hay.
      A high-fat diet (HFD) promotes metastasis through increased uptake of saturated fatty acids (SFAs). The fatty acid transporter CD36 has been implicated in this process, but a detailed understanding of CD36 function is lacking. During matrix detachment, endoplasmic reticulum (ER) stress reduces SCD1 protein, resulting in increased lipid saturation. Subsequently, CD36 is induced in a p38- and AMPK-dependent manner to promote preferential uptake of monounsaturated fatty acids (MUFAs), thereby maintaining a balance between SFAs and MUFAs. In attached cells, CD36 palmitoylation is required for MUFA uptake and protection from palmitate-induced lipotoxicity. In breast cancer mouse models, CD36-deficiency induced ER stress while diminishing the pro-metastatic effect of HFD, and only a palmitoylation-proficient CD36 rescued this effect. Finally, AMPK-deficient tumors have reduced CD36 expression and are metastatically impaired, but ectopic CD36 expression restores their metastatic potential. Our results suggest that, rather than facilitating HFD-driven tumorigenesis, CD36 plays a supportive role by preventing SFA-induced lipotoxicity.
    Keywords:  CD36; cancer metabolism; fatty acids; matrix detachment; metastasis; palmitoylation
    DOI:  https://doi.org/10.1016/j.cmet.2023.09.012
  10. Sci Rep. 2023 Oct 17. 13(1): 17666
    Combined metabolomic and lipidomic analysis uncovers metabolic profile and biomarkers for papillary thyroid carcinoma.
    Zipeng Wang, Yiqin Yang, Yurong Xing, Dandan Si, Suhua Wang, Jiashuo Lin, Cai Li, Ji Zhang, Detao Yin.
      Papillary thyroid carcinoma (PTC) is the most common endocrine malignancy with a rapidly increasing incidence. The pathogenesis of PTC is unclear, but metabolic and lipidomic reprogramming may play a role in tumor growth. We applied ultra-performance liquid chromatography-tandem mass spectrometry to perform widely targeted metabolomics and lipidomics on plasma samples from 94 patients with PTC and 100 healthy controls. We identified 113 differential metabolites and 236 differential lipids, mainly involved in branched-chain amino acid metabolism, glutamate and glutamine metabolism, tricarboxylic acid cycle, and lipid metabolism. We also screened three potential metabolite biomarkers: sebacic acid, L-glutamine, and indole-3-carboxaldehyde. These biomarkers showed excellent diagnostic performance for PTC in both discovery and validation cohorts, with areas under the receiver operating characteristic curves of 0.994 and 0.925, respectively. Our findings reveal distinct metabolic and lipidomic features of PTC and provide novel targets for diagnosis and treatment.
    DOI:  https://doi.org/10.1038/s41598-023-41176-4
  11. EMBO Rep. 2023 Oct 17. e56865
    A1 is induced by pathogen ligands to limit myeloid cell death and NLRP3 inflammasome activation.
    Mary Speir, Hazel Tye, Timothy A Gottschalk, Daniel S Simpson, Tirta M Djajawi, Pankaj Deo, Rebecca L Ambrose, Stephanie A Conos, Jack Emery, Gilu Abraham, Ashlyn Pascoe, Sebastian A Hughes, Ashley Weir, Edwin D Hawkins, Isabella Kong, Marco J Herold, Jaclyn S Pearson, Najoua Lalaoui, Thomas Naderer, James E Vince, Kate E Lawlor.
      Programmed cell death pathways play an important role in innate immune responses to infection. Activation of intrinsic apoptosis promotes infected cell clearance; however, comparatively little is known about how this mode of cell death is regulated during infections and whether it can induce inflammation. Here, we identify that the pro-survival BCL-2 family member, A1, controls activation of the essential intrinsic apoptotic effectors BAX/BAK in macrophages and monocytes following bacterial lipopolysaccharide (LPS) sensing. We show that, due to its tight transcriptional and post-translational regulation, A1 acts as a molecular rheostat to regulate BAX/BAK-dependent apoptosis and the subsequent NLRP3 inflammasome-dependent and inflammasome-independent maturation of the inflammatory cytokine IL-1β. Furthermore, induction of A1 expression in inflammatory monocytes limits cell death modalities and IL-1β activation triggered by Neisseria gonorrhoeae-derived outer membrane vesicles (NOMVs). Consequently, A1-deficient mice exhibit heightened IL-1β production in response to NOMV injection. These findings reveal that bacteria can induce A1 expression to delay myeloid cell death and inflammatory responses, which has implications for the development of host-directed antimicrobial therapeutics.
    Keywords:  BCL-2A1; NLRP3; TLR ligation; mitochondrial apoptosis; myeloid cells
    DOI:  https://doi.org/10.15252/embr.202356865
  12. iScience. 2023 Oct 20. 26(10): 108059
    Metabolic stratification of human breast tumors reveal subtypes of clinical and therapeutic relevance.
    Mohammad A Iqbal, Shumaila Siddiqui, Kirk Smith, Prithvi Singh, Bhupender Kumar, Salem Chouaib, Sriram Chandrasekaran.
      Extensive metabolic heterogeneity in breast cancers has limited the deployment of metabolic therapies. To enable patient stratification, we studied the metabolic landscape in breast cancers (∼3000 patients combined) and identified three subtypes with increasing degrees of metabolic deregulation. Subtype M1 was found to be dependent on bile-acid biosynthesis, whereas M2 showed reliance on methionine pathway, and M3 engaged fatty-acid, nucleotide, and glucose metabolism. The extent of metabolic alterations correlated strongly with tumor aggressiveness and patient outcome. This pattern was reproducible in independent datasets and using in vivo tumor metabolite data. Using machine-learning, we identified robust and generalizable signatures of metabolic subtypes in tumors and cell lines. Experimental inhibition of metabolic pathways in cell lines representing metabolic subtypes revealed subtype-specific sensitivity, therapeutically relevant drugs, and promising combination therapies. Taken together, metabolic stratification of breast cancers can thus aid in predicting patient outcome and designing precision therapies.
    Keywords:  Medical informatics; cancer; computational bioinformatics
    DOI:  https://doi.org/10.1016/j.isci.2023.108059
  13. Cell Rep. 2023 Oct 13. pii: S2211-1247(23)01276-7. [Epub ahead of print]42(10): 113264
    Aspartyl-tRNA synthetase 2 orchestrates iron-sulfur metabolism in hematopoietic stem cells via fine-tuning alternative RNA splicing.
    Xuan Gu, Kailing Li, Meng Zhang, Yandan Chen, Jingchao Zhou, Chunxu Yao, Yong Zang, Jiefeng He, Jun Wan, Bin Guo.
      Aspartyl-tRNA synthetase 2 (Dars2) is involved in the regulation of mitochondrial protein synthesis and tissue-specific mitochondrial unfolded protein response (UPRmt). The role of Dars2 in the self-renewal and differentiation of hematopoietic stem cells (HSCs) is unknown. Here, we show that knockout (KO) of Dars2 significantly impairs the maintenance of hematopoietic stem and progenitor cells (HSPCs) without involving its tRNA synthetase activity. Dars2 KO results in significantly reduced expression of Srsf2/3/6 and impairs multiple events of mRNA alternative splicing (AS). Dars2 directly localizes to Srsf3-labeled spliceosomes in HSPCs and regulates the stability of Srsf3. Dars2-deficient HSPCs exhibit aberrant AS of mTOR and Slc22a17. Dars2 KO greatly suppresses the levels of labile ferrous iron and iron-sulfur cluster-containing proteins, which dampens mitochondrial metabolic activity and DNA damage repair pathways in HSPCs. Our study reveals that Dars2 plays a crucial role in the iron-sulfur metabolism and maintenance of HSPCs by modulating RNA splicing.
    Keywords:  CP: Metabolism; CP: Stem cell research
    DOI:  https://doi.org/10.1016/j.celrep.2023.113264
  14. Cell Death Dis. 2023 Oct 16. 14(10): 682
    Pyrroline-5-carboxylate reductase 1 reprograms proline metabolism to drive breast cancer stemness under psychological stress.
    Bai Cui, Bin He, Yanping Huang, Cenxin Wang, Huandong Luo, Jinxin Lu, Keyu Su, Xiaoyu Zhang, Yuanyuan Luo, Zhuoran Zhao, Yuqing Yang, Yunkun Zhang, Fan An, Hong Wang, Eric W-F Lam, Keith W Kelley, Ling Wang, Quentin Liu, Fei Peng.
      Cancer stem-like cells (CSCs) contribute to cancer metastasis, drug resistance and tumor relapse, yet how amino acid metabolism promotes CSC maintenance remains exclusive. Here, we identify that proline synthetase PYCR1 is critical for breast cancer stemness and tumor growth. Mechanistically, PYCR1-synthesized proline activates cGMP-PKG signaling to enhance cancer stem-like traits. Importantly, cGMP-PKG signaling mediates psychological stress-induced cancer stem-like phenotypes and tumorigenesis. Ablation of PYCR1 markedly reverses psychological stress-induced proline synthesis, cGMP-PKG signaling activation and cancer progression. Clinically, PYCR1 and cGMP-PKG signaling components are highly expressed in breast tumor specimens, conferring poor survival in breast cancer patients. Targeting proline metabolism or cGMP-PKG signaling pathway provides a potential therapeutic strategy for breast patients undergoing psychological stress. Collectively, our findings unveil that PYCR1-enhanced proline synthesis displays a critical role in maintaining breast cancer stemness.
    DOI:  https://doi.org/10.1038/s41419-023-06200-5
  15. EMBO Rep. 2023 Oct 16. e56845
    Nutritional and metabolic control of germ cell fate through O-GlcNAc regulation.
    Yohei Hayashi, Yukiko Tando, Yumi Ito-Matsuoka, Kaho Ikuta, Asuka Takehara, Katsutaro Morino, Hiroshi Maegawa, Yasuhisa Matsui.
      Fate determination of primordial germ cells (PGCs) is regulated in a multi-layered manner, involving signaling pathways, epigenetic mechanisms, and transcriptional control. Chemical modification of macromolecules, including epigenetics, is expected to be closely related with metabolic mechanisms but the detailed molecular machinery linking these two layers remains poorly understood. Here, we show that the hexosamine biosynthetic pathway controls PGC fate determination via O-linked β-N-acetylglucosamine (O-GlcNAc) modification. Consistent with this model, reduction of carbohydrate metabolism via a maternal ketogenic diet that decreases O-GlcNAcylation levels causes repression of PGC formation in vivo. Moreover, maternal ketogenic diet intake until mid-gestation affects the number of ovarian germ cells in newborn pups. Taken together, we show that nutritional and metabolic mechanisms play a previously unappreciated role in PGC fate determination.
    Keywords:  O-GlcNAcylation; germ cells; glucose metabolism; ketogenic diet; maternal nutrition
    DOI:  https://doi.org/10.15252/embr.202356845
  16. Nat Metab. 2023 Oct 19.
    The cellular states and fates of shed intestinal cells.
    Keren Bahar Halpern, Yael Korem Kohanim, Adi Biram, Yotam Harnik, Adi Egozi, Oran Yakubovsky, Ziv Shulman, Shalev Itzkovitz.
      The intestinal epithelium is replaced every few days1. Enterocytes are shed into the gut lumen predominantly from the tips of villi2,3 and have been believed to rapidly die upon their dissociation from the tissue4,5. However, technical limitations prohibited studying the cellular states and fates of shed intestinal cells. Here we show that shed epithelial cells remain viable and upregulate distinct anti-microbial programmes upon shedding, using bulk and single-cell RNA sequencing of male mouse intestinal faecal washes. We further identify abundant shedding of immune cells, which is elevated in mice with dextran sulfate sodium-induced colitis. We find that faecal host transcriptomics reflect changes in the intestinal tissue following perturbations. Our study suggests potential functions of shed cells in the intestinal lumen and demonstrates that host cell transcriptomes in intestinal washes can be used to probe tissue states.
    DOI:  https://doi.org/10.1038/s42255-023-00905-9
  17. FEBS J. 2023 Oct 18.
    The GR-KLF15 axis promotes suppression of hepatic lipogenesis during fasting.
    Jie Lu, Li Dong, Magdalene K Montgomery.
      Fasting leads to many physiological changes in peripheral tissues, including the liver, where suppression of de novo lipogenesis through inhibition of sterol regulatory element-binding protein 1 (SREBP-1) expression and/or activity is a key adaptation to preserve glucose for maintenance of blood glucose levels. Yoshinori Takeuchi and colleagues provide novel mechanistic insights into the regulation of SREBP-1 expression during fasting and highlight the importance of the hypothalamic-pituitary-adrenal axis and, particularly, glucocorticoid-induced binding of the glucocorticoid receptor to enhancer regions of the KLF15 (Kruppel-like factor 15) gene as a novel mechanism underlying the suppression of SREBP-1 during fasting.
    Keywords:  SREBP-1; fasting; glucocorticoid; lipid metabolism; lipogenesis
    DOI:  https://doi.org/10.1111/febs.16978
  18. Mol Cell Proteomics. 2023 Oct 13. pii: S1535-9476(23)00177-9. [Epub ahead of print] 100666
    High-resolution structural proteomics of mitochondria using the 'Build and Retrieve' methodology.
    Zhemin Zhang, Marios L Tringides, Christopher E Morgan, Masaru Miyagi, Jason A Mears, Charles L Hoppel, Edward W Yu.
      The application of integrated systems biology to the field of structural biology is a promising new direction, although it is still in the infant stages of development. Here we report the use of single particle cryo-electron microscopy (cryo-EM) to identify multiple proteins from three enriched heterogeneous fractions prepared from human liver mitochondrial lysate. We simultaneously identify and solve high-resolution structures of nine essential mitochondrial enzymes with key metabolic functions, including fatty acid catabolism, reactive oxidative species clearance and amino acid metabolism. Our methodology also identified multiple distinct members of the acyl-CoA dehydrogenase family. This work highlights the potential of cryo-EM to explore tissue proteomics at the atomic level.
    Keywords:  Aminotransferase; Catalase; Dehydrogenase; Dismutase; Isomerase
    DOI:  https://doi.org/10.1016/j.mcpro.2023.100666
  19. J Biol Chem. 2023 Oct 18. pii: S0021-9258(23)02384-0. [Epub ahead of print] 105356
    The dimerized pentraxin-like domain of the adhesion G protein-coupled receptor 112 (ADGRG4) suggests function in sensing mechanical forces.
    Björn Kieslich, Renato H Weiße, Jana Brendler, Albert Ricken, Torsten Schöneberg, Norbert Sträter.
      Adhesion G protein-coupled receptors (aGPCRs) feature large extracellular regions (ECRs) with modular domains that often resemble protein classes of various function. The pentraxin (PTX) domain, which is predicted by sequence homology within the ECR of four different aGPCR members, is well known to form pentamers and other oligomers. Oligomerization of GPCRs is frequently reported and mainly driven by interactions of the seven-transmembrane region and N- or C-termini. While the functional importance of dimers is well-established for some class C GPCRs, relatively little is known about aGPCR multimerization. Here, we showcase the example of ADGRG4, an orphan aGPCR that possesses a PTX-like domain at its very N-terminal tip, followed by an extremely long stalk containing serine-threonine repeats. Using X-ray crystallography and biophysical methods we determined the structure of this unusual PTX-like domain and provide experimental evidence for a homodimer equilibrium of this domain which is Ca2+-independent and driven by intermolecular contacts that differ vastly from the known soluble PTXs. The formation of this dimer seems to be conserved in mammalian ADGRG4 indicating functional relevance. Our data alongside of theoretical considerations lead to the hypothesis that ADGRG4 acts as an in vivo sensor for shear forces in enterochromaffin and Paneth cells of the small intestine.
    Keywords:  X-ray structure; adhesion G protein-coupled receptor; pentraxin; signal transduction
    DOI:  https://doi.org/10.1016/j.jbc.2023.105356
  20. Diabetes. 2023 Oct 17. pii: db230495. [Epub ahead of print]
    Fatty Acids Increase GDF15 and Reduce Food Intake Through a GFRAL Signaling Axis.
    Dongdong Wang, Maria Joy Therese Jabile, Junfeng Lu, Logan K Townsend, Celina M Valvano, Jaya Gautam, Battsetseg Batchuluun, Evangelia E Tsakiridis, James S V Lally, Gregory R Steinberg.
      In contrast to the well-defined biological feedback loops controlling glucose, the mechanisms by which the body responds to changes in fatty acid availability are less clearly defined. GDF15 suppresses the consumption of diets high in fat but is paradoxically increased in obese mice fed a high-fat diet. Given this interrelationship, we investigated whether diets high in fat could directly increase GDF15 independently of obesity. We found that fatty acids increase GDF15 levels dose-dependently with the greatest response observed with linolenic acid. GDF15 mRNA expression was modestly increased in the gastrointestinal tract, however, kidney GDF15 mRNA was ~1000-fold higher and was increased by over 3-fold with subsequent RNAscope analysis showing elevated expression within the cortex and outer medulla. Treatment of wildtype mice with linolenic acid reduced food intake and body mass, however, this effect was disappeared in mice lacking the GDF15 receptor GFRAL. An equal caloric load of glucose did not suppress food intake or reduce body mass in either WT or GFRAL KO mice. These data indicate that fatty acids such as linolenic acid increases GDF15 and suppresses food intake through a mechanism requiring GFRAL. These data suggest that a primary physiological function of GDF15 may be as a fatty acid sensor designed to protect cells from fatty acid overload.
    DOI:  https://doi.org/10.2337/db23-0495
  21. Proc Natl Acad Sci U S A. 2023 Oct 24. 120(43): e2301733120
    The murine retinal pigment epithelium requires peroxisomal β-oxidation to maintain lysosomal function and prevent dedifferentiation.
    Sai Kocherlakota, Yannick Das, Daniëlle Swinkels, Maarten Vanmunster, Manon Callens, Stefan Vinckier, Frédéric M Vaz, Debasish Sinha, Paul P Van Veldhoven, Marc Fransen, Myriam Baes.
      Retinal pigment epithelium (RPE) cells have to phagocytose shed photoreceptor outer segments (POS) on a daily basis over the lifetime of an organism, but the mechanisms involved in the digestion and recycling of POS lipids are poorly understood. Although it was frequently assumed that peroxisomes may play an essential role, this was never investigated. Here, we show that global as well as RPE-selective loss of peroxisomal β-oxidation in multifunctional protein 2 (MFP2) knockout mice impairs the digestive function of lysosomes in the RPE at a very early age, followed by RPE degeneration. This was accompanied by prolonged mammalian target of rapamycin activation, lipid deregulation, and mitochondrial structural anomalies without, however, causing oxidative stress or energy shortage. The RPE degeneration caused secondary photoreceptor death. Notably, the deterioration of the RPE did not occur in an Mfp2/rd1 mutant mouse line, characterized by absent POS shedding. Our findings prove that peroxisomal β-oxidation in the RPE is essential for handling the polyunsaturated fatty acids present in ingested POS and shed light on retinopathy in patients with peroxisomal disorders. Our data also have implications for gene therapy development as they highlight the importance of targeting the RPE in addition to the photoreceptor cells.
    Keywords:  lipids; lysosomes; peroxisomes; retinal degeneration; retinal pigment epithelium
    DOI:  https://doi.org/10.1073/pnas.2301733120
  22. EMBO J. 2023 Oct 17. e113527
    Hematopoietic stem cells undergo a lymphoid to myeloid switch in early stages of emergency granulopoiesis.
    Karolina Vanickova, Mirko Milosevic, Irina Ribeiro Bas, Monika Burocziova, Asumi Yokota, Petr Danek, Srdjan Grusanovic, Mateusz Chiliński, Dariusz Plewczynski, Jakub Rohlena, Hideyo Hirai, Katerina Rohlenova, Meritxell Alberich-Jorda.
      Emergency granulopoiesis is the enhanced and accelerated production of granulocytes that occurs during acute infection. The contribution of hematopoietic stem cells (HSCs) to this process was reported; however, how HSCs participate in emergency granulopoiesis remains elusive. Here, using a mouse model of emergency granulopoiesis we observe transcriptional changes in HSCs as early as 4 h after lipopolysaccharide (LPS) administration. We observe that the HSC identity is changed towards a myeloid-biased HSC and show that CD201 is enriched in lymphoid-biased HSCs. While CD201 expression under steady-state conditions reveals a lymphoid bias, under emergency granulopoiesis loss of CD201 marks the lymphoid-to-myeloid transcriptional switch. Mechanistically, we determine that lymphoid-biased CD201+ HSCs act as a first response during emergency granulopoiesis due to direct sensing of LPS by TLR4 and downstream activation of NF-κΒ signaling. The myeloid-biased CD201- HSC population responds indirectly during an acute infection by sensing G-CSF, increasing STAT3 phosphorylation, and upregulating LAP/LAP* C/EBPβ isoforms. In conclusion, HSC subpopulations support early phases of emergency granulopoiesis due to their transcriptional rewiring from a lymphoid-biased to myeloid-biased population and thus establishing alternative paths to supply elevated numbers of granulocytes.
    Keywords:  CD201; emergency granulopoiesis; lymphoid-biased HSC; myeloid-biased HSC
    DOI:  https://doi.org/10.15252/embj.2023113527
  23. Cancer Cell. 2023 Oct 16. pii: S1535-6108(23)00328-8. [Epub ahead of print]
    Tumor-resident Lactobacillus iners confer chemoradiation resistance through lactate-induced metabolic rewiring.
    Lauren E Colbert, Molly B El Alam, Rui Wang, Tatiana Karpinets, David Lo, Erica J Lynn, Timothy A Harris, Jacob H Elnaggar, Kyoko Yoshida-Court, Katarina Tomasic, Julianna K Bronk, Julie Sammouri, Ananta V Yanamandra, Adilene V Olvera, Lily G Carlin, Travis Sims, Andrea Y Delgado Medrano, Tatiana Cisneros Napravnik, Madison O'Hara, Daniel Lin, Chike O Abana, Hannah X Li, Patricia J Eifel, Anuja Jhingran, Melissa Joyner, Lilie Lin, Lois M Ramondetta, Andrew M Futreal, Kathleen M Schmeler, Geena Mathew, Stephanie Dorta-Estremera, Jianhua Zhang, Xiaogang Wu, Nadim J Ajami, Matthew Wong, Cullen Taniguchi, Joseph F Petrosino, K Jagannadha Sastry, Pablo C Okhuysen, Sara A Martinez, Lin Tan, Iqbal Mahmud, Philip L Lorenzi, Jennifer A Wargo, Ann H Klopp.
      Tumor microbiota can produce active metabolites that affect cancer and immune cell signaling, metabolism, and proliferation. Here, we explore tumor and gut microbiome features that affect chemoradiation response in patients with cervical cancer using a combined approach of deep microbiome sequencing, targeted bacterial culture, and in vitro assays. We identify that an obligate L-lactate-producing lactic acid bacterium found in tumors, Lactobacillus iners, is associated with decreased survival in patients, induces chemotherapy and radiation resistance in cervical cancer cells, and leads to metabolic rewiring, or alterations in multiple metabolic pathways, in tumors. Genomically similar L-lactate-producing lactic acid bacteria commensal to other body sites are also significantly associated with survival in colorectal, lung, head and neck, and skin cancers. Our findings demonstrate that lactic acid bacteria in the tumor microenvironment can alter tumor metabolism and lactate signaling pathways, causing therapeutic resistance. Lactic acid bacteria could be promising therapeutic targets across cancer types.
    Keywords:  cervical cancer; chemoradiation; lactate; metabolism; microbiome; radiation
    DOI:  https://doi.org/10.1016/j.ccell.2023.09.012
  24. STAR Protoc. 2023 Oct 13. pii: S2666-1667(23)00599-3. [Epub ahead of print]4(4): 102632
    A redox-based characterization of human immune cell subsets by polychromatic flow cytometry.
    Christina Pitsillidou, Ivan Muradore, Elena Pontarini, Milena Bertolotti, Alessandra Roberto.
      Cellular redox state determinants are traditionally studied using fluorescent microscopy and immunoblot analysis; however, no procedure has been developed for simultaneous measurement in various immune cell subsets. Here, we present a flow cytometry assay for measuring antioxidant defense systems and reactive oxygen species simultaneously in T, B, and natural killer lymphocytes. We describe steps for preparing and treating peripheral blood mononuclear cells, surface and dye staining, cell fixation/permeabilization, and intracellular staining. We then detail machine standardization, acquisition, and analysis.
    Keywords:  Cell Biology; Flow Cytometry; Immunology
    DOI:  https://doi.org/10.1016/j.xpro.2023.102632
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