bims-glucam Biomed News
on Glutamine cancer metabolism
Issue of 2024–12–01
nineteen papers selected by
Sreeparna Banerjee, Middle East Technical University
  1. Loss of mitochondrial enzyme GPT2 leads to reprogramming of synaptic glutamate metabolism.
  2. Aberrant Energy Metabolism in Tumors and Potential Therapeutic Targets.
  3. Amino Acid Deprivation in Glioblastoma: The Role in Survival and the Tumour Microenvironment-A Narrative Review.
  4. ACSS1-dependent acetate utilization rewires mitochondrial metabolism to support AML and melanoma tumor growth and metastasis.
  5. The role of metabolic reprogramming in liver cancer and its clinical perspectives.
  6. Energy metabolism in osteoprogenitors and osteoblasts: role of the Pentose Phosphate Pathway.
  7. Emerging role of metabolic reprogramming in the immune microenvironment and immunotherapy of thyroid cancer.
  8. Tumor energy metabolism: implications for therapeutic targets.
  9. NFE2L2 and SLC25A39 drive cuproptosis resistance through GSH metabolism.
  10. Cancer Therapies Targeting Cellular Metabolism.
  11. Metabolism and mRNA translation: a nexus of cancer plasticity.
  12. cpt1b Regulates Cardiomyocyte Proliferation Through Modulation of Glutamine Synthetase in Zebrafish.
  13. PIKFYVE inhibition induces endosome- and lysosome-derived vacuole enlargement via ammonium accumulation.
  14. MAT2a and AHCY inhibition disrupts antioxidant metabolism and reduces glioblastoma cell survival.
  15. Metabolites and Metabolic Functional Changes-Potential Markers for Endothelial Cell Senescence.
  16. Biosynthesis-Encoded Lipogenic Acetyl-CoA Measurement Using NMR Reveals Glucose-Driven Lipogenesis and Glutamine's Alternative Roles in Kidney Cancer.
  17. Effects of Glutamine or Glucose Deprivation on Inflammation and Tight Junction Disruption in Yak Rumen Epithelial Cells.
  18. Can selenenyl sulfides be a substrate of glutathione reductase enzyme? A theoretical insight.
  19. A Metabolomic Approach to Unexplained Syncope.
  1. Mol Brain. 2024 Nov 27. 17(1): 87
    Loss of mitochondrial enzyme GPT2 leads to reprogramming of synaptic glutamate metabolism.
    Ozan Baytas, Shawn M Davidson, Julie A Kauer, Eric M Morrow.
      Recessive loss-of-function mutations in the mitochondrial enzyme Glutamate Pyruvate Transaminase 2 (GPT2) cause intellectual disability in children. Given this cognitive disorder, and because glutamate metabolism is tightly regulated to sustain excitatory neurotransmission, here we investigate the role of GPT2 in synaptic function. GPT2 catalyzes a reversible reaction interconverting glutamate and pyruvate with alanine and alpha-ketoglutarate, a TCA cycle intermediate; thereby, GPT2 may play an important role in linking mitochondrial tricarboxylic acid (TCA) cycle with synaptic transmission. In mouse brain, we find that GPT2 is enriched in mitochondria of synaptosomes (isolated synaptic terminals). Loss of Gpt2 in mouse appears to lead to reprogramming of glutamate and glutamine metabolism, and to decreased glutamatergic synaptic transmission. Whole-cell patch-clamp recordings in pyramidal neurons of CA1 hippocampal slices from Gpt2-null mice reveal decreased excitatory post-synaptic currents (mEPSCs) without changes in mEPSC frequency, or importantly, changes in inhibitory post-synaptic currents (mIPSCs). Additional evidence of defective glutamate release included reduced levels of glutamate released from Gpt2-null synaptosomes measured biochemically. Glutamate release from synaptosomes was rescued to wild-type levels by alpha-ketoglutarate supplementation. Additionally, we observed evidence of altered metabolism in isolated Gpt2-null synaptosomes: decreased TCA cycle intermediates, and increased glutamate dehydrogenase activity. Notably, alterations in the TCA cycle and the glutamine pool were alleviated by alpha-ketoglutarate supplementation. In conclusion, our data support a model whereby GPT2 mitochondrial activity may contribute to glutamate availability in pre-synaptic terminals, thereby highlighting potential interactions between pre-synaptic mitochondrial metabolism and synaptic transmission.
    Keywords:  Cognitive development; Disease; GPT2; Glutamate; Intellectual disability; Neurometabolic; Neurometabolism; Synapse; TCA cycle
    DOI:  https://doi.org/10.1186/s13041-024-01154-x
  2. Genes Chromosomes Cancer. 2024 Nov;63(11): e70008
    Aberrant Energy Metabolism in Tumors and Potential Therapeutic Targets.
    Shuhao Fan, Jianhua Guo, Hui Nie, Huabao Xiong, Yong Xia.
      Energy metabolic reprogramming is frequently observed during tumor progression as tumor cells necessitate adequate energy production for rapid proliferation. Although current medical research shows promising prospects in studying the characteristics of tumor energy metabolism and developing anti-tumor drugs targeting energy metabolism, there is a lack of systematic compendiums and comprehensive reviews in this field. The objective of this study is to conduct a systematic review on the characteristics of tumor cells' energy metabolism, with a specific focus on comparing abnormalities between tumor and normal cells, as well as summarizing potential targets for tumor therapy. Additionally, this review also elucidates the aberrant mechanisms underlying four major energy metabolic pathways (glucose, lipid, glutamine, and mitochondria-dependent) during carcinogenesis and tumor progression. Through the utilization of graphical representations, we have identified anomalies in crucial energy metabolism pathways, encompassing transporter proteins (glucose transporter, CD36, and ASCT2), signaling molecules (Ras, AMPK, and PTEN), as well as transcription factors (Myc, HIF-1α, CREB-1, and p53). The key molecules responsible for aberrant energy metabolism in tumors may serve as potential targets for cancer therapy. Therefore, this review provides an overview of the distinct energy-generating pathways within tumor cells, laying the groundwork for developing innovative strategies for precise cancer treatment.
    Keywords:  energy metabolism abnormality; glucose metabolism; glutamine metabolism; lipid metabolism; oxidative phosphorylation
    DOI:  https://doi.org/10.1002/gcc.70008
  3. Biomedicines. 2024 Oct 29. pii: 2481. [Epub ahead of print]12(11):
    Amino Acid Deprivation in Glioblastoma: The Role in Survival and the Tumour Microenvironment-A Narrative Review.
    Keven Du, Leila Grocott, Giulio Anichini, Kevin O'Neill, Nelofer Syed.
       BACKGROUND: Glioblastoma is the most common and aggressive primary brain tumour, characterised by its invasive nature and complex metabolic profile. Emerging research highlights the role of amino acids (AAs) in glioblastoma metabolism, influencing tumour growth and the surrounding microenvironment.
    METHODS: This narrative review synthesises recent pre-clinical studies focusing on the metabolic functions of AAs in glioblastoma. Key areas include the effects of AA deprivation on tumour growth, adaptive mechanisms, and the tumour microenvironment.
    RESULTS: The effects related to arginine, glutamine, methionine, and cysteine deprivation have been more extensively reported. Arginine deprivation in arginine-auxotrophic glioblastomas induces apoptosis and affects cell adhesion, while glutamine deprivation disrupts metabolic pathways and enhances autophagy. Methionine and cysteine deprivation impact lipid metabolism and ferroptosis. Tumour adaptive mechanisms present challenges, and potential compensatory responses have been identified. The response of the microenvironment to AA deprivation, including immune modulation, is critical to determining therapeutic outcomes.
    CONCLUSIONS: Targeting AA metabolism offers a promising approach for glioblastoma treatment, with potential targeted drugs showing clinical promise. However, the complexity of tumour adaptive mechanisms and their impact on the microenvironment necessitates further research to optimise combination therapies and improve therapeutic efficacy.
    Keywords:  amino acid deprivation; cancer metabolism; glioblastoma; high-grade gliomas
    DOI:  https://doi.org/10.3390/biomedicines12112481
  4. Cell Rep. 2024 Nov 21. pii: S2211-1247(24)01339-1. [Epub ahead of print]43(12): 114988
    ACSS1-dependent acetate utilization rewires mitochondrial metabolism to support AML and melanoma tumor growth and metastasis.
    Sabina I Hlavaty, Kelsey N Salcido, Katherine A Pniewski, Dzmitry Mukha, Weili Ma, Toshitha Kannan, Joel Cassel, Yellamelli V V Srikanth, Qin Liu, Andrew Kossenkov, Joseph M Salvino, Qing Chen, Zachary T Schug.
      Cancer cells often use alternative nutrient sources to support their metabolism and proliferation. One important alternative nutrient source for many cancers is acetate. Acetate is metabolized into acetyl-coenzyme A (CoA) by acetyl-CoA synthetases 1 and 2 (ACSS1 and ACSS2), which are found in the mitochondria and cytosol, respectively. We show that ACSS1 and ACSS2 are differentially expressed in cancer. Melanoma, breast cancer, and acute myeloid leukemia cells expressing ACSS1 readily use acetate for acetyl-CoA biosynthesis and to fuel mitochondrial metabolism. ACSS1-dependent acetate metabolism decreases the relative contributions of glucose and glutamine to the tricarboxylic acid (TCA) cycle and alters the pentose phosphate pathway and redox state of cancer cells. ACSS1 knockdown decreases acute myeloid leukemia burden in vivo and inhibits melanoma tumor and metastatic growth. Our study highlights a key role for ACSS1-dependent acetate metabolism for cancer growth, raising the potential for ACSS1-targeting therapies in cancer.
    Keywords:  ACSS1; ACSS2; ACSS2 inhibitor; AML; CP: Cancer; CP: Metabolism; acetate; cancer; melanoma; metabolism; metastasis
    DOI:  https://doi.org/10.1016/j.celrep.2024.114988
  5. Front Oncol. 2024 ;14 1454161
    The role of metabolic reprogramming in liver cancer and its clinical perspectives.
    Mengxiao Lu, Yingjie Wu, MinMing Xia, Yixin Zhang.
      Primary liver cancer (PLC), which includes hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA), remains a leading cause of cancer-related death worldwide. Chronic liver diseases, such as hepatitis B and C infections and metabolic dysfunction-associated steatotic liver disease (MASLD), are key risk factors for PLC. Metabolic reprogramming, a defining feature of cancer, enables liver cancer cells to adapt to the demands of rapid proliferation and the challenging tumor microenvironment (TME). This manuscript examines the pivotal role of metabolic reprogramming in PLC, with an emphasis on the alterations in glucose, lipid, and amino acid metabolism that drive tumor progression. The Warburg effect, marked by increased glycolysis, facilitates rapid energy production and biosynthesis of cellular components in HCC. Changes in lipid metabolism, including elevated de novo fatty acid synthesis and lipid oxidation, support membrane formation and energy storage essential for cancer cell survival. Amino acid metabolism, particularly glutamine utilization, supplies critical carbon and nitrogen for nucleotide synthesis and maintains redox homeostasis. These metabolic adaptations not only enhance tumor growth and invasion but also reshape the TME, promoting immune escape. Targeting these metabolic pathways presents promising therapeutic opportunities for PLC. This review underscores the interaction between metabolic reprogramming and tumor immunity, suggesting potential metabolic targets for innovative therapeutic strategies. A comprehensive understanding of PLC's intricate metabolic landscape may lead to more effective treatments and better patient outcomes. Integrating metabolomics, genomics, and proteomics in future research will be vital for identifying precise therapeutic targets and advancing personalized therapies for liver cancer.
    Keywords:  Warburg effect; amino acid metabolism; hepatocellular carcinoma; lipid metabolism; liver cancer; metabolic dysfunction-associated steatotic liver disease; metabolic reprogramming
    DOI:  https://doi.org/10.3389/fonc.2024.1454161
  6. J Biol Chem. 2024 Nov 26. pii: S0021-9258(24)02518-3. [Epub ahead of print] 108016
    Energy metabolism in osteoprogenitors and osteoblasts: role of the Pentose Phosphate Pathway.
    Sarah E Catheline, Charles O Smith, Matthew McArthur, Chen Yu, Paul S Brookes, Roman A Eliseev.
      Bioenergetic preferences of osteolineage cells, including osteoprogenitors and osteoblasts (OB), are a matter of intense debate. Early studies pointed to OB reliance on glucose and aerobic glycolysis while more recent works indicated the importance of glutamine as a mitochondrial fuel. Aiming to clarify this issue, we performed metabolic tracing of 13C-labeled glucose and glutamine in human osteolineage cells: bone marrow stromal (a.k.a. mesenchymal stem) cells (BMSC) and BMSC-derived OBs. Glucose tracing showed non-canonical direction of glucose metabolism with high labeling of early glycolytic steps and the Pentose Phosphate Pathway (PPP) but very low labeling of late glycolytic steps and the Krebs cycle. Labeling of Krebs cycle and late steps of glycolysis was primarily from glutamine. These data suggest that in osteolineage cells, glucose is metabolized primarily via the PPP while glutamine is metabolized in the mitochondria, also feeding into the late steps of glycolysis likely via the malate-aspartate shuttle (MAS). This metabolic setup did not change after induction of differentiation. To evaluate the importance of this setup for osteolineage cells, we used the inhibitors of either PPP or MAS and observed a significant reduction in both cell growth and ability to differentiate. In sum, we observed a distinct metabolic wiring in osteolineage cells with high flux of glucose through the PPP and glutamine flux fueling both mitochondria and late steps of glycolysis. This wiring likely reflects their unique capacity to rapidly proliferate and produce extracellular matrix, e.g. after bone fracture.
    Keywords:  Malate-Aspartate Shuttle; Mitochondria; Osteoblasts; Osteoprogenitors; Pentose Phosphate Pathway
    DOI:  https://doi.org/10.1016/j.jbc.2024.108016
  7. Int Immunopharmacol. 2024 Nov 26. pii: S1567-5769(24)02224-0. [Epub ahead of print]144 113702
    Emerging role of metabolic reprogramming in the immune microenvironment and immunotherapy of thyroid cancer.
    Shouhua Li, Hengtong Han, Kaili Yang, Xiaoxiao Li, Libin Ma, Ze Yang, Yong-Xun Zhao.
      The metabolic reprogramming of cancer cells is a hallmark of many malignancies. To meet the energy acquisition needs of tumor cells for rapid proliferation, tumor cells reprogram their nutrient metabolism, which is caused by the abnormal expression of transcription factors and signaling molecules related to energy metabolic pathways as well as the upregulation and downregulation of abnormal metabolic enzymes, receptors, and mediators. Thyroid cancer (TC) is the most common endocrine tumor, and immunotherapy has become the mainstream choice for clinical benefit after the failure of surgical, endocrine, and radioiodine therapies. TC change the tumor microenvironment (TME) through nutrient competition and metabolites, causing metabolic reprogramming of immune cells, profoundly changing immune cell function, and promoting immune evasion of tumor cells. A deeper understanding of how metabolic reprogramming alters the TME and controls immune cell fate and function will help improve the effectiveness of TC immunotherapy and patient outcomes. This paper aims to elucidate the metabolic communication that occurs between immune cells around TC and discusses how metabolic reprogramming in TC affects the immune microenvironment and the effectiveness of anti-cancer immunotherapy. Finally, targeting key metabolic checkpoints during metabolic reprogramming, combined with immunotherapy, is a promising strategy.
    Keywords:  Immune microenvironment; Immunometabolism; Immunotherapy; Metabolic reprogramming; Thyroid cancers
    DOI:  https://doi.org/10.1016/j.intimp.2024.113702
  8. Mol Biomed. 2024 11 29. 5(1): 63
    Tumor energy metabolism: implications for therapeutic targets.
    Youwu Hu, Wanqing Liu, WanDi Fang, Yudi Dong, Hong Zhang, Qing Luo.
      Tumor energy metabolism plays a crucial role in the occurrence, progression, and drug resistance of tumors. The study of tumor energy metabolism has gradually become an emerging field of tumor treatment. Recent studies have shown that epigenetic regulation is closely linked to tumor energy metabolism, influencing the metabolic remodeling and biological traits of tumor cells. This review focuses on the primary pathways of tumor energy metabolism and explores therapeutic strategies to target these pathways. It covers key areas such as glycolysis, the Warburg effect, mitochondrial function, oxidative phosphorylation, and the metabolic adaptability of tumors. Additionally, this article examines the role of the epigenetic regulator SWI/SNF complex in tumor metabolism, specifically its interactions with glucose, lipids, and amino acids. Summarizing therapeutic strategies aimed at these metabolic pathways, including inhibitors of glycolysis, mitochondrial-targeted drugs, exploitation of metabolic vulnerabilities, and recent developments related to SWI/SNF complexes as potential targets. The clinical significance, challenges, and future directions of tumor metabolism research are discussed, including strategies to overcome drug resistance, the potential of combination therapy, and the application of new technologies.
    Keywords:  Drug resistance; Glycolysis; Mitochondrial phosphorylation; SWI/SNF complex; Therapeutic targets; Tumor energy metabolism
    DOI:  https://doi.org/10.1186/s43556-024-00229-4
  9. Sci Rep. 2024 Nov 28. 14(1): 29579
    NFE2L2 and SLC25A39 drive cuproptosis resistance through GSH metabolism.
    Jiao Liu, Hu Tang, Fangquan Chen, Changfeng Li, Yangchun Xie, Rui Kang, Daolin Tang.
      Cuproptosis is a recently discovered form of regulated cell death triggered by mitochondrial copper accumulation and proteotoxic stress. Here, we provide the first evidence that glutathione (GSH), a major non-protein thiol in cells, acts as a cuproptosis inhibitor in pancreatic ductal adenocarcinoma (PDAC) cells. Mechanistically, GSH inhibits cuproptosis by chelating copper, contrasting its role in blocking ferroptosis by inhibiting lipid peroxidation. The classical cuproptosis inducer, ES-Cu (elesclomol plus copper), increases the protein stability of the transcription factor NFE2L2 (also known as NRF2), leading to the upregulation of gene expression of glutamate-cysteine ligase modifier subunit (GCLM) and glutamate-cysteine ligase catalytic subunit (GCLC). GCLM and GCLC are rate-limiting enzymes in GSH synthesis, and increased GSH is transported into mitochondria via the solute carrier family 25 member 39 (SLC25A39) transporter. Consequently, genetic inhibition of the NFE2L2-GSH-SLC25A39 pathway enhances cuproptosis-mediated tumor suppression in cell culture and in mouse tumor models. These findings not only reveal distinct mechanisms of GSH in inhibiting cuproptosis and ferroptosis, but also suggest a potential combination strategy to suppress PDAC tumor growth.
    Keywords:  Copper; Cuproptosis; Elesclomol; Glutathione; NFE2L2; SLC25A39
    DOI:  https://doi.org/10.1038/s41598-024-81317-x
  10. Cold Spring Harb Perspect Med. 2024 Nov 25. pii: a041657. [Epub ahead of print]
    Cancer Therapies Targeting Cellular Metabolism.
    Benjamin Morris, Alejandro Gutierrez.
      Cancer is caused by mutations that drive aberrant growth, proliferation, and invasion, thus overriding regulatory mechanisms that normally link these processes to organismal needs and cellular physiology. This imposes demands for the production of energy and biomass and for survival in microenvironments that are often nonphysiologic and nutrient-poor, which are met by rewiring of cellular metabolism. The resultant dependence of tumor cells on altered metabolism can induce sensitivity to specific metabolic perturbations that can be exploited for cancer therapy. Some cancers are caused by mutations that impart a novel function to metabolic enzymes, leading to the production of a tumor-promoting metabolite that is dispensable in normal cells, representing an ideal therapeutic target. Tumors can also exploit metabolic regulation of cellular immunity to evade antitumor immune responses, and deciphering this biology has revealed potential targets for therapeutic intervention. Here, we discuss a number of illustrative examples highlighting the therapeutic potential and the challenges of targeting metabolism for cancer therapy.
    DOI:  https://doi.org/10.1101/cshperspect.a041657
  11. Trends Cell Biol. 2024 Nov 27. pii: S0962-8924(24)00225-3. [Epub ahead of print]
    Metabolism and mRNA translation: a nexus of cancer plasticity.
    Xinpu Tang, Kaixiu Li, Yuqing Wang, Stéphane Rocchi, Shensi Shen, Michael Cerezo.
      Tumors often face energy deprivation due to mutations, hypoxia, and nutritional deficiencies within the harsh tumor microenvironment (TME), and as an effect of anticancer treatments. This metabolic stress triggers adaptive reprogramming of mRNA translation, which in turn adjusts metabolic plasticity and associated signaling pathways to ensure tumor cell survival. Emerging evidence is beginning to reveal the complex interplay between metabolism and mRNA translation, shedding light on the mechanisms that synchronize ribosome assembly and reconfigure translation programs under metabolic stress. This review explores recent advances in our understanding of the coordination between metabolism and mRNA translation, offering insights that could inform therapeutic strategies targeting both cancer metabolism and translation, with the aim of disrupting cancer cell plasticity and survival.
    Keywords:  cancer cell plasticity; mRNA translation; tumor metabolism
    DOI:  https://doi.org/10.1016/j.tcb.2024.10.009
  12. J Cardiovasc Dev Dis. 2024 Nov 01. pii: 344. [Epub ahead of print]11(11):
    cpt1b Regulates Cardiomyocyte Proliferation Through Modulation of Glutamine Synthetase in Zebrafish.
    Xiaohan Cheng, Jingyi Ju, Wenping Huang, Zongyi Duan, Yanchao Han.
      Carnitine palmitoyltransferase 1b (Cpt1b) is a crucial rate-limiting enzyme in fatty acid metabolism, but its role and mechanism in early cardiac development remains unclear. Here, we show that cpt1b regulates cardiomyocyte proliferation during zebrafish development. Knocking out entire cpt1b coding sequences leads to impaired cardiomyocyte proliferation, while cardiomyocyte-specific overexpression of cpt1b promotes cardiomyocyte proliferation. RNA sequencing analysis and pharmacological studies identified glutamine synthetase as a key downstream effector of cpt1b in regulating cardiomyocyte proliferation. Our study elucidates a novel mechanism whereby cpt1b promotes zebrafish cardiomyocyte proliferation through glutamine synthetase, which provides new perspectives on the significance of fatty acid metabolism in heart development and the interplay between fatty acid and amino acid metabolic pathways.
    Keywords:  cardiomyocyte proliferation; cpt1b; glul; metabolism; zebrafish
    DOI:  https://doi.org/10.3390/jcdd11110344
  13. J Cell Sci. 2024 Nov 26. pii: jcs.262236. [Epub ahead of print]
    PIKFYVE inhibition induces endosome- and lysosome-derived vacuole enlargement via ammonium accumulation.
    Junsuke Uwada, Hitomi Nakazawa, Takeshi Kiyoi, Takashi Yazawa, Ikunobu Muramatsu, Takayoshi Masuoka.
      FYVE-type zinc finger-containing phosphoinositide kinase (PIKFYVE), that is essential for PtdIns(3,5)P2 production, is an important regulator of lysosomal homeostasis. PIKFYVE dysfunction leads to cytoplasmic vacuolization; however, the underlying mechanism remains unknown. In this study, we explored the cause of vacuole enlargement upon PIKFYVE inhibition in DU145 prostate cancer cells. Enlargement of vacuoles by PIKFYVE inhibition required glutamine and its metabolism by glutaminases. Addition of ammonia, a metabolite of glutamine, was sufficient to enlarge vacuoles via PIKFYVE inhibition. Moreover, PIKFYVE inhibition led to intracellular ammonium accumulation. Endosome-lysosome permeabilization resulted in ammonium leakage from the cells, indicating ammonium accumulation in the endosomes and lysosomes. Ammonium accumulation and vacuole expansion were suppressed by the lysosomal lumen neutralization. It is therefore assumed that PIKFYVE inhibition interferes with the efflux of NH4+, which is protonated NH3 in the lysosomal lumen, leading to osmotic swelling of vacuoles. Notably, glutamine or ammonium is required for PIKFYVE inhibition-induced suppression of lysosomal function and autophagic flux. In conclusion, this study showed that PIKfyve inhibition disrupts lysosomal homeostasis via ammonium accumulation.
    Keywords:  Ammonium; Endosome; Glutamine; Lysosome; PIKFYVE; TRPML1
    DOI:  https://doi.org/10.1242/jcs.262236
  14. bioRxiv. 2024 Nov 24. pii: 2024.11.23.624981. [Epub ahead of print]
    MAT2a and AHCY inhibition disrupts antioxidant metabolism and reduces glioblastoma cell survival.
    Emma C Rowland, Matthew D'Antuono, Anna Jermakowicz, Nagi G Ayad.
      Glioblastoma (GBM) is a highly aggressive primary malignant adult brain tumor that inevitably recurs with a fatal prognosis. This is due in part to metabolic reprogramming that allows tumors to evade treatment. We therefore must uncover the pathways mediating these adaptations to develop novel and effective treatments. We searched for genes that are essential in GBM cells as measured by a whole-genome pan-cancer CRISPR screen available from DepMap and identified the methionine metabolism genes MAT2A and AHCY . We conducted genetic knockdown, evaluated mitochondrial respiration, and performed targeted metabolomics to study the function of these genes in GBM. We demonstrate that MAT2A or AHCY knockdown induces oxidative stress, hinders cellular respiration, and reduces the survival of GBM cells. Furthermore, selective MAT2a or AHCY inhibition reduces GBM cell viability, impairs oxidative metabolism, and changes the metabolic profile of these cells towards oxidative stress and cell death. Mechanistically, MAT2a or AHCY regulates spare respiratory capacity, the redox buffer cystathionine, lipid and amino acid metabolism, and prevents DNA damage in GBM cells. Our results point to the methionine metabolic pathway as a novel vulnerability point in GBM.
    Significance: We demonstrated that methionine metabolism maintains antioxidant production to facilitate pro-tumorigenic ROS signaling and GBM tumor cell survival. Importantly, targeting this pathway in GBM can potentially reduce tumor growth and improve survival in patients.
    DOI:  https://doi.org/10.1101/2024.11.23.624981
  15. Biomolecules. 2024 Nov 20. pii: 1476. [Epub ahead of print]14(11):
    Metabolites and Metabolic Functional Changes-Potential Markers for Endothelial Cell Senescence.
    Jingyuan Ya, Alison Whitby, Ulvi Bayraktutan.
      Accumulation of senescent endothelial cells (ECs) in vasculature represents a key step in the development of vascular aging and ensuing age-related diseases. Given that removal of senescent ECs may prevent disease and improve health and wellbeing, the discovery of novel biomarkers that effectively identify senescent cells is of particular importance. As crucial elements for biological pathways and reliable bioindicators of cellular processes, metabolites demand attention in this context. Using senescent human brain microvascular endothelial cells (HBMECs) displaying a secretory phenotype and significant morphological, nuclear, and enzymatic changes compared to their young counterparts, this study has shown that senescent HBMECs lose their endothelial characteristics as evidenced by the disappearance of CD31/PECAM-1 from interendothelial cell junctions. The metabolic profiling of young versus senescent HBMECs also indicates significant differences in glucose, glutamine, and fatty acid metabolism. The analysis of intracellular and secreted metabolites proposes L-proline, L-glutamate, NAD+, and taurine/hypotaurine pathway components as potential biomarkers. However, further studies are required to assess the value of these agents as potential biomarkers and therapeutic targets.
    Keywords:  age-related disease; aging; biomarkers; endothelial cells; metabolites; metabolomics; senescence
    DOI:  https://doi.org/10.3390/biom14111476
  16. J Am Chem Soc. 2024 Nov 29.
    Biosynthesis-Encoded Lipogenic Acetyl-CoA Measurement Using NMR Reveals Glucose-Driven Lipogenesis and Glutamine's Alternative Roles in Kidney Cancer.
    Sihyang Jo, Munjun Seo, Thi Ha Nguyen, Jin Wook Cha, Yong Jin An, Sunghyouk Park.
      Fatty acid de novo synthesis (FADNS) is a critical process in lipogenesis that is characteristically altered in clear cell renal cell carcinoma (ccRCC), which is the major type of kidney cancer. An important challenge in studying the FADNS process has been the accurate measurement of cytosolic lipogenic acetyl-CoA (AcCoA), the precursor in FADNS, due to its compartmentalization within cells. Here, we describe a novel NMR-based method to decode the isotopic enrichment of lipogenic AcCoA, which, as we demonstrated, is encoded in the simple signal ratios of the geminal methyl groups of lanosterol during its biosynthesis. The approach was validated based on the independence of the tracer enrichment and species along with the expected FADNS modulation using differentially enriched tracers and a well-studied drug. Application of this technique to 786-O ccRCC cells showed that glucose may serve as a major carbon source for lipogenic AcCoA in FADNS at physiological nutrient concentrations, at odds with previous studies that indicated glutamine's dominant role through reductive carboxylation under higher nutrient conditions. Further investigation into glutamine's alternative roles in ccRCC cells suggested its major involvement in the bioenergetic TCA cycle, pyrimidine synthesis, and glutathione synthesis, which is also critical in ccRCC growth. The glutamine-dependent glutathione synthesis was also suggested as a possible metabolic vulnerability compared to normal kidney cells using a glutathione synthesis inhibitor. The current study provides a simple tool for studying an important aspect of lipid metabolism and suggests translational implications for targeting glucose-driven lipogenesis and glutamine-supported glutathione synthesis in ccRCC.
    DOI:  https://doi.org/10.1021/jacs.4c11809
  17. Animals (Basel). 2024 Nov 12. pii: 3232. [Epub ahead of print]14(22):
    Effects of Glutamine or Glucose Deprivation on Inflammation and Tight Junction Disruption in Yak Rumen Epithelial Cells.
    Ziqi Yue, Junmei Wang, Rui Hu, Quanhui Peng, Hongrui Guo, Huawei Zou, Jianxin Xiao, Yahui Jiang, Zhisheng Wang.
      Yak is a special free-ranging cattle breed in the plateau areas of Qinghai and Tibet. Pasture withering in cold-season pastures results in energy deficiency in yaks, which undermines the rumen epithelial barrier. However, the leading factor causing rumen epithelial injury remains unknown. Glutamine (Gln), a conditionally essential amino acid, is insufficient under pathological conditions. Glucose (GLU) is an important energy source. Thus, we explored the effects of Gln or GLU deprivation on the barrier function of yak rumen epithelial cells and investigated the underlying mechanisms, as well as the differences in rumen epithelial barrier function between Gln deprivation (Gln-D) and GLU deprivation (GLU-D). In previous work, we constructed the yak rumen epithelial cells (YRECs) line by transferring the human telomerase reverse transcriptase gene (hTERT) and simian virus 40 large T antigen (SV40T) into primary YRECs. The YRECs were exposed to normal, Gln-D, GLU-D, and serum replacement (SR) media for 6, 12, and 24 h. Our data displayed that cell viability and tight junction protein expression in the SR group were not significantly changed compared to the normal group. Whereas, compared with the SR group, Gln-D treated for more than 12 h reduced cell viability and proliferation, and GLU-D treated for more than 12 h damaged the cell morphology and reduced cell viability and proliferation. The cell proliferation and cell viability were decreased more in GLU-D than in Gln-D. In addition, Gln-D treated for more than 12 h disrupted YREC cellular partially tight junctions by inducing oxidative stress and inflammation, and GLU-D treated for more than 12 h disrupted YREC cellular tight junctions by inducing apoptosis, oxidative stress, and inflammation. Compared with Gln-D, GLU-D more significantly induced cell injury and reduced tight junction protein levels. Our results provided evidence that GLU-D induced damage through the p38 mitogen-activated protein kinase (p38 MAPK)/c-junN-terminal kinase (JNK) signaling pathway, which was more serious than Gln-D treated for more than 12 h.
    Keywords:  glucose deprivation; glutamine deprivation; inflammation; tight junction; yak rumen epithelial cells
    DOI:  https://doi.org/10.3390/ani14223232
  18. RSC Adv. 2024 Nov 25. 14(51): 37797-37802
    Can selenenyl sulfides be a substrate of glutathione reductase enzyme? A theoretical insight.
    Vishnu Rama Chari, Raghu Nath Behera.
      Glutathione reductase (GR) catalyzes the reduction of glutathione disulfide (GSSG) to glutathione. As selenium is a congener of sulfur, the possibility of reducing selenenyl sulfide (RSeSG) at the catalytic site of GR has been investigated using density functional theory. Calculations on the redox potential and the Se-S bond strength of some studied RSeSG compounds with a phenyl selenide backbone suggested that the unsubstituted and amine-based selenenyl sulfide intermediates could have a promising tendency to be reduced at the catalytic site of GR.
    DOI:  https://doi.org/10.1039/d4ra06738j
  19. Biomedicines. 2024 Nov 19. pii: 2641. [Epub ahead of print]12(11):
    A Metabolomic Approach to Unexplained Syncope.
    Susanna Longo, Ilaria Cicalini, Damiana Pieragostino, Vincenzo De Laurenzi, Jacopo M Legramante, Rossella Menghini, Stefano Rizza, Massimo Federici.
      Background: This study aims to identify a metabolomic signature that facilitates the classification of syncope and the categorization of the unexplained syncope (US) to aid in its management. Methods: We compared a control group (CTRL, n = 10) with a transient loss of consciousness (TLC) group divided into the OH group (n = 23) for orthostatic syncope, the NMS group (n = 26) for neuromediated syncope, the CS group (n = 9) for cardiological syncope, and the US group (n = 27) for US defined as syncope without a precise categorization after first- and second-level diagnostic approaches. Results: The CTRL and the TLC groups significantly differed in metabolic profile. A new logistic regression model has been developed to predict how the US will be clustered. Using differences in lysophosphatidylcholine with 22 carbon atom (C22:0-LPC) levels, 96% of the US belongs to the NMS and 4% to the CS subgroup. Differences in glutamine and lysine (GLN/LYS) levels clustered 95% of the US in the NMS and 5% in the CS subgroup. Conclusions: We hypothesize a possible role of C22:0 LPC and GLN/LYS in re-classifying US and differentiating it from cardiological syncope.
    Keywords:  cardiometabolic risk factors; cardiovascular diseases; glutamine; lysine; lysophosphatidylcholine; metabolomics; unexplained syncope
    DOI:  https://doi.org/10.3390/biomedicines12112641
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