bims-glucam 2025-02-23 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2025–02–23
sixteen papers selected by
Sreeparna Banerjee, Middle East Technical University

Metformin combined with CB-839 specifically inhibits KRAS-mutant ovarian cancer.
Mitochondrial glutamic-oxaloacetic transaminase (GOT2) in the growth of C2C12 myoblasts.
Amino acid metabolism in breast cancer: Pathogenic drivers and therapeutic opportunities.
Anaplerosis by medium-chain fatty acids through complex interplay with glucose and glutamine metabolism.
Immunostimulatory Hydrogel with Synergistic Blockage of Glutamine Metabolism and Chemodynamic Therapy for Postoperative Management of Glioblastoma.
Association between folate and glutamine metabolism and prognosis of kidney cancer.
Histone deacetylase inhibiting nanoprodrugs for enhanced chemodynamic therapy through multistage downregulating glutathione.
Metabolite pathway alterations identified by magnetic resonance metabolomics in a proximal tubular epithelial cell line treated with TGF-β1.
BIX01294 suppresses PDAC growth through inhibition of glutaminase-mediated glutathione dynamics.
Unraveled cancer cell survival-associated amino acid metabolism of HepG2 cells altered by Thai rat-tailed radish microgreen extract examined by untargeted LC-MS/MS analysis.
Characterisation of SLC38A8 and Its Role in Retinal Pathways and Disease.
Genetic and functional dissection of the glutamate-proline pathway reveals a shortcut for glutamate catabolism in Leishmania.
Roles of selenium-containing glutathione peroxidases and thioredoxin reductases in the regulation of processes associated with glioblastoma progression.
Macrophage SUCLA2 coupled glutaminolysis manipulates obesity through AMPK.
Glutathione reductase underlies the stability of mutant p53 by antagonizing protein glutathionylation.
Identification of glutamate-related disease-dependent alterations in subventricular NSCs of the 3xTg Alzheimer's disease model, could they be involved in attempting damage repair?

Sci Rep. 2025 Feb 19. 15(1): 6072

Metformin combined with CB-839 specifically inhibits KRAS-mutant ovarian cancer.

Han Wu, Jialin Zhang, Qiujie Wang, Zijiao Li, Linlin Li, Ya Xie.

  KRAS mutations can cause metabolic reprogramming in ovarian cancer, leading to an increased metastatic capacity. This study investigated the metabolic reprogramming changes induced by KRAS mutations in ovarian cancer and the mechanism of action of metformin combined with a glutaminase 1 inhibitor (CB-839). KRAS-mutant ovarian cancer accounted for 14% of ovarian cancers. The expression of glucose metabolism-related (PFKFB3, HK2, GLUT1, and PDK2) and glutamine metabolism-related enzymes (GLS1 and ASCT2) was elevated in KRAS-mutant ovarian cancer cells compared with that in wild-type cells. KRAS-mutant cells had a higher aerobic oxidative capacity than did wild-type cells. Metformin inhibited proliferation, the expression of glucose metabolism-related enzymes, and the aerobic oxidative capacity of KRAS-mutant cells compared with those of control cells. Furthermore, it enhanced the expression of glutamine metabolism-related enzymes in KRAS-mutant cells. Metformin combined with CB-839 inhibited the proliferation and aerobic oxidation of KRAS-mutant cells to a greater extent than that observed in wild-type cells. Additionally, the inhibitory effects of metformin and CB-839 in the KRAS-mutant ovarian cancer NOD-SCID mouse model were significantly stronger than those in the drug-alone group. KRAS mutations lead to enhanced glucose and glutamine metabolism in ovarian cancer cells, which was inhibited by metformin combined with CB-839.

Keywords:  KRAS mutation; Metabolic reprogramming; Ovarian cancer

DOI:  https://doi.org/10.1038/s41598-025-90963-8
J Bioenerg Biomembr. 2025 Feb 15.

Mitochondrial glutamic-oxaloacetic transaminase (GOT2) in the growth of C2C12 myoblasts.

Ritu Som, Brian D Fink, Adam J Rauckhorst, Eric B Taylor, William I Sivitz.

  Glutamine is well recognized as critical to the growth of most cell types. Within mitochondria glutamine is converted to glutamate by glutaminase. Oxaloacetate and glutamate then react to form alpha-ketoglutarate (α-KG) and aspartate catalyzed by glutamic-oxaloacetic transaminase (GOT2) or directly converted to α-KG by glutamate dehydrogenase (GDH). We investigated the role of GOT2 in mediating glutamate metabolism and cell growth in undifferentiated C2C12 cells. CRISPR mediated GOT2 knockout (KO) impaired cell growth, partially overcome by higher concentrations of glutamine. Mitochondrial respiration did not differ between KO and wildtype (WT) cells. Metabolite profiling showed that GOT2KO decreased aspartate by about 50% in KO versus WT cells. In contrast, α-KG increased. Metabolites reflecting the pentose phosphate pathway were significantly increased in KO cells. Metabolic pathway analyses revealed alteration of the TCA cycle, the pentose phosphate pathway, and amino acid metabolism. Glutamine 13C-tracing revealed decreased generation of aspartate, increased ribulose phosphate and evidence for reductive carboxylation of α-KG to isocitrate in KO cells. GDH expression was detected in C2C12 cells but did not differ between WT and GOT2KO mitochondria. GDH is not or barely expressed in adult muscle, however, we observed clear expression in pre-weanling mice. Cytosolic glutamic-oxaloacetic transaminase, GOT1, expression did not differ between GOT2KO and WT cells. In summary, GOT2 is necessary for glutamate flux and generation of downstream metabolites needed for the growth of C2C12 myoblasts. Although respiration did not differ, lack of aspartate and other compounds needed for cell proliferation may have been major factors impairing growth.

Keywords:  Glutamate; Glutamate dehydrogenase; Glutamic oxaloacetic transaminase; Mitochondria; Myoblasts; Skeletal muscle

DOI:  https://doi.org/10.1007/s10863-025-10053-2
Protein Cell. 2025 Feb 20. pii: pwaf011. [Epub ahead of print]

Amino acid metabolism in breast cancer: Pathogenic drivers and therapeutic opportunities.

Yawen Liu, Xiangyun Zong, Patricia Altea-Manzano, Jie Fu.

  Amino acid metabolism plays a critical role in the progression and development of breast cancer. Cancer cells, including those in breast cancer, reprogram amino acid metabolism to meet the demands of rapid proliferation, survival, and immune evasion. This includes alterations in the uptake and utilization of amino acids such as glutamine, serine, glycine, and arginine, which provide essential building blocks for biosynthesis, energy production, and redox homeostasis. Notably, the metabolic phenotypes of breast cancer cells vary across molecular subtypes and disease stages, emphasizing the need for patient stratification and personalized therapeutic strategies. Advances in multi-level diagnostics, including phenotyping and predictive tools such as AI-based analysis and body fluid profiling, have highlighted the potential for tailoring treatments to individual metabolic profiles. Enzymes such as glutaminase and serine hydroxymethyltransferase, often upregulated in breast cancer, represent promising therapeutic targets. Understanding the interplay between amino acid metabolism and breast cancer biology, alongside the integration of personalized medicine approaches, can uncover novel insights into tumor progression and guide the development of precision therapies. This review explores the metabolic pathways of amino acids in breast cancer, with a focus on their implications for personalized treatment strategies.

Keywords:  amino acid metabolism; breast cancer; cancer therapy; metabolic reprogramming; personalized medicine

DOI:  https://doi.org/10.1093/procel/pwaf011
J Biol Chem. 2025 Feb 13. pii: S0021-9258(25)00155-3. [Epub ahead of print] 108307

Anaplerosis by medium-chain fatty acids through complex interplay with glucose and glutamine metabolism.

Hannah M German, Jolita Ciapaite, Nanda M Verhoeven-Duif, Judith J M Jans.

  The constant replenishment of tricarboxylic acid (TCA) cycle intermediates, or anaplerosis, is crucial to ensure optimal TCA cycle activity in times of high biosynthetic demand. In inborn metabolic diseases, anaplerosis is often affected, leading to impaired TCA cycle flux and ATP production. In these cases, anaplerotic compounds can be a therapy option. Triheptanoin, a triglyceride containing three heptanoate chains, is thought to be anaplerotic through production of propionyl- and acetyl-CoA. However, the precise mechanism underlying its anaplerotic action remains poorly understood. In this study, we performed a comprehensive in vitro analysis of heptanoate metabolism and compared it to that of octanoate, an even-chain fatty acid which only provides acetyl-CoA. Using stable isotope tracing, we demonstrate that both heptanoate and octanoate contribute carbon to the TCA cycle in HEK293T cells, confirming direct anaplerosis. Furthermore, by using labeled glucose and glutamine, we show that heptanoate and octanoate decrease the contribution of glucose-derived carbon and increase the influx of glutamine-derived carbon into the TCA cycle. Our findings also point towards a change in redox homeostasis, indicated by an increased NAD+/NADH ratio, accompanied by a decreased lactate/pyruvate ratio and increased de novo serine biosynthesis. Taken together, these results highlight the broad metabolic effects of heptanoate and octanoate supplementation, suggesting that therapeutic efficacy may strongly depend on specific disease pathophysiology. Furthermore, they underline the need for careful selection of fatty acid compound and concentration to optimize anaplerotic action.

Keywords:  Anaplerosis; fatty acids; isotopic tracer; mass spectrometry (MS); metabolic disease; metabolomics; redox regulation

DOI:  https://doi.org/10.1016/j.jbc.2025.108307
Adv Sci (Weinh). 2025 Feb 20. e2412507

Immunostimulatory Hydrogel with Synergistic Blockage of Glutamine Metabolism and Chemodynamic Therapy for Postoperative Management of Glioblastoma.

Yiran Guo, Tianhe Jiang, Sen Liang, Anhe Wang, Jieling Li, Yi Jia, Qi Li, Jian Yin, Shuo Bai, Junbai Li.

  Glioblastoma multiforme (GBM) is one of the most lethal malignant brain tumors in the central nervous system. Patients face many challenges after surgery, including tumor recurrence, intracranial pressure increase due to cavitation, and limitations associated with immediate postoperative oral chemotherapy. Here an injected peptide gel with in situ immunostimulatory functions is developed to coordinate the regulation of glutamine metabolism and chemodynamic therapy for overcoming these postoperative obstacles. The methodology entails crafting injectable gel scaffolds with short peptide molecules, incorporating the glutaminase inhibitor CB-839 and copper peptide self-assembled particles (Cu-His NPs) renowned for their chemodynamic therapy (CDT) efficacy. By fine-tuning glutamic acid production via metabolic pathways, this system not only heightens the therapeutic prowess of copper peptide particles in CDT but also escalates intracellular oxidative stress. This dual mechanism culminates in augmented immunogenic cell death within glioblastoma multiforme cells and improves a conducive immune microenvironment. Based on the concept of metabolic reprogramming, this treatment strategy has great potential to significantly reduce GBM tumor recurrence and prolong median survival in murine models.

Keywords:  glioblastoma multiforme; glutamine metabolism; self‐assembly; short peptides

DOI:  https://doi.org/10.1002/advs.202412507
Front Nutr. 2024 ;11 1506967

Association between folate and glutamine metabolism and prognosis of kidney cancer.

Jiaxuan Qin, Chaoyue Ouyang, Xuan Zhuang.

   Background: Recent studies have shown that folate metabolism might influence cancer progression by regulating mitochondrial metabolism and glutamine is involved in the development and progression of several malignancies. This study aimed to explore the association between folate and glutamine metabolism and prognosis of kidney cancer.
Methods: We performed expression analysis, survival analysis, genetic alteration analysis, and tumor immune infiltrate analysis of related genes using platforms such as UALCAN, GEPIA, GEPIA2, cBioPortal, and TIMER. Serum folate, vitamin B12, and methylmalonic acid levels and clinical information of participants in the United States diagnosed with kidney cancer was obtained from the National Health and Nutrition Examination Survey (NHANES) and analyzed using software R.
Results: We observed that RNA expression levels of certain folate and glutamine metabolism-related genes, particularly MTHFD2 and SLC1A5, were associated with the prognosis of kidney renal clear cell carcinoma (KIRC). Expression differences in these genes were notable between high-stage and low-stage and N1 vs. N0 lymph node metastasis status in KIRC. There was a positive association between glutamine metabolism-related genes and folate metabolism-related genes in KIRC. SLC1A5 was positively correlated with MTHFD2 in KIRC. Folate and glutamine metabolism might play a synchronous role in KIRC prognosis. Strong correlations between MTHFD2 and SLC1A5 expression with KIRC immune infiltrates were found. Higher levels of serum folate may be related to improved cancer-specific survival (CSS) in kidney cancer patients in the U.S.
Conclusion: Folate and glutamine metabolism-related genes, especially SLC1A5 and MTHFD2, were associated with the prognosis, tumor stage, and lymph node metastasis status in KIRC. Higher KIRC SLC1A5 or MTHFD2 expression levels were associated with higher tumor stages, increased lymph node metastasis possibilities, poorer OS, and poorer RFS. Elevated levels of serum folate may be associated with improved CSS in kidney cancer patients in the United States.

Keywords:  bioinformatics; folate; glutamine; kidney cancer; kidney renal clear cell carcinoma; prognosis

DOI:  https://doi.org/10.3389/fnut.2024.1506967
Int J Biol Macromol. 2025 Feb 17. pii: S0141-8130(25)01733-7. [Epub ahead of print]305(Pt 2): 141184

Histone deacetylase inhibiting nanoprodrugs for enhanced chemodynamic therapy through multistage downregulating glutathione.

Yongxin Liu, Xinlu Zhang, Xu Zhang, Guocheng Wang, Xue Li, Suixin Xing, Chen Cao, Yuewei Li, Lei Han, Sheng Wang.

  The unique redox homeostasis in tumor cells makes chemodynamic therapy (CDT) a promising strategy for cancer treatment. However, high glutathione (GSH) level within tumor cells severely impacts the efficacy of CDT. Therefore, reducing intracellular GSH levels has become an approach to enhance CDT. Here, we propose a HDAC inhibiting nanoprodrug consisting of an amphiphilic reactive oxygen species (ROS)-responsive polyprodrug and a GSH-responsive dimer. The high ROS level in tumor tissues can trigger the release of cinnamaldehyde and ferrocene to upregulate intracellular ROS levels through generation of hydroxyl radicals. Additionally, the dimer can react with intracellular GSH to release histone deacetylase (HDAC) inhibitors for inhibiting HDAC, thereby suppressing GSH synthesis by reducing precursor supply. The multistage depletion of GSH can further enhance oxidative damage of hydroxyl radicals to cancer cells. This study provides a promising HDAC-inhibiting strategy to achieve GSH depletion for enhanced CDT.

Keywords:  Glutathione; Histone deacetylase; Reactive oxygen species

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.141184
Physiol Rep. 2025 Feb;13(4): e70249

Metabolite pathway alterations identified by magnetic resonance metabolomics in a proximal tubular epithelial cell line treated with TGF-β1.

Tyrone L R Humphries, Soobin Lee, Aaron J Urquhart, David A Vesey, Aaron S Micallef, Clay Winterford, Andrew J Kassianos, Graham J Galloway, Ross S Francis, Glenda C Gobe.

  Tubulointerstitial fibrosis is a characteristic hallmark of chronic kidney disease (CKD). Metabolic perturbations in cellular energy metabolism contribute to the pathogenesis of CKD, but the chemical contributors remain unclear. The aim of this investigation was to use two dimensional 1H-nuclear magnetic resonance (2D-COSY) metabolomics to identify the chemical changes of kidney fibrogenesis. An in vitro transforming growth factor-β1 (TGF-β1)-induced model of kidney fibrogenesis with human kidney-2 (HK-2) proximal tubular epithelial cells (PTEC) was used. The model was validated by assaying for various pro-fibrotic molecules, using quantitative PCR and Western blotting. 2D-COSY was performed on treated cells. Morphological and functional changes characteristic of tubulointerstitial fibrosis were confirmed in the model; expression of fibronectin, collagen type IV, smooth muscle actin, oxidative stress enzymes increased (p < 0.05). NMR metabolomics provided evidence of altered metabolite signatures associated with glycolysis and glutamine metabolism, with decreased myo-inositol and choline, and metabolites of the oxidative phase of the pentose phosphate pathway with increased glucose and glucuronic acid. The altered PTEC cellular metabolism likely supports the rapid fibrogenic energy demands. These results, using 2D-COSY metabolomics, support development of a biomarker panel of fibrosis detectable using clinical magnetic resonance spectroscopy to diagnose and manage CKD.

Keywords:  2D‐COSY; NMR, nuclear magnetic resonance; TGF‐β1; metabolomics; metabonomics; proximaltubular epithelial cell; two‐dimensional correlated spectroscopy

DOI:  https://doi.org/10.14814/phy2.70249
Mol Metab. 2025 Feb 15. pii: S2212-8778(25)00020-1. [Epub ahead of print] 102113

BIX01294 suppresses PDAC growth through inhibition of glutaminase-mediated glutathione dynamics.

Se Seul Im, Jihyeon Seo, Ji Eun You, Hye Won Bang, YongHwan Kim, Jiyeon Kweon, Yongsub Kim, Dong-Myung Shin, Jaekyoung Son.

   OBJECTIVES: Increased expression of glutaminase (GLS) has been found to correlate with more aggressive disease and poorer prognosis in patients with several types of cancer, including breast, lung, and pancreatic cancer. G9a histone methyltransferase inhibitors may have anticancer activity. The present study assessed whether BIX01294 (BIX), a G9a histone methyltransferase inhibitor, can inhibit glutaminase (GLS) in pancreatic ductal adenocarcinoma (PDAC) cells.
METHODS: The effects of BIX on mitochondrial metabolism in PDAC cells were evaluated by targeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) metabolomic analysis. To assess the impact of BIX on glutathione dynamics, real-time changes in glutathione levels were monitored by FreSHtracer-based GSH assays.
RESULTS: BIX significantly inhibited the growth of PDAC cells, both in vitro and in vivo, and robustly induced apoptotic cell death. BIX significantly increased the cellular NADP+/NADPH ratio and decreased the ratio of reduced-to-oxidized glutathione (GSH:GSSG). In addition, BIX decreased GSH levels and increased ROS levels. N-acetyl-l-cysteine (NAC) supplementation dramatically rescued PDAC cells from BIX-induced apoptosis. Furthermore, BIX inhibited the transcription of GLS by inhibiting Jumonji-domain histone demethylases but not G9a histone methyltransferase. One Jumonji-domain histone demethylase, KDM6B, epigenetically regulated GLS expression by binding to the GLS gene promoter.
CONCLUSIONS: Collectively, these findings suggest that BIX could be a potent therapeutic agent in patients with PDAC through its inhibition of GLS-mediated cellular redox balance.

Keywords:  BIX01294; Glutaminase; Glutathione; KDM6B; Pancreatic cancer

DOI:  https://doi.org/10.1016/j.molmet.2025.102113
Food Chem. 2025 Feb 03. pii: S0308-8146(25)00457-1. [Epub ahead of print]474 143206

Unraveled cancer cell survival-associated amino acid metabolism of HepG2 cells altered by Thai rat-tailed radish microgreen extract examined by untargeted LC-MS/MS analysis.

Karnchanok Kaimuangpak, Marko Lehtonen, Jarkko Rautio, Natthida Weerapreeyakul.

  Thai rat-tailed radish (RS) microgreens are enriched in macro- and micronutrients and phytochemicals with anticancer potential. This study investigates the antiproliferative effects of RS in the liver HepG2 cell model and untargeted liquid chromatography-mass spectrometry (LC-MS) metabolomics analysis. RS was partitioned in water and dichloromethane (DCM). DCM was collected and evaporated to yield crude extract. The extract exhibited antiproliferation with inhibitory concentrations (IC50) of 612.5 ± 24.7 μg/ml at 24 h and 568.6 ± 11.0 μg/ml at 48 h. Metabolic pathways relevant to the anticancer effects are amino acid metabolism, including (1) alanine, aspartate, and glutamate metabolism; (2) nicotinate and nicotinamide metabolism; and (3) cysteine and methionine metabolism. Significantly, glutamine was upregulated, and aspartic acid, NAD, 5'-methylthioadenosine, cystathionine, and S-adenosylhomocysteine were downregulated. This finding suggested plausible effects of RS on liver cancer cell survival and invasion activities.

Keywords:  Anticancer; Liver cancer; Metabolomics; Superfood; Thai rat-tailed radish

DOI:  https://doi.org/10.1016/j.foodchem.2025.143206
Clin Exp Ophthalmol. 2025 Feb 16.

Characterisation of SLC38A8 and Its Role in Retinal Pathways and Disease.

Chen Weiner, Idan Hecht, Jiri Lindovsky, Marcela Palkova, Michaela Krupkova, Petr Kasparek, Jan Prochazka, Radislav Sedlacek, Alina Kotlyar, Nir Raini, Yonathan Zehavi, Yevgeni Yegorov, Pnina Hilman, Ranin Basel, Ramzia Abu-Hamed, Noam Shomron, Eran Pras.

   BACKGROUND: This study investigates the role of the SLC38A8 gene. SLC38A8 facilitates glutamine influx, which converts to glutamate in the visual pathway. Mutations in SLC38A8 are associated with FHONDA syndrome, a subtype of foveal hypoplasia with congenital nystagmus and optic-nerve-decussation defects without pigmentation leading to severe vision loss.
METHODS: In vivo and in vitro methods were conducted using retinal cell lines overexpressing SLC38A8, and Slc38a8/Slc38a7 gene-edited mice to evaluate visual function and physiological changes. Statistical analyses included two-way ANOVA, multiple regression, and ANCOVA.
RESULTS: In vitro, SLC38A8 overexpression influenced retinal gene expression, light detection, and visual perception, as well as glutamine and glutamate dynamics. In Y79SNAT8-OE cells, glutamate levels were significantly higher under light conditions compared to dark conditions at 12 h (3.4 ± 0.16 nmol/μl vs. 3.9 ± 0.17 nmol/μl, p = 0.0011) and 17 h (3.6 ± 0.22 nmol/μl vs. 4.5 ± 0.24 nmol/μl, p = 0.0001), a pattern not observed in control cells. SLC38A8 expression also increased significantly (RQ = 2.1 ± 0.11, p < 0.05) in Y79 cells under glutamine deprivation. In vivo, Slc38a8-truncated gene mice exhibited altered testicular morphology, with significantly reduced volume (70.9 ± 5.1 mm3 vs. 85.5 ± 6.7 mm3, p = 0.023), and reduced length (4.8 ± 0.2 mm vs. 5.4 ± 0.4 mm, p = 0.0169), alongside degenerative changes in germinal epithelium, and elevated liver enzyme. Despite normal eye morphology, retinal thickness, and visual evoked potentials, electroretinogram and behavioural tests indicated enhanced scotopic responsiveness with significant increases in a-wave (162.98 ± 14.1 μv vs. 133.9 ± 36.9 μv, p = 1.5e-07) and b-wave amplitudes (274.82 ± 25.2 μv vs. 199.9 ± 56.1 μv, p = 3.02e-09).
CONCLUSIONS: Our findings underscore SLC38A8 role in retinal function and glutamine-glutamate metabolism, with clinical implications for FHONDA and potential future dietary intervention targeting glutamine or glutamate.

Keywords:   SLC38A8 ; FHONDA syndrome; glutamine‐glutamate cycle; phototransduction; retinal function

DOI:  https://doi.org/10.1111/ceo.14504
FEBS J. 2025 Feb 17.

Genetic and functional dissection of the glutamate-proline pathway reveals a shortcut for glutamate catabolism in Leishmania.

Gustavo Daniel Campagnaro, Angela Kaysel Cruz.

  Trypanosomatids are early-divergent eukaryotes that have adapted to parasitism. During their life cycles, these parasites switch between a mammalian and an invertebrate host, and the ability to adapt their metabolism to different nutritional sources is instrumental for their success. In the invertebrate host, these protists have access to high amounts of amino acids and efficiently utilise it for energy production. Proline is a particularly efficient energy source for trypanosomes. Glutamate is also efficiently used by Trypanosoma cruzi and can be converted into proline as part of the glutamate-proline pathway prior to its intramitochondrial catabolism. By employing a series of genetic modifications and functional analysis, we show here that Leishmania parasites, the causative agents of leishmaniases, can utilise proline, glutamate and glutamine as energy sources, and although these parasites possess all the genes necessary for the biosynthesis of proline from glutamate, this pathway has, at best, limited function, with at least one of its components (pyrroline-5-carboxylate reductase) assuming divergent functions in different life cycle stages of the parasite. In fact, we show that the catabolism of glutamate is independent of proline biosynthesis and the former is most likely directly imported into the mitochondrion and catabolised to recover the cellular redox metabolism and increase mitochondrial membrane potential. Moreover, our data suggest a relevant role for glutamate dehydrogenase in nutritional stress response in Leishmania. These findings highlight relevant differences in amino acid metabolism between Trypanosoma and Leishmania and suggest a diversification in amino acid metabolic pathways within Trypanosomatidae.

Keywords:  Leishmania; glutamate–proline pathway; mitochondrial metabolism; moonlight activity; proline–glutamate

DOI:  https://doi.org/10.1111/febs.70030
Arch Biochem Biophys. 2025 Feb 14. pii: S0003-9861(25)00057-8. [Epub ahead of print]766 110344

Roles of selenium-containing glutathione peroxidases and thioredoxin reductases in the regulation of processes associated with glioblastoma progression.

Elena G Varlamova.

  Glioblastoma remains the most common and aggressive primary tumor of the central nervous system in adults. Current treatment options include standard surgical resection combined with radiation/chemotherapy, but such protocol most likely only delays the inevitable. Therefore, the problem of finding therapeutic targets to prevent the occurrence and development of this severe oncological disease is currently acute. It is known that the functions of selenoproteins in the regulation of carcinogenesis processes are not unambiguous. Either they exhibit cytotoxic activity on cancer cells, or cytoprotective. A special place in the progression of oncological diseases of various etiologies is occupied by proteins of the thioredoxin and glutathione systems. These are two cellular antioxidant systems that regulate redox homeostasis, counteracting the increased production of reactive oxygen species in cells. The review reflects the latest data on the role of key enzymes of these redox systems in the regulation of processes associated with the progression of glioblastoma. A thorough consideration of these issues will expand fundamental knowledge about the functions of selenium-containing thioredoxin reductases and glutathione peroxidases in the therapy of glioblastomas and provide an understanding of the prospects for the treatment of this aggressive oncological disease.

Keywords:  Glioblastoma; Glutathione peroxidases; Selenoproteins; Thioredoxin reductases

DOI:  https://doi.org/10.1016/j.abb.2025.110344
Nat Commun. 2025 Feb 18. 16(1): 1738

Macrophage SUCLA2 coupled glutaminolysis manipulates obesity through AMPK.

Chang Peng, Haowen Jiang, Liya Jing, Wenhua Yang, Xiaotong Guan, Hanlin Wang, Sike Yu, Yutang Cao, Min Wang, Huan Ma, Zan Lv, Hongyu Gu, Chunmei Xia, Xiaozhen Guo, Bin Sun, Aili Wang, Cen Xie, Wenbiao Wu, Luyiyi Lu, Jiayi Song, Saifei Lei, Rui Wu, Yi Zang, Erjiang Tang, Jia Li.

Obesity is regarded as a chronic inflammatory disease involving adipose tissue macrophages (ATM), but whether immunometabolic reprogramming of ATM affects obesity remains unclarified. Here we show that in ATM glutaminolysis is the fundamental metabolic flux providing energy and substrate, bridging with AMP-activated protein kinase (AMPK) activity, succinate-induced interleukin-1β (IL-1β) production, and obesity. Abrogation of AMPKα in myeloid cells promotes proinflammatory ATM, impairs thermogenesis and energy expenditure, and aggravates obesity in mice fed with high-fat diet (HFD). Conversely, IL-1β neutralization or myeloid IL-1β abrogation prevents obesity caused by AMPKα deficiency. Mechanistically, ATP generated from glutaminolysis suppresses AMPK to decrease phosphorylation of the β subunit of succinyl-CoA synthetase (SUCLA2), thereby resulting in the activation of succinyl-CoA synthetase and the overproduction of succinate and IL-1β; by contrast, siRNA-mediated SUCLA2 knockdown reduces obesity induced by HFD in mice. Lastly, phosphorylated SUCLA2 in ATM correlates negatively with obesity in humans. Our results thus implicate a glutaminolysis/AMPK/SUCLA2/IL-1β axis of inflammation and obesity regulation in ATM.

DOI: https://doi.org/10.1038/s41467-025-57044-w
Redox Biol. 2025 Jan 30. pii: S2213-2317(25)00035-7. [Epub ahead of print]81 103522

Glutathione reductase underlies the stability of mutant p53 by antagonizing protein glutathionylation.

Liansheng Wang, Suqin Zhong, Xinru Fan, Yuxue Xu, Meimei Wang, Youcui Xu, Yuanyuan Cai, Zhong Cao, Zhiming Ye, Longping Wen, Pengfei Wei.

  Mutp53 level is widely variable among individual cancer cells in tumor tissues, and within cells a higher level of mutp53 is usually observed in the nucleus as compared to the cytoplasm. This spatial heterogeneity in mutp53 expression has been well documented and likely plays an important role in tumor therapeutic resistance. However, its underlying mechanism remains poorly understood. In this study, we first revealed a critical role of micro-environmental reducing status in regulating mutp53 stability and spatially heterogeneous accumulation. Immunofluorescence and ThiolTracker Violet dye staining demonstrated a clear correlation between the cellular mutp53 level and the reducibility in the patient-derived tumor tissues and mutp53-expressing cancer cell lines. The nucleus exhibited both higher reducibility and more mutp53 accumulation than the cytoplasm did. Supplementing GSH exacerbated the accumulation of mutp53, while consuming GSH led to extensive depletion of mutp53, suggesting that the environmental reducing status kept mutp53 stability. Mechanistically, S-glutathionylation could trigger ubiquitination and proteasomal degradation of mutp53. A highly-reducing local environment preserved mutp53 stability by inhibiting glutathionylation and subsequent proteasomal degradation of mutp53, which also provided an explanation for the differential accumulation of mutp53 proteins in the nucleus and cytoplasm. Thirdly, we revealed that the expression level of glutathione reductase (GR) was positively correlated with mutp53 accumulation across the cultured mutp53-expressing cell lines, patient-derived tumor tissues and patient databases. Over-expression of GR reinforced the environmental reducibility, affected glutathionylation and improved mutp53 accumulation, while inhibiting GR either by chemical inhibitors or genetic approach induced massive clearance of a variety of mutp53 and effectively retarded the growth of p53-mutated cell-derived xenografts in mice. These studies provided an explanation for the widely-observed spatial heterogeneous accumulation of mutp53 proteins, and inhibiting GR or directly consuming GSH represented a promising strategy for mutp53 carrying cancer therapy.

Keywords:  GSH/GSSG ratio; Glutathione reductase; Glutathionylation; Mutant p53; Mutant p53-carrying cancer; Ubiquitin-proteasome system

DOI:  https://doi.org/10.1016/j.redox.2025.103522
Cell Tissue Res. 2025 Feb 17.

Identification of glutamate-related disease-dependent alterations in subventricular NSCs of the 3xTg Alzheimer's disease model, could they be involved in attempting damage repair?

Giorgia Cerqueni, Valentina Terenzi, Alessandra Preziuso, Tiziano Serfilippi, Silvia Piccirillo, Mariangela Di Vincenzo, Patrizia Ambrogini, Salvatore Amoroso, Monia Orciani, Vincenzo Lariccia, Simona Magi.

  Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterised by several factors, such as impaired glutamate neurotransmission affecting crucial functions. Neural stem cells (NSCs) are present in the adult brains of all mammalian species and contribute to the continuous generation of neural cells throughout life. The disruption of glutamate levels during the development of AD could impact NSCs' functionality, influencing their response to the microenvironment. In this work, we isolated adult neural stem cells from both triple transgenic (3xTg)-AD mice and age-matched wild type (WT) mice in order to gather information on any differences between them, particularly concerning the potential mechanisms involved in the internalisation of glutamate and its utilisation for energy production. The 3xTg model offers the ability to recapitulate human pathology with both plaque and tangle hallmarks that are involved in the process of glutamate release. In vitro culture 3xTg NSCs showed a slight morphological difference compared to WT cells and a massive reduction of proliferation and viability. Furthermore, 3xTg NSCs displayed an increase in the expression of glutamate transporters and glutamine synthetase, while glutamate dehydrogenase did not show any reduction, which is typical in AD brains. Data obtained from this basic research study suggest a possible involvement of glutamate in the cellular energy balance, indicating an attempted response of NSCs to the cytotoxic microenvironment in the early stage of AD pathology. This finding is of great interest, as it corroborates the hypothesis that targeting the glutamatergic system could be an extremely promising strategy for new therapeutics in AD.

Keywords:  3xTg; Alzheimer’s disease; Energy production; Glutamate; NSCs; Triple immunofluorescence

DOI:  https://doi.org/10.1007/s00441-025-03954-6