bims-mepmim Biomed News
on Metabolites in pathological microenvironments and immunometabolism
Issue of 2024‒08‒11
seventeen papers selected by
Erika Mariana Palmieri, NIH/NCI Laboratory of Cancer ImmunoMetabolism
  1. Hierarchical tricarboxylic acid cycle regulation by hepatocyte arginase 2 links the urea cycle to oxidative metabolism.
  2. SLC25A48 controls mitochondrial choline import and metabolism.
  3. AMPK activation induces RALDH+ tolerogenic dendritic cells by rewiring glucose and lipid metabolism.
  4. Metabolic and transcriptomic reprogramming during contact inhibition-induced quiescence is mediated by YAP-dependent and YAP-independent mechanisms.
  5. Glycosphingolipid synthesis mediates immune evasion in KRAS-driven cancer.
  6. A co-ordinated transcriptional programme in the maternal liver supplies long chain polyunsaturated fatty acids to the conceptus using phospholipids.
  7. O-GlcNAcylation: A Major Nutrient/Stress Sensor that Regulates Cellular Physiology.
  8. Purinosomes spatially co-localize with mitochondrial transporters.
  9. The hemodynamic response to nitrite is acute and dependent upon tissue perfusion.
  10. Epigenetic repression of de novo cysteine synthetases induces intra-cellular accumulation of cysteine in hepatocarcinoma by up-regulating the cystine uptake transporter xCT.
  11. The polyunsaturated fatty acid docosahexaenoic affects mitochondrial function in prostate cancer cells.
  12. Neutrophil trapping and nexocytosis, mast cell-mediated processes for inflammatory signal relay.
  13. Cxcr4 regulates a pool of adipocyte progenitors and contributes to adiposity in a sex-dependent manner.
  14. Aspartate in tumor microenvironment and beyond: Metabolic interactions and therapeutic perspectives.
  15. Host-microbe interactions rewire metabolism in a C. elegans model of leucine breakdown deficiency.
  16. TDP-43 dysfunction leads to bioenergetic failure and lipid metabolic rewiring in human cells.
  17. CD38 deletion to preserve CAR T cell metabolism and promote functional persistence.
  1. Cell Metab. 2024 Aug 01. pii: S1550-4131(24)00278-X. [Epub ahead of print]
    Hierarchical tricarboxylic acid cycle regulation by hepatocyte arginase 2 links the urea cycle to oxidative metabolism.
    Yiming Zhang, Cassandra B Higgins, Stefani Tica, Joshua A Adams, Jiameng Sun, Shannon C Kelly, Xiaoyu Zong, Dennis J Dietzen, Terri Pietka, Samuel J Ballentine, Leah Shriver, Gary Patti, Yin Cao, Brian J DeBosch.
      Urea cycle impairment and its relationship to obesity and inflammation remained elusive, partly due to the dramatic clinical presentation of classical urea cycle defects. We generated mice with hepatocyte-specific arginase 2 deletion (Arg2LKO) and revealed a mild compensated urea cycle defect. Stable isotope tracing and respirometry revealed hepatocyte urea and TCA cycle flux defects, impaired mitochondrial oxidative metabolism, and glutamine anaplerosis despite normal energy and glucose homeostasis during early adulthood. Yet during middle adulthood, chow- and diet-induced obese Arg2LKO mice develop exaggerated glucose and lipid derangements, which are reversible by replacing the TCA cycle oxidative substrate nicotinamide adenine dinucleotide. Moreover, serum-based hallmarks of urea, TCA cycle, and mitochondrial derangements predict incident fibroinflammatory liver disease in 106,606 patients nearly a decade in advance. The data reveal hierarchical urea-TCA cycle control via ARG2 to drive oxidative metabolism. Moreover, perturbations in this circuit may causally link urea cycle compromise to fibroinflammatory liver disease.
    Keywords:  arginase; diabetes; fasting; metabolic dysfunction-associated steatohepatitis; metabolic dysfunction-associated steatotic liver disease; nicotinamide adenine dinucleotide; nicotinamide riboside; obesity; tricarboxylic acid cycle; urea cycle
    DOI:  https://doi.org/10.1016/j.cmet.2024.07.007
  2. Cell Metab. 2024 Aug 01. pii: S1550-4131(24)00281-X. [Epub ahead of print]
    SLC25A48 controls mitochondrial choline import and metabolism.
    Anthony R P Verkerke, Xu Shi, Mark Li, Yusuke Higuchi, Tadashi Yamamuro, Daisuke Katoh, Hiroshi Nishida, Christopher Auger, Ichitaro Abe, Robert E Gerszten, Shingo Kajimura.
      Choline is an essential nutrient for the biosynthesis of phospholipids, neurotransmitters, and one-carbon metabolism with a critical step being its import into mitochondria. However, the underlying mechanisms and biological significance remain poorly understood. Here, we report that SLC25A48, a previously uncharacterized mitochondrial inner-membrane carrier protein, controls mitochondrial choline transport and the synthesis of choline-derived methyl donors. We found that SLC25A48 was required for brown fat thermogenesis, mitochondrial respiration, and mitochondrial membrane integrity. Choline uptake into the mitochondrial matrix via SLC25A48 facilitated the synthesis of betaine and purine nucleotides, whereas loss of SLC25A48 resulted in increased production of mitochondrial reactive oxygen species and imbalanced mitochondrial lipids. Notably, human cells carrying a single nucleotide polymorphism on the SLC25A48 gene and cancer cells lacking SLC25A48 exhibited decreased mitochondrial choline import, increased oxidative stress, and impaired cell proliferation. Together, this study demonstrates that SLC25A48 regulates mitochondrial choline catabolism, bioenergetics, and cell survival.
    Keywords:  bioenergetics; brown adipose tissue; cancer metabolism; choline; mitochondria; purine nucleotides
    DOI:  https://doi.org/10.1016/j.cmet.2024.07.010
  3. J Cell Biol. 2024 Oct 07. pii: e202401024. [Epub ahead of print]223(10):
    AMPK activation induces RALDH+ tolerogenic dendritic cells by rewiring glucose and lipid metabolism.
    Eline C Brombacher, Thiago A Patente, Alwin J van der Ham, Tijmen J A Moll, Frank Otto, Fenne W M Verheijen, Esther A Zaal, Arnoud H de Ru, Rayman T N Tjokrodirijo, Celia R Berkers, Peter A van Veelen, Bruno Guigas, Bart Everts.
      Dendritic cell (DC) activation and function are underpinned by profound changes in cellular metabolism. Several studies indicate that the ability of DCs to promote tolerance is dependent on catabolic metabolism. Yet the contribution of AMP-activated kinase (AMPK), a central energy sensor promoting catabolism, to DC tolerogenicity remains unknown. Here, we show that AMPK activation renders human monocyte-derived DCs tolerogenic as evidenced by an enhanced ability to drive differentiation of regulatory T cells, a process dependent on increased RALDH activity. This is accompanied by several metabolic changes, including increased breakdown of glycerophospholipids, enhanced mitochondrial fission-dependent fatty acid oxidation, and upregulated glucose catabolism. This metabolic rewiring is functionally important as we found interference with these metabolic processes to reduce to various degrees AMPK-induced RALDH activity as well as the tolerogenic capacity of moDCs. Altogether, our findings reveal a key role for AMPK signaling in shaping DC tolerogenicity and suggest AMPK as a target to direct DC-driven tolerogenic responses in therapeutic settings.
    DOI:  https://doi.org/10.1083/jcb.202401024
  4. Nat Commun. 2024 Aug 08. 15(1): 6777
    Metabolic and transcriptomic reprogramming during contact inhibition-induced quiescence is mediated by YAP-dependent and YAP-independent mechanisms.
    Soeun Kang, Maciek R Antoniewicz, Nissim Hay.
      Metabolic rewiring during the proliferation-to-quiescence transition is poorly understood. Here, using a model of contact inhibition-induced quiescence, we conducted 13C-metabolic flux analysis in proliferating (P) and quiescent (Q) mouse embryonic fibroblasts (MEFs) to investigate this process. Q cells exhibit reduced glycolysis but increased TCA cycle flux and mitochondrial respiration. Reduced glycolytic flux in Q cells correlates with reduced glycolytic enzyme expression mediated by yes-associated protein (YAP) inhibition. The increased TCA cycle activity and respiration in Q cells is mediated by induced mitochondrial pyruvate carrier (MPC) expression, rendering them vulnerable to MPC inhibition. The malate-to-pyruvate flux, which generates NADPH, is markedly reduced by modulating malic enzyme 1 (ME1) dimerization in Q cells. Conversely, the malate dehydrogenase 1 (MDH1)-mediated oxaloacetate-to-malate flux is reversed and elevated in Q cells, driven by high mitochondrial-derived malate levels, reduced cytosolic oxaloacetate, elevated MDH1 levels, and a high cytoplasmic NAD+/NADH ratio. Transcriptomic analysis revealed large number of genes are induced in Q cells, many of which are associated with the extracellular matrix (ECM), while YAP-dependent and cell cycle-related genes are repressed. The results suggest that high TCA cycle flux and respiration in Q cells are required to generate ATP and amino acids to maintain de-novo ECM protein synthesis and secretion.
    DOI:  https://doi.org/10.1038/s41467-024-51117-y
  5. Nature. 2024 Aug 07.
    Glycosphingolipid synthesis mediates immune evasion in KRAS-driven cancer.
    Mariluz Soula, Gokhan Unlu, Rachel Welch, Aleksey Chudnovskiy, Beste Uygur, Vyom Shah, Hanan Alwaseem, Paul Bunk, Vishvak Subramanyam, Hsi-Wen Yeh, Artem Khan, Søren Heissel, Hani Goodarzi, Gabriel D Victora, Semir Beyaz, Kıvanç Birsoy.
      Cancer cells frequently alter their lipids to grow and adapt to their environment1-3. Despite the critical functions of lipid metabolism in membrane physiology, signalling and energy production, how specific lipids contribute to tumorigenesis remains incompletely understood. Here, using functional genomics and lipidomic approaches, we identified de novo sphingolipid synthesis as an essential pathway for cancer immune evasion. Synthesis of sphingolipids is surprisingly dispensable for cancer cell proliferation in culture or in immunodeficient mice but required for tumour growth in multiple syngeneic models. Blocking sphingolipid production in cancer cells enhances the anti-proliferative effects of natural killer and CD8+ T cells partly via interferon-γ (IFNγ) signalling. Mechanistically, depletion of glycosphingolipids increases surface levels of IFNγ receptor subunit 1 (IFNGR1), which mediates IFNγ-induced growth arrest and pro-inflammatory signalling. Finally, pharmacological inhibition of glycosphingolipid synthesis synergizes with checkpoint blockade therapy to enhance anti-tumour immune response. Altogether, our work identifies glycosphingolipids as necessary and limiting metabolites for cancer immune evasion.
    DOI:  https://doi.org/10.1038/s41586-024-07787-1
  6. Nat Commun. 2024 Aug 08. 15(1): 6767
    A co-ordinated transcriptional programme in the maternal liver supplies long chain polyunsaturated fatty acids to the conceptus using phospholipids.
    Risha Amarsi, Samuel Furse, Mary A M Cleaton, Sarah Maurel, Alice L Mitchell, Anne C Ferguson-Smith, Nicolas Cenac, Catherine Williamson, Albert Koulman, Marika Charalambous.
      The long and very long chain polyunsaturated fatty acids (LC-PUFAs) are preferentially transported by the mother to the fetus. Failure to supply LC-PUFAs is strongly linked with stillbirth, fetal growth restriction, and impaired neurodevelopmental outcomes. However, dietary supplementation during pregnancy is unable to simply reverse these outcomes, suggesting imperfectly understood interactions between dietary fatty acid intake and the molecular mechanisms of maternal supply. Here we employ a comprehensive approach combining untargeted and targeted lipidomics with transcriptional profiling of maternal and fetal tissues in mouse pregnancy. Comparison of wild-type mice with genetic models of impaired lipid metabolism allows us to describe maternal hepatic adaptations required to provide LC-PUFAs to the developing fetus. A late pregnancy-specific, selective activation of the Liver X Receptor signalling pathway dramatically increases maternal supply of LC-PUFAs within circulating phospholipids. Crucially, genetic ablation of this pathway in the mother reduces LC-PUFA accumulation by the fetus, specifically of docosahexaenoic acid (DHA), a critical nutrient for brain development.
    DOI:  https://doi.org/10.1038/s41467-024-51089-z
  7. J Biol Chem. 2024 Aug 05. pii: S0021-9258(24)02136-7. [Epub ahead of print] 107635
    O-GlcNAcylation: A Major Nutrient/Stress Sensor that Regulates Cellular Physiology.
    Lance Wells, Gerald W Hart.
      
    DOI:  https://doi.org/10.1016/j.jbc.2024.107635
  8. J Biol Chem. 2024 Aug 02. pii: S0021-9258(24)02121-5. [Epub ahead of print] 107620
    Purinosomes spatially co-localize with mitochondrial transporters.
    Zhou Sha, Stephen J Benkovic.
      In this study, we advance our understanding of the spatial relationship between the purinosome, a liquid condensate consisting of six enzymes involved in de novo purine biosynthesis, and mitochondria. Previous research has shown that purinosomes move along tubulin toward mitochondria, suggesting a direct uptake of glycine from mitochondria. Here, we propose that the purinosome is located proximally to the mitochondrial transporters SLC25A13 and SLC25A38, facilitating the uptake of glycine, aspartate, and glutamate, essential factors for purine synthesis. We utilized the proximity ligation assay (PLA) and APEX proximity labeling to investigate the association between purinosome proteins and mitochondrial transporters. Our results indicate that purinosome assembly occurs close to the mitochondrial membrane under purine-deficient conditions, with the transporters migrating to be adjacent to the purinosome. Furthermore, both targeted and non-targeted analyses suggest that the SLC25A13-APEX2-V5 probe accurately reflects endogenous cellular status. These findings provide insights into the spatial organization of purine biosynthesis and lay the groundwork for further investigations into additional proteins involved in this pathway.
    Keywords:  APEX; Purinosomes; de novo purine biosynthesis; mitochondrial transporter; proximity ligation assay (PLA)
    DOI:  https://doi.org/10.1016/j.jbc.2024.107620
  9. Nitric Oxide. 2024 Aug 02. pii: S1089-8603(24)00093-4. [Epub ahead of print]150 47-52
    The hemodynamic response to nitrite is acute and dependent upon tissue perfusion.
    Luke S Dunaway, Khatera Saii, Anthea LoBue, Shruthi Nyshadham, Nasim Abib, Sophia K Heuser, Skylar A Loeb, Ulf Simonsen, Miriam M Cortese-Krott, Brant E Isakson.
      In the vasculature, nitric oxide (NO) is produced in the endothelium by endothelial nitric oxide synthase (eNOS) and is critical for the regulation of blood flow and blood pressure. Blood flow may also be regulated by the formation of nitrite-derived NO catalyzed by hemoproteins under hypoxic conditions. We sought to investigate whether nitrite administration may affect tissue perfusion and systemic hemodynamics in WT and eNOS knockout mice. We found that global eNOS KO mice show decreased tissue perfusion compared to WT mice by using laser speckle contrast imaging. To study both the acute and long-term effects of sodium nitrite (0, 0.1, 1, and 10 mg/kg) on peripheral blood flow and systemic blood pressure, a bolus of nitrite was delivered intraperitoneally every 24 h over 4 consecutive days. We found that nitrite administration resulted in a dose-dependent and acute increase in peripheral blood flow in eNOS KO mice but had no effects in WT mice. The nitrite induced changes in tissue perfusion were transient, as determined by intraindividual comparisons of tissue perfusion 24-h after injection. Accordingly, 10 mg/kg sodium nitrite acutely decreased blood pressure in eNOS KO mice but not in WT mice as determined by invasive Millar catheterization. Interestingly, we found the vasodilatory effects of nitrite to be inversely correlated to baseline tissue perfusion. These results demonstrate the nitrite acutely recovers hypoperfusion and hypertension in global eNOS KO mice and suggest the vasodilatory actions of nitrite are dependent upon tissue hypoperfusion.
    DOI:  https://doi.org/10.1016/j.niox.2024.07.005
  10. Cancer Metab. 2024 Aug 07. 12(1): 23
    Epigenetic repression of de novo cysteine synthetases induces intra-cellular accumulation of cysteine in hepatocarcinoma by up-regulating the cystine uptake transporter xCT.
    Tomoaki Yamauchi, Yumi Okano, Daishu Terada, Sai Yasukochi, Akito Tsuruta, Yuya Tsurudome, Kentaro Ushijima, Naoya Matsunaga, Satoru Koyanagi, Shigehiro Ohdo.
      BACKGROUND: The metabolic reprogramming of amino acids is critical for cancer cell growth and survival. Notably, intracellular accumulation of cysteine is often observed in various cancers, suggesting its potential role in alleviating the oxidative stress associated with rapid proliferation. The liver is the primary organ for cysteine biosynthesis, but much remains unknown about the metabolic alterations of cysteine and their mechanisms in hepatocellular carcinoma cells.METHODS: RNA-seq data from patients with hepatocarcinoma were analyzed using the TNMplot database. The underlying mechanism of the oncogenic alteration of cysteine metabolism was studied in mice implanted with BNL 1ME A.7 R.1 hepatocarcinoma.
    RESULTS: Database analysis of patients with hepatocellular carcinoma revealed that the expression of enzymes involved in de novo cysteine synthesis was down-regulated accompanying with increased expression of the cystine uptake transporter xCT. Similar alterations in gene expression have also been observed in a syngeneic mouse model of hepatocarcinoma. The enhanced expression of DNA methyltransferase in murine hepatocarcinoma cells caused methylation of the upstream regions of cysteine synthesis genes, thereby repressing their expression. Conversely, suppression of de novo cysteine synthesis in healthy liver cells induced xCT expression by up-regulating the oxidative-stress response factor NRF2, indicating that reduced de novo cysteine synthesis repulsively increases cystine uptake via enhanced xCT expression, leading to intracellular cysteine accumulation. Furthermore, the pharmacological inhibition of xCT activity decreased intracellular cysteine levels and suppressed hepatocarcinoma tumor growth in mice.
    CONCLUSIONS: Our findings indicate an underlying mechanism of the oncogenic alteration of cysteine metabolism in hepatocarcinoma and highlight the efficacy of alteration of cysteine metabolism as a viable therapeutic target in cancer.
    Keywords:  Cysteine metabolism; DNA methylation; Erastin; Hepatocarcinoma; NRF2; de novo cysteine synthesis; xCT
    DOI:  https://doi.org/10.1186/s40170-024-00352-4
  11. Cancer Metab. 2024 Aug 07. 12(1): 24
    The polyunsaturated fatty acid docosahexaenoic affects mitochondrial function in prostate cancer cells.
    Guilherme Henrique Tamarindo, Caroline Fidalgo Ribeiro, Alana Della Torre Silva, Alex Castro, Ícaro Putinhon Caruso, Fátima Pereira Souza, Sebastião Roberto Taboga, Massimo Loda, Rejane Maira Góes.
      BACKGROUND: Prostate cancer (PCa) shows a rewired metabolism featuring increased fatty acid uptake and synthesis via de novo lipogenesis, both sharply related to mitochondrial physiology. The docosahexaenoic acid (DHA) is an omega-3 polyunsaturated fatty acid (PUFA) that exerts its antitumoral properties via different mechanisms, but its specific action on mitochondria in PCa is not clear. Therefore, we investigated whether the DHA modulates mitochondrial function in PCa cell lines.METHODS: Here, we evaluated mitochondrial function of non-malignant PNT1A and the castration-resistant (CRPC) prostate 22Rv1 and PC3 cell lines in response to DHA incubation. For this purpose, we used Seahorse extracellular flux assay to assess mitochondria function, [14C]-glucose to evaluate its oxidation as well as its contribution to fatty acid synthesis, 1H-NMR for metabolite profile determination, MitoSOX for superoxide anion production, JC-1 for mitochondrial membrane polarization, mass spectrometry for determination of phosphatidylglycerol levels and composition, staining with MitoTracker dye to assess mitochondrial morphology under super-resolution in addition to Transmission Electron Microscopy, In-Cell ELISA for COX-I and SDH-A protein expression and flow cytometry (Annexin V and 7-AAD) for cell death estimation.
    RESULTS: In all cell lines DHA decreased basal respiratory activity, ATP production, and the spare capacity in mitochondria. Also, the omega-3 induced mitochondrial hyperpolarization, ROS overproduction and changes in membrane phosphatidylglycerol composition. In PNT1A, DHA led to mitochondrial fragmentation and it increased glycolysis while in cancer cells it stimulated glucose oxidation, but decreased de novo lipogenesis specifically in 22Rv1, indicating a metabolic shift. In all cell lines, DHA modulated several metabolites related to energy metabolism and it was incorporated in phosphatidylglycerol, a precursor of cardiolipin, increasing the unsaturation index in the mitochondrial membrane. Accordingly, DHA triggered cell death mainly in PNT1A and 22Rv1.
    CONCLUSION: In conclusion, mitochondrial metabolism is significantly affected by the PUFA supplementation to the point that cells are not able to proliferate or survive under DHA-enriched condition. Moreover, combination of DHA supplementation with inhibition of metabolism-related pathways, such as de novo lipogenesis, may be synergistic in castration-resistant prostate cancer.
    Keywords:  Docosahexaenoic acid; Lipid metabolism; Mitochondria; Omega-3 polyunsaturated fatty acids; Prostate cancer cells
    DOI:  https://doi.org/10.1186/s40170-024-00348-0
  12. Cell. 2024 Jul 27. pii: S0092-8674(24)00774-8. [Epub ahead of print]
    Neutrophil trapping and nexocytosis, mast cell-mediated processes for inflammatory signal relay.
    Michael Mihlan, Stefanie Wissmann, Alina Gavrilov, Lukas Kaltenbach, Marie Britz, Kristin Franke, Barbara Hummel, Andrea Imle, Ryo Suzuki, Manuel Stecher, Katharina M Glaser, Axel Lorentz, Peter Carmeliet, Takehiko Yokomizo, Ingo Hilgendorf, Ritwick Sawarkar, Alba Diz-Muñoz, Joerg M Buescher, Gerhard Mittler, Marcus Maurer, Karoline Krause, Magda Babina, Luise Erpenbeck, Marcus Frank, Angelika S Rambold, Tim Lämmermann.
      Neutrophils are sentinel immune cells with essential roles for antimicrobial defense. Most of our knowledge on neutrophil tissue navigation derived from wounding and infection models, whereas allergic conditions remained largely neglected. Here, we analyzed allergen-challenged mouse tissues and discovered that degranulating mast cells (MCs) trap living neutrophils inside them. MCs release the attractant leukotriene B4 to re-route neutrophils toward them, thus exploiting a chemotactic system that neutrophils normally use for intercellular communication. After MC intracellular trap (MIT) formation, neutrophils die, but their undigested material remains inside MC vacuoles over days. MCs benefit from MIT formation, increasing their functional and metabolic fitness. Additionally, they are more pro-inflammatory and can exocytose active neutrophilic compounds with a time delay (nexocytosis), eliciting a type 1 interferon response in surrounding macrophages. Together, our study highlights neutrophil trapping and nexocytosis as MC-mediated processes, which may relay neutrophilic features over the course of chronic allergic inflammation.
    Keywords:  allergy; cell-cell interaction; cell-in-cell structures; innate immune response; intravital imaging; leukocyte dynamics; mast cell; neutrophil
    DOI:  https://doi.org/10.1016/j.cell.2024.07.014
  13. Nat Commun. 2024 Aug 05. 15(1): 6622
    Cxcr4 regulates a pool of adipocyte progenitors and contributes to adiposity in a sex-dependent manner.
    Benjamin M Steiner, Abigail M Benvie, Derek Lee, Yuwei Jiang, Daniel C Berry.
      Sex steroids modulate the distribution of mammalian white adipose tissues. Moreover, WAT remodeling requires adipocyte progenitor cells. Nevertheless, the sex-dependent mechanisms regulating adipocyte progenitors remain undetermined. Here, we uncover Cxcr4 acting in a sexually dimorphic manner to affect a pool of proliferating cells leading to restriction of female fat mass. We find that deletion of Cxcr4 in Pparγ-expressing cells results in female, not male, lipodystrophy, which cannot be restored by high-fat diet consumption. Additionally, Cxcr4 deletion is associated with a loss of a pool of proliferating adipocyte progenitors. Cxcr4 loss is accompanied by the upregulation of estrogen receptor alpha in adipose-derived PPARγ-labelled cells related to estradiol hypersensitivity and stalled adipogenesis. Estrogen removal or administration of antiestrogens restores WAT accumulation and dynamics of adipose-derived cells in Cxcr4-deficient mice. These findings implicate Cxcr4 as a female adipogenic rheostat, which may inform strategies to target female adiposity.
    DOI:  https://doi.org/10.1038/s41467-024-50985-8
  14. Biochim Biophys Acta Mol Basis Dis. 2024 Aug 05. pii: S0925-4439(24)00444-7. [Epub ahead of print]1870(8): 167451
    Aspartate in tumor microenvironment and beyond: Metabolic interactions and therapeutic perspectives.
    Julian Wong Soon, Maria Antonietta Manca, Agnieszka Laskowska, Julia Starkova, Katerina Rohlenova, Jakub Rohlena.
      Aspartate is a proteinogenic non-essential amino acid with several essential functions in proliferating cells. It is mostly produced in a cell autonomous manner from oxalacetate via glutamate oxalacetate transaminases 1 or 2 (GOT1 or GOT2), but in some cases it can also be salvaged from the microenvironment via transporters such as SLC1A3 or by macropinocytosis. In this review we provide an overview of biosynthetic pathways that produce aspartate endogenously during proliferation. We discuss conditions that favor aspartate uptake as well as possible sources of exogenous aspartate in the microenvironment of tumors and bone marrow, where most available data have been generated. We highlight metabolic fates of aspartate, its various functions, and possible approaches to target aspartate metabolism for cancer therapy.
    Keywords:  Amino acid; Biosynthesis; Cancer; Leukemia; Malate-aspartate shuttle; Respiratory chain; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.bbadis.2024.167451
  15. Nat Metab. 2024 Aug 08.
    Host-microbe interactions rewire metabolism in a C. elegans model of leucine breakdown deficiency.
    Yong-Uk Lee, Bennett W Fox, Rui Guo, Brian J Curtis, Jingfang Yu, Sookyung Kim, Shivani Nanda, Victor Baumann, L Safak Yilmaz, Cole M Haynes, Frank C Schroeder, Albertha J M Walhout.
      In humans, defects in leucine catabolism cause a variety of inborn errors in metabolism. Here, we use Caenorhabditis elegans to investigate the impact of mutations in mccc-1, an enzyme that functions in leucine breakdown. Through untargeted metabolomic and transcriptomic analyses we find extensive metabolic rewiring that helps to detoxify leucine breakdown intermediates via conversion into previously undescribed metabolites and to synthesize mevalonate, an essential metabolite. We also find that the leucine breakdown product 3,3-hydroxymethylbutyrate (HMB), commonly used as a human muscle-building supplement, is toxic to C. elegans and that bacteria modulate this toxicity. Unbiased genetic screens revealed interactions between the host and microbe, where components of bacterial pyrimidine biosynthesis mitigate HMB toxicity. Finally, upregulated ketone body metabolism genes in mccc-1 mutants provide an alternative route for biosynthesis of the mevalonate precursor 3-hydroxy-3-methylglutaryl-CoA. Our work demonstrates that a complex host-bacteria interplay rewires metabolism to allow host survival when leucine catabolism is perturbed.
    DOI:  https://doi.org/10.1038/s42255-024-01098-5
  16. Redox Biol. 2024 Aug 05. pii: S2213-2317(24)00279-9. [Epub ahead of print]75 103301
    TDP-43 dysfunction leads to bioenergetic failure and lipid metabolic rewiring in human cells.
    Miriam Ceron-Codorniu, Pascual Torres, Anna Fernàndez-Bernal, Santiago Rico-Rios, José Ce Serrano, Maria P Miralles, Maria Beltran, Ana Garcera, Rosa M Soler, Reinald Pamplona, Manuel Portero-Otín.
      The dysfunction of TAR DNA-binding protein 43 (TDP-43) is implicated in various neurodegenerative diseases, though the specific contributions of its toxic gain-of-function versus loss-of-function effects remain unclear. This study investigates the impact of TARDBP loss on cellular metabolism and viability using human-induced pluripotent stem cell-derived motor neurons and HeLa cells. TARDBP silencing led to reduced metabolic activity and cell growth, accompanied by neurite degeneration and decreased oxygen consumption rates in both cell types. Notably, TARDBP depletion induced a metabolic shift, impairing ATP production, increasing metabolic inflexibility, and elevating free radical production, indicating a critical role for TDP-43 in maintaining cellular bioenergetics. Furthermore, TARDBP loss triggered non-apoptotic cell death, increased ACSL4 expression, and reprogrammed lipid metabolism towards lipid droplet accumulation, while paradoxically enhancing resilience to ferroptosis inducers. Overall, our findings highlight those essential cellular traits such as ATP production, metabolic activity, oxygen consumption, and cell survival are highly dependent on TARDBP function.
    Keywords:  ACSL4; Amyotrophic lateral sclerosis; Homeostasis; In vitro models; TDP-43
    DOI:  https://doi.org/10.1016/j.redox.2024.103301
  17. Mol Ther Oncol. 2024 Sep 19. 32(3): 200847
    CD38 deletion to preserve CAR T cell metabolism and promote functional persistence.
    Viviana Rubino, Prasad S Adusumilli, Undrakh Ganbaatar.
      
    DOI:  https://doi.org/10.1016/j.omton.2024.200847
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