bims-toxgon 2025-11-16 papers

bims-toxgon

Biomed News

on Toxoplasma gondii metabolism

Issue of 2025–11–16
fifteen papers selected by
Lakesh Kumar, BITS Pilani

Calcium transfer from the ER to other organelles for optimal signaling in Toxoplasma gondii.
Transfection of the free-living alga Chromera velia enables direct comparisons with its parasitic apicomplexan relative, Toxoplasma gondii.
MiR-4332 modulates oxidative stress, inflammasome activation through notch1 signaling during Toxoplasma gondii infection.
Pleiotropic Effects on Tachyzoite and Host Cell Proteomes in Knock-Out Clones of the Open Reading Frames 297720 and 319730 Constitutively Expressed in T. gondii ShSp1 Tachyzoites.
Emerging functions for nonhistone protein acetylation in budding yeast.
Biomolecular Fingerprints of Sirtuin Activity in Senescent Fibroblasts Identified via Synchrotron-Based FTIR.
Cyclophilins as key players in protozoan parasite infections.
Plasmodium actin-like proteins are essential for DNA segregation during male gametogenesis and malaria transmission.
PFKFB2 Is Pivotal for Metabolic Flexibility and Differential Glucose Utilization.
Mitochondrial NAD+-mediated mitophagy alleviates type I interferon response to the cytosolic mitochondrial dna.
The splicing factor PTBP1 interacts with RUNX1 and is required for leukemia cell survival.
ATP citrate lyase (ACLY) promotes the occurrence of gastric cancer through regulating lipid metabolism.
Glutamine metabolism reprogramming promotes bladder cancer progression via PYCR1: a multi-omics and functional validation study.
SLC25A11 Is Associated with KDM2A-Dependent Reduction in rRNA Transcription Induced by Aminooxyacetic Acid.
Sphingolipid and methionine metabolism in aging.

Elife. 2025 Nov 12. pii: RP101894. [Epub ahead of print]13

Calcium transfer from the ER to other organelles for optimal signaling in Toxoplasma gondii.

Zhu-Hong Li, Beejan Asady, Le Chang, Myriam Andrea Hortua Triana, Catherine Li, Isabelle Coppens, Silvia N J Moreno.

  Ca2+ signaling in cells begins with the opening of Ca2+ channels in either the plasma membrane (PM) or endoplasmic reticulum (ER), leading to a sharp increase in the physiologically low (<100 nM) cytosolic Ca2+ level. The temporal and spatial regulation of Ca²+ is crucial for the precise activation of key biological processes. In the apicomplexan parasite Toxoplasma gondii, which infects approximately one-third of the global population, Ca²+ signaling governs essential aspects of the parasite's infection cycle. T. gondii relies on Ca²+ signals to regulate pathogenic traits, with several Ca²+-signaling components playing critical roles. Ca2+ entry from the extracellular environment has been demonstrated in T. gondii for both, extracellular parasites, exposed to high Ca2+, and intracellular parasites, which acquire Ca²+ from host cells during host Ca²+ signaling events. Active egress, an essential step of the parasite's infection cycle, is preceded by a large increase in cytosolic Ca2+, most likely initiated by release from intracellular stores. However, extracellular Ca2+ is also necessary to reach a cytosolic Ca2+ threshold required for timely egress. In this study, we investigated the mechanism of intracellular Ca²+ store replenishment and identified a central role for the SERCA-Ca2+-ATPase in maintaining Ca²+ homeostasis within the ER and in other organelles. We demonstrate mitochondrial Ca2+ uptake, which occurs by transfer of Ca2+ from the ER, likely through membrane contact sites. Our findings suggest that the T. gondii ER plays a key role in sequestering and redistributing Ca²+ to intracellular organelles following Ca²+ influx at the PM.

Keywords:  SERCA; Toxoplasma gondii; calcium signaling; cell biology; endoplasmic reticulum; membrane contact sites; mitochondria; toxoplasma gondii

DOI:  https://doi.org/10.7554/eLife.101894
J Cell Sci. 2025 Nov 10. pii: jcs.264400. [Epub ahead of print]

Transfection of the free-living alga Chromera velia enables direct comparisons with its parasitic apicomplexan relative, Toxoplasma gondii.

Isadonna F Tengganu, Ke Hu.

  Chromera velia is a photosynthetic, free-living alga closely related to the apicomplexan parasites, a phylum of intracellular pathogens responsible for many devastating diseases, including malaria, cryptosporidiosis, and toxoplasmosis. With molecular and cellular landmarks clearly related to but distinguishable from those found in apicomplexan parasites, Chromera provides an opportunity to investigate the evolutionary origin of the structures and processes needed for intracellular parasitism. However, tools for defining localization and functions of gene products do not exist for Chromera, which creates a major bottleneck for exploring its biology. Here we report two major advances in exploring the cell biology of this free-living relative of a large group of intracellular parasites: 1) successful cell transformation, and 2) the implementation of expansion microscopy. The initial analysis enabled by these tools generated new insights into subcellular organization in different life stages of Chromera. These new developments boost the potential of Chromera as a model system for understanding the evolution of parasitism in apicomplexans.

Keywords:  Apicomplexa; Chromera velia; Evolutionary cell biology; Parasitism; Toxoplasma; Transfection

DOI:  https://doi.org/10.1242/jcs.264400
Int J Biol Macromol. 2025 Nov 06. pii: S0141-8130(25)09293-1. [Epub ahead of print]333(Pt 1): 148736

MiR-4332 modulates oxidative stress, inflammasome activation through notch1 signaling during Toxoplasma gondii infection.

Shifan Zhu, Ming Liang, Fan Xu, Kangzhi Xu, Xuewei Zou, Dandan Liu, Xinjun Zhang, Siyang Huang, Jinjun Xu, Jianping Tao, Zhaofeng Hou.

  Toxoplasma gondii manipulates host cell pathways through complex strategies. Oxidative stress and inflammasome activation are key to its pathogenesis, yet the mechanisms by which the parasite triggers these processes to cause host damage remain unclear. In this study, we revealed that T. gondii drives an oxidative stress-inflammation cascade culminating in cellular apoptosis. Specifically, T. gondii infection triggered increased ROS production and disrupted redox homeostasis in host cells, accompanied by protective activation of the Nrf2/Ho-1 antioxidant signaling pathway, NLRP3 inflammasome activation, and significantly elevated apoptosis rates. Mechanistically, this study first demonstrates that T. gondii induces marked downregulation of miR-4332, which activates the Notch1 signaling pathway. This activation mediates transcriptional responses associated with oxidative stress, inflammasome activation, and apoptosis through nuclear effectors. miRNA gain- and loss-of-function experiments established Notch1 signaling as being under miR-4332-dependent regulation, confirming the pleiotropic regulatory properties of miR-4332 in the oxidative stress-inflammation-apoptosis cascade. Functional rescue experiments showed that Notch1 inhibitors significantly reversed T. gondii-induced pathological cascades. This study reveals that T. gondii manipulates the host antioxidant defense via the miR-4332/Notch1 axis, promoting oxidative stress and inflammation. These findings offer new insights into parasite-induced pathology and host adaptation.

Keywords:  Apoptosis; Inflammasome; MiR-4332; Notch1 signaling pathway; Oxidative stress; Toxoplasma gondii

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.148736
Int J Mol Sci. 2025 Oct 27. pii: 10433. [Epub ahead of print]26(21):

Pleiotropic Effects on Tachyzoite and Host Cell Proteomes in Knock-Out Clones of the Open Reading Frames 297720 and 319730 Constitutively Expressed in T. gondii ShSp1 Tachyzoites.

Kai Pascal Alexander Hänggeli, Joachim Müller, Manfred Heller, Anne-Christine Uldry, Sophie Braga-Lagache, David Arranz-Solís, Luis-Miguel Ortega-Mora, Andrew Hemphill.

  Toxoplasma gondii, the causative agent of toxoplasmosis widespread in animals and humans, is an intracellular apicomplexan protozoan parasite infecting a variety of host cells. Gene editing using CRISPR-Cas9 has become a standard tool to investigate the molecular genetics of this interaction. With respect to gene knock-out (KO) studies, the general paradigm implies that the gene of interest is expressed in the wildtype and that only the gene of interest is affected by the knock-out. Consequently, the observed phenotype depends on the presence or absence of genes of interest. To challenge this paradigm, we knocked out two open reading frames (ORFs) constitutively expressed in T. gondii ShSp1 tachyzoites, but not essential, namely ORF 297720 encoding a trehalose-6-phosphatase homolog and ORF 319730 encoding a You2 C2C2 zinc finger homolog. We analyzed the proteomes of tachyzoites isolated at a late stage of infection, as well as intracellular tachyzoites and host cells at an early stage of infection. The intended KO proteins were present in the T. gondii Sp1 wildtype but absent in the KO clones. Moreover, besides differentially expressed (DE) proteins specific to each KO, 17 DE proteins common to both KOs were identified in isolated tachyzoites and 39 in intracellular tachyzoites. Moreover, 76 common DE proteins were identified in host cells. Network and enrichment analyses showed that these proteins were functionally related to antiviral defense mechanisms. These results indicate that the KO of a gene of interest may not only affect the expression of other genes of the target organism, which in our case is T. gondii, but also the gene expression of its host cells. Therefore, phenotypes of KO strains may not be causally related to the KO of a given gene. Overall, this study highlights that genetic manipulation in T. gondii can lead to system-wide proteomic shifts in both parasite and host, emphasizing the need for cautious interpretation of knock-out-based functional analyses.

Keywords:  determinism; gene editing; host–parasite interaction; model system; systems biology

DOI:  https://doi.org/10.3390/ijms262110433
Trends Biochem Sci. 2025 Nov 10. pii: S0968-0004(25)00246-4. [Epub ahead of print]

Emerging functions for nonhistone protein acetylation in budding yeast.

Cameron Gibson, Idin Lantz, Michael Downey.

  Lysine acetylation is a post-translational modification (PTM) that is traditionally studied as a modifier of histones. In recent years, nonhistone protein acetylation has also emerged as a ubiquitous modification in eukaryotes. Recent advances in mass spectrometry (MS) workflows suggest that a majority of proteins are acetylated at some point during their life cycle. However, only a few of these acetylations have been studied for their functional significance. Here, we review the function of acetylations on key nonhistone proteins involved in chromatin remodeling and DNA damage repair, protein homeostasis, and metabolic coordination of the cell cycle in Saccharomyces cerevisiae. We discuss the diverse roles of acetylation in regulating these pathways, while highlighting emerging themes and open questions in the field.

Keywords:  DNA damage response; autophagy; cell cycle; heat shock; metabolism; post-translational modifications

DOI:  https://doi.org/10.1016/j.tibs.2025.10.005
Int J Mol Sci. 2025 Oct 29. pii: 10495. [Epub ahead of print]26(21):

Biomolecular Fingerprints of Sirtuin Activity in Senescent Fibroblasts Identified via Synchrotron-Based FTIR.

Irene Fernández-Duran, Tanja Dučić, Alejandro Vaquero.

  Sirtuins are NAD+-dependent enzymes widely implicated in organismal ageing. In particular, nuclear-located sirtuins are histone deacetylases and/or monoADPrybosiltransferases that exert key roles in maintaining genomic stability. Although sirtuins have been reported to play an inhibitory role in cellular senescence, their specific targets and underlying mechanisms remain poorly understood. In this study, we use single-cell Synchrotron radiation-based Fourier-transform infrared spectroscopy (FTIR) to identify changes in biomolecular composition associated with cellular senescence induced by oxidative stress and replicative passaging in human primary fibroblasts. We also use the sirtuin activator resveratrol to determine which of these changes may be related to sirtuin activity. Resveratrol induced changes related to nuclear architecture, such as DNA conformation and nucleic acid-protein abundance ratios. Individual targeting of nuclear sirtuins was used to validate impaired DNA/protein ratios experimentally and provided a specific structural footprint associated with sirtuins in the context of cellular senescence. Altogether, this study reveals for the first time a sirtuin-dependent structural and biomolecular signature of senescence through single-cell FTIR, offering new insights into the cellular events underlying cellular senescence.

Keywords:  Fourier-transform infrared spectroscopy; cellular senescence; genomic stability; resveratrol; sirtuins

DOI:  https://doi.org/10.3390/ijms262110495
Parasit Vectors. 2025 Nov 11. 18(1): 457

Cyclophilins as key players in protozoan parasite infections.

Reza Mansouri, Enrique Granado-Aparicio, Claudia Alcedo, Julio López-Abán, Reza Shafiei, Antonio Muro, Raúl Manzano-Román, Sajad Rashidi.

  Cyclophilins (Cyps), a highly conserved family of immunophilins with peptidyl-prolyl cis-trans isomerase (PPIase) activity, play pivotal roles in protein folding, cell signaling, immune modulation, and host-pathogen interactions. In protozoan infections, parasite-encoded Cyps are essential for immune evasion, oxidative stress regulation, and pathogen survival. This review highlights the multifaceted roles of Cyps in Plasmodium, Toxoplasma, Trypanosoma, and Leishmania, with particular emphasis on their involvement in host cell invasion, replication, and immunomodulation. Key Cyps-such as Plasmodium Cyp19B, Toxoplasma Cyp18, Leishmania major Cyp19, and Trypanosoma Cyp19-have been implicated in oxidative stress management, host cell entry, and immune suppression. Given these critical functions, Cyps represent promising therapeutic targets; cyclosporine A (CsA) and its analogs inhibit parasite proliferation by disrupting Cyp activity. Moreover, parasite-derived Cyps show potential as vaccine candidates, eliciting protective immunity in models of leishmaniasis, toxoplasmosis, and Chagas disease. Host Cyps further influence infection outcomes by modulating mitochondrial permeability, cytokine production, and macrophage polarization. For example, mitochondrial CypD regulates cell death pathways in Trypanosoma cruzi-induced cardiac pathology. Despite these advances, further research is required to validate the therapeutic and prophylactic potential of Cyps. Future studies should investigate stage-specific Cyp functions, host-pathogen interactions, and the development of nonimmunosuppressive Cyp inhibitors to advance targeted antiparasitic strategies.

Keywords:  Cyclophilin; Infection; Protozoan parasite; Therapeutic target; Vaccine development

DOI:  https://doi.org/10.1186/s13071-025-07098-y
PLoS Pathog. 2025 Nov;21(11): e1013687

Plasmodium actin-like proteins are essential for DNA segregation during male gametogenesis and malaria transmission.

Aastha Varshney, Eisha Pandey, Nirdosh, Satish Mishra.

Protozoan parasites of the genus Plasmodium cause malaria and involve infection of multiple hosts and cell types during the life cycle. Producing sexually fit gametocytes is essential for transmitting the Plasmodium parasite into an anopheline mosquito vector. After the uptake of malaria parasites, male gametocytes undergo three rounds of DNA replication to produce eight nucleated flagellar gametes. Here, we report that the actin-like proteins Alp5a and Alp5b are involved in DNA segregation during male gametogenesis. The Plasmodium-specific Alp5a and Alp5b can be superimposed on human Arp2 and Arp3, localize to the nucleus, and interact with each other. Alp5a and Alp5b are individually dispensable for the development of P. berghei blood stages, but are simultaneously indispensable for parasite viability. Consistent with genetic studies, the inhibitory activity of the Arp2/3 complex inhibitor in Plasmodium supports an essential role for this complex during the blood stage. Deletion of Alp5a or Alp5b had no impact on actin nucleation, parasite growth, or gametocytemia during the blood stage. The knockout parasites were able to invade the mosquito midgut and form oocysts; however, these oocysts were significantly smaller in size and failed to mature, ultimately leading to their death. Genetic crosses revealed defects in male gamete integrity. We found that the reduced oocyst development was due to impaired DNA segregation during male gametogenesis. Our study provides molecular insights into the fundamental requirements of the Alps in Plasmodium, which are essential for malaria transmission.

DOI: https://doi.org/10.1371/journal.ppat.1013687
J Am Heart Assoc. 2025 Nov 11. e043921

PFKFB2 Is Pivotal for Metabolic Flexibility and Differential Glucose Utilization.

Kylene M Harold, Satoshi Matsuzaki, Atul Pranay, Jie Zhu, Anna Faakye, Kenneth M Humphries.

   BACKGROUND: The heart's constant energy demands make metabolic flexibility critical to its function as nutrient availability varies. The enzyme phosphofructokinase-2/fructose 2,6-bisphosphatase (PFKFB2) contributes to this flexibility by acting as a positive or negative regulator of cardiac glycolysis. We have previously shown that PFKFB2 is degraded in the diabetic heart and that a cardiac-specific PFKFB2 knockout (cKO) impacts ancillary glucose pathways and mitochondrial substrate preference. Therefore, defining PFKFB2's role in mitochondrial metabolic flexibility is paramount to understanding both metabolic homeostasis and metabolic syndromes. Further, it is unknown how PFKFB2 loss impacts the heart's response to acute stress. Here, we examined how cardiac mitochondrial flexibility and the posttranslational modification O-GlcNAcylation are affected in cKO mice in response to fasting or pharmacologic stimulation.
METHODS: cKO and litter-matched controls were euthanized in the fed or fasted (12 hours) states, with or without a 20-minute stimulant stress of caffeine and epinephrine. Mitochondrial respiration, metabolomics, and changes to systemic glucose homeostasis were evaluated.
RESULTS: cKO mice had moderate impairment in mitochondrial metabolic flexibility, affecting downstream glucose oxidation, respiration, and carnitine palmitoyl transferase 1 activity. O-GlcNAcylation, a product of ancillary glucose metabolism, was upregulated in cKO hearts in the fed state, but this was ameliorated in the fasted state. Furthermore, metabolic remodeling in response to PFKFB2 loss was sufficient to impact circulating glucose in fasted and stressed states.
CONCLUSIONS: PFKFB2 is essential for fed-to-fasted changes in cardiac metabolism and plays an important regulatory role in protein O-GlcNAcylation. Its loss also affects systemic glucose homeostasis under stressed conditions.

Keywords:  O‐GlcNAc; O‐GlcNAcylation; PFK‐2; glycolysis; metabolic flexibility

DOI:  https://doi.org/10.1161/JAHA.125.043921
Autophagy. 2025 Nov 13.

Mitochondrial NAD+-mediated mitophagy alleviates type I interferon response to the cytosolic mitochondrial dna.

Tian Lan, Dantong Shang, Lan Lin, Haoyu Wang, Juan Zou, Mengxin Hu, Hanhua Cheng, Rongjia Zhou.

  Mitochondrial nicotinamide adenine dinucleotide (NAD+) plays a central role in energy metabolism, yet its roles and mechanisms in mitophagy and innate immunity remain poorly understood. In this study, we identify mitochondrial NAD+ depletion that causes mitophagy dysfunction and inflammation. We find that depletion of mitochondrial NAD+ owing to deficiency of the mitochondrial NAD+ transporter SLC25A51 impairs BNIP3-mediated mitophagy. Loss of mitochondrial NAD+ inhibits SIRT3-mediated deacetylation of FOXO3, leading to transcriptional downregulation of BNIP3 and subsequent disruption of MAP1LC3B/LC3B recruitment. Notably, mitochondrial NAD+ depletion promotes mitochondrial DNA (mtDNA) release from mitochondria to the cytosol upon oxidative stress, thereby exacerbating the type I interferon response to free cytosolic mtDNA via activation of the CGAS-STING1 signaling pathway. Our findings reveal a novel mechanistic link among mitochondrial NAD+, mitophagy, and mtDNA-induced inflammation by genetic manipulation of cell lines, highlighting mitochondrial NAD+ as a potential therapeutic target for mitigating sterile inflammation triggered by free cytosolic mtDNA. Thus, the study provides new insights into the crosstalk among mitochondrial homeostasis, inflammation, and innate immunity.

Keywords:  Cytosolic mtDNA; SLC25A51; inflammation; innate immunity; mitochondrial NAD+; mitophagy

DOI:  https://doi.org/10.1080/15548627.2025.2589909
Leukemia. 2025 Nov 10.

The splicing factor PTBP1 interacts with RUNX1 and is required for leukemia cell survival.

Arjun Dhir, Alexander Ethell, Riley Watkins, Calvin Lam, Kevin Tur-Rodriguez, Jimmie Persinger, Kasidy K Dobish, Sipra Panda, Shannon M Buckley, Samantha A Swenson, Sandipan Brahma, M Jordan Rowley, R Katherine Hyde.

Runt-related Transcription Factor 1 (RUNX1) is essential for definitive hematopoiesis and is among the most frequently mutated genes in leukemia. Previous work from our lab demonstrated that Histone Deacetylase 1 (HDAC1), a known RUNX1 partner, is unexpectedly required for active transcription suggesting a non-histone role for HDAC1 in regulating components of the RUNX1 complex. Here, we use proteomics, genomics, and long-read transcriptomics to identify novel RUNX1 interacting partners and decipher their role in gene regulation and RNA splicing in leukemia cells. We demonstrate that Polypyrimidine Tract Binding Protein 1 (PTBP1) interacts with RUNX1 in an HDAC1-dependent manner. Chromatin profiling revealed extensive genome-wide overlap in sites occupied by RUNX1 and PTBP1, with significant enrichment at promoters of actively transcribed genes. Loss of PTBP1 in AML cells led to widespread alterations in RNA splicing and decreased expression of genes whose promoters are bound by both factors, including metabolic genes. In agreement with these findings, we found that loss of PTBP1 reduced glycolysis and glucose uptake and ultimately caused cell death. Based on our data, we propose that the interaction between RUNX1 and PTBP1 facilitates expression of metabolic proteins essential for leukemia cell growth and survival.

DOI: https://doi.org/10.1038/s41375-025-02799-w
Transl Cancer Res. 2025 Oct 31. 14(10): 6975-6989

ATP citrate lyase (ACLY) promotes the occurrence of gastric cancer through regulating lipid metabolism.

Sijia Zhang, Yihuang Liu, Xia Zhang, Nailin Zhang, Jianhui Sun, Pingping Chen.

   Background: Gastric cancer (GC) is a leading cause of cancer-related mortality worldwide, and lipid metabolism reprogramming plays a crucial role in tumor progression. ATP citrate lyase (ACLY), a key enzyme in de novo lipid synthesis, has been implicated in multiple cancers, but its role in GC remains incompletely understood. This study aimed to investigate the expression, prognostic significance, and potential molecular mechanisms of ACLY in GC, with a particular focus on its relationship with lipid metabolism and ubiquitination.
Methods: VOSviewer and Bibliometrix were used for analysis of the PubMed database related to GC and lipid metabolism. The expression levels of ACLY in GC tissues and normal tissues in The Cancer Genome Atlas (TCGA) database were compared and western blot was used to detect. The relationship between ACLY and the prognosis of GC patients was analyzed through bioinformatics. Genome Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment were performed for ACLY-related genes, and three gene data related to ACLY, lipid metabolism and GC were analyzed. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) analyzed substances in 2-furoic acid-treated and normal HGC-27 cells.
Results: Lipid metabolism and patient prognosis is a hot topic in the field of GC. Compared with that in normal tissues, the level of ACLY in GC tissues is significantly greater, and it is associated with poor patient prognosis. The prognosis of patients with GC is related to age, node (N) stage and metastasis (M) stage. The functions of the ACLY-related genes in cell differentiation and the structure, signal transduction and enzyme activity of GC are enriched. ACLY is correlated with lipid metabolism genes in GC. The content of fatty acids in GC cells decreased after 2-furoic acid treatment.
Conclusions: ACLY regulates lipid metabolism to affect the occurrence and development of GC.

Keywords:  ATP citrate lyase (ACLY); The Cancer Genome Atlas (TCGA); gastric cancer (GC)

DOI:  https://doi.org/10.21037/tcr-2025-814
J Transl Med. 2025 Nov 13. 23(1): 1277

Glutamine metabolism reprogramming promotes bladder cancer progression via PYCR1: a multi-omics and functional validation study.

Xinjia Ding, Enkui Zhang, Zhou Huang, Xiaohui Li, Zhigao Wang, Yanping Wu, Chao Liu, Shikai Wu.

   BACKGROUND: Bladder cancer (BLCA) is a prevalent malignancy worldwide, with advanced stages linked to poor prognosis. Although immune checkpoint inhibitors (ICIs) show clinical promise in treating both operable and advanced BLCA, predicting patient responses remains a major challenge. Glutamine metabolism, a key aspect of metabolic reprogramming, has been implicated in tumor progression and immune modulation. However, the exact role of glutamine metabolism in BLCA remains poorly understood. This study aims to explore its association with clinical outcomes and immunotherapy response while functionally validating key regulatory genes.
METHODS: An integrated approach combining targeted metabolomics, single-cell RNA sequencing, and bulk transcriptomic data was used to profile glutamine metabolism in BLCA comprehensively and identify potential metabolic biomarkers. A prognostic model, termed GMscore, based on glutamine metabolism, was constructed using principal component analysis (PCA). Key regulatory genes were identified through random forest analysis. Functional assays, including in vitro proliferation, migration, and metabolic assays, as well as in vivo xenograft models, were employed to validate the findings.
RESULTS: Targeted metabolomics revealed increased glutamine metabolism in BLCA cell lines. The GMscore model, developed and validated across multiple cohorts, accurately predicted patient survival. In two immunotherapy cohorts (IMvigor210 and GSE91061), a lower GMscore correlated with improved therapeutic response, suggesting its potential as a predictive biomarker for immunotherapy efficacy. PYCR1 was identified as a key regulatory gene, exhibiting high expression in epithelial cells and cancer-associated fibroblasts (CAFs). Functional assays demonstrated that PYCR1 knockdown inhibited cell proliferation and migration and suppressed tumor growth in vivo. Mechanistically, PYCR1 facilitated proline synthesis through P5CS and activated the PI3K/AKT/mTOR signaling pathway, which modulated glutamine utilization and metabolic reprogramming in BLCA.
CONCLUSIONS: This study provides a comprehensive analysis of glutamine metabolism in BLCA and introduces a clinically relevant prognostic model. PYCR1 was identified as a central metabolic regulator, underscoring its critical role in tumor development and progression.

Keywords:  Bladder cancer; Glutamine metabolism; Metabolic reprogramming; PYCR1; Prognostic model; Tumor microenvironment

DOI:  https://doi.org/10.1186/s12967-025-07386-2
Cells. 2025 Oct 22. pii: 1655. [Epub ahead of print]14(21):

SLC25A11 Is Associated with KDM2A-Dependent Reduction in rRNA Transcription Induced by Aminooxyacetic Acid.

Yuji Tanaka, Nagisa Miyazawa, Yuuki Toba.

  The malate-aspartate shuttle (MAS) is an NADH shuttle that transports cytoplasmic reducing equivalents to the mitochondria for producing energy. We previously demonstrated that K-demethylase 2A (KDM2A), a jmjC-type histone demethylase, decreases ribosomal RNA (rRNA) transcription via demethylation of H3K36me2 in the rRNA gene promoter region in response to energy reduction in MCF-7 cells. However, whether MAS inhibition is involved in KDM2A activity has not been investigated. In this study, we demonstrate that aminooxyacetic acid (AOA), which inhibits aspartate transaminase (AST/GOT) in MAS, decreased intracellular ATP levels and reduced rRNA transcription via KDM2A-dependent reduction in H3K36me2 levels in the rRNA gene promoter in MCF-7 cells. On the other hand, N-phenylmaleimide (NPM), which inhibits the mitochondrial αKG/malate carrier SLC25A11 in MAS, also decreased intracellular ATP levels but did not induce KDM2A activity. Additionally, NPM pretreatment or knockdown of SLC25A11 inhibited AOA-induced KDM2A activity. Dimethyl αKG, a cell-permeable αKG, restored KDM2A activity inhibited by NPM-pretreatment in AOA-treated cells. These results demonstrate that AOA and NPM have different abilities to induce a decrease in rRNA transcription via KDM2A. Furthermore, the αKG/malate carrier SLC25A11 is associated with KDM2A-dependent reduction in rRNA transcription via demethylation under MAS inhibition.

Keywords:  K-demethylase 2A (KDM2A); SLC25A11; malate–aspartate shuttle (MAS); ribosomal RNA (rRNA)

DOI:  https://doi.org/10.3390/cells14211655
J Cell Sci. 2025 Nov 01. pii: jcs264026. [Epub ahead of print]138(21):

Sphingolipid and methionine metabolism in aging.

Daniel Adebayo, Eseiwi Obaseki, Kashvi Vasudeva, Marwa Aboumourad, Ahmad Sleiman, Sumit Bandyopadhyay, Lindsey Kreinbring, Hanaa Hariri.

  Sphingolipids are essential for cell membrane structure and the regulation of organelle functions. Sphingolipid synthesis requires the coordinated activity of multiple organelles, including the endoplasmic reticulum, Golgi, lysosomes and mitochondria, which are connected via membrane contact sites. Metabolic remodeling of sphingolipid pathways is observed in aging and numerous age-related disorders. However, numerous studies have highlighted the complex and species-specific roles of sphingolipid metabolism in aging. In budding yeast, inhibition of sphingolipid synthesis extends lifespan by a mechanism that is poorly understood. Recent findings suggest that inhibition of sphingolipid synthesis in cells mimics methionine restriction, a condition known to extend lifespan across different experimental models. However, how sphingolipid remodeling alters cellular methionine levels, and whether this directly influences aging, remains unclear. In this Review, we explore the roles of sphingolipids in organelle function, highlighting their metabolic connections to methionine restriction and aging.

Keywords:  Aging; Metabolism; Methionine; Sphingolipids

DOI:  https://doi.org/10.1242/jcs.264026