bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2025–03–02
39 papers selected by
Christian Frezza, Universität zu Köln
  1. Mitochondrial superoxide regulates pro-inflammatory macrophages.
  2. A systems-level, semi-quantitative landscape of metabolic flux in C. elegans.
  3. MARIGOLD and MitoCIAO, two searchable compendia to visualize and functionalize protein complexes during mitochondrial remodeling.
  4. Glyoxalase 2 coordinates de novo serine biosynthesis.
  5. Pre-existing stem cell heterogeneity dictates clonal responses to the acquisition of leukemic driver mutations.
  6. Methionine cycle inhibition disrupts antioxidant metabolism and reduces glioblastoma cell survival.
  7. A Quantitative Approach to Mapping Mitochondrial Specialization and Plasticity.
  8. Determination of Nutrient Ligand-Sensor Binding Affinity.
  9. Visualization of Subcellular mTOR Complex 1 Activity with a FRET-Based Sensor (TORCAR).
  10. Systems-level design principles of metabolic rewiring in an animal.
  11. Fission yeast metabolome dynamics during phosphate starvation and replenishment.
  12. Viperin expression leads to downregulation of mitochondrial genes through misincorporation of ddhCTP by mitochondrial RNA polymerase.
  13. Dietary cysteine enhances intestinal stemness via CD8 + T cell-derived IL-22.
  14. Unveiling the cell-type-specific landscape of cellular senescence through single-cell transcriptomics using SenePy.
  15. Circadian clock features define novel subtypes among breast cancer cells and shape drug sensitivity.
  16. Glycolytic reprogramming shapes the histone acetylation profile of activated CD4+ T cells in juvenile idiopathic arthritis.
  17. Dysregulation of mitochondrial α-ketoglutarate dehydrogenase leads to elevated lipid peroxidation in CHCHD2-linked Parkinson's disease models.
  18. Centriole structural integrity defects are a crucial feature of hydrolethalus syndrome.
  19. Mitochondrial substrate oxidation regulates distinct cell differentiation outcomes.
  20. TAX1BP1-dependent autophagic degradation of STING1 impairs anti-tumor immunity.
  21. How quickly are you ageing? What molecular 'clocks' can tell you about your health.
  22. Metabolic Objectives and Trade-Offs: Inference and Applications.
  23. Nellie: automated organelle segmentation, tracking and hierarchical feature extraction in 2D/3D live-cell microscopy.
  24. Odd-chain dicarboxylic acid feeding recapitulates the biochemical phenotype of glutaric aciduria type 1 in mice.
  25. Programs, origins and immunomodulatory functions of myeloid cells in glioma.
  26. Arginine Deprivation Induces Quiescence and Confers Vulnerability to Ferroptosis in Colorectal Cancer.
  27. Characterization of the glutathione redox state in the Golgi apparatus.
  28. The response of mitochondrial position to glucose stimulation in a model system of the pancreatic beta cell.
  29. Maintenance of p-eIF2α levels by the eIF2B complex is vital for colorectal cancer.
  30. Germline Mutations in Renal Neoplasms and Their Clinicopathological Correlations.
  31. Lineage plasticity of the integrated stress response is a hallmark of cancer evolution.
  32. Cancer-independent somatic mutation of the wild-type NF1 allele in normal tissues in neurofibromatosis type 1.
  33. Human glycolysis isomerases are inhibited by weak metabolite modulators.
  34. Macrophages recycle phagocytosed bacteria to fuel immunometabolic responses.
  35. EHBP1 suppresses liver fibrosis in metabolic dysfunction-associated steatohepatitis.
  36. Single-cell and spatial genomic landscape of non-small cell lung cancer brain metastases.
  37. Extracellular vesicles transport gasdermin pores, amplifying inflammatory cell death.
  38. What makes biological age epigenetic clocks tick.
  39. Mechano-oncogenic cytoskeletal remodeling drives leukemic transformation with mitochondrial vesicle-mediated STING activation.
  1. Nat Metab. 2025 Feb 24.
    Mitochondrial superoxide regulates pro-inflammatory macrophages.
      
    DOI:  https://doi.org/10.1038/s42255-025-01223-y
  2. Nature. 2025 Feb 26.
    A systems-level, semi-quantitative landscape of metabolic flux in C. elegans.
    Hefei Zhang, Xuhang Li, L Tenzin Tseyang, Gabrielle E Giese, Hui Wang, Bo Yao, Jingyan Zhang, Rachel L Neve, Elizabeth A Shank, Jessica B Spinelli, L Safak Yilmaz, Albertha J M Walhout.
      Metabolic flux, or the rate of metabolic reactions, is one of the most fundamental metrics describing the status of metabolism in living organisms. However, measuring fluxes across the entire metabolic network remains nearly impossible, especially in multicellular organisms. Computational methods based on flux balance analysis have been used with genome-scale metabolic network models to predict network-level flux wiring1-6. However, such approaches have limited power because of the lack of experimental constraints. Here, we introduce a strategy that infers whole-animal metabolic flux wiring from transcriptional phenotypes in the nematode Caenorhabditis elegans. Using a large-scale Worm Perturb-Seq (WPS) dataset for roughly 900 metabolic genes7, we show that the transcriptional response to metabolic gene perturbations can be integrated with the metabolic network model to infer a highly constrained, semi-quantitative flux distribution. We discover several features of adult C. elegans metabolism, including cyclic flux through the pentose phosphate pathway, lack of de novo purine synthesis flux and the primary use of amino acids and bacterial RNA as a tricarboxylic acid cycle carbon source, all of which we validate by stable isotope tracing. Our strategy for inferring metabolic wiring based on transcriptional phenotypes should be applicable to a variety of systems, including human cells.
    DOI:  https://doi.org/10.1038/s41586-025-08635-6
  3. Cell Metab. 2025 Feb 20. pii: S1550-4131(25)00017-8. [Epub ahead of print]
    MARIGOLD and MitoCIAO, two searchable compendia to visualize and functionalize protein complexes during mitochondrial remodeling.
    Giovanni Rigoni, Enrique Calvo, Christina Glytsou, Marta Carro-Alvarellos, Masafumi Noguchi, Martina Semenzato, Charlotte Quirin, Federico Caicci, Natascia Meneghetti, Mattia Sturlese, Takaya Ishihara, Stefano Moro, Chiara Rampazzo, Naotada Ishihara, Fabrizio Bezzo, Leonardo Salviati, Jesùs Vazquez, Gabriele Sales, Chiara Romualdi, Jose Antonio Enriquez, Luca Scorrano, Maria Eugenia Soriano.
      Mitochondrial proteins assemble dynamically in high molecular weight complexes essential for their functions. We generated and validated two searchable compendia of these mitochondrial complexes. Following identification by mass spectrometry of proteins in complexes separated using blue-native gel electrophoresis from unperturbed, cristae-remodeled, and outer membrane-permeabilized mitochondria, we created MARIGOLD, a mitochondrial apoptotic remodeling complexome database of 627 proteins. MARIGOLD elucidates how dynamically proteins distribute in complexes upon mitochondrial membrane remodeling. From MARIGOLD, we developed MitoCIAO, a mitochondrial complexes interactome tool that, by statistical correlation, calculates the likelihood of protein cooccurrence in complexes. MitoCIAO correctly predicted biologically validated interactions among components of the mitochondrial cristae organization system (MICOS) and optic atrophy 1 (OPA1) complexes. We used MitoCIAO to functionalize two ATPase family AAA domain-containing 3A (ATAD3A) complexes: one with OPA1 that regulates mitochondrial ultrastructure and the second containing ribosomal proteins that is essential for mitoribosome stability. These compendia reveal the dynamic nature of mitochondrial complexes and enable their functionalization.
    Keywords:  ATAD3A; OPA1; cristae remodeling; interactome; mitochondria; mitochondrial complexes; mitoribosome stability
    DOI:  https://doi.org/10.1016/j.cmet.2025.01.017
  4. Chembiochem. 2025 Feb 23. e202401086
    Glyoxalase 2 coordinates de novo serine biosynthesis.
    Marissa N Trujillo, Erin Q Jennings, Dominique O Farrera, Naoya Kitamura, Colin C Anderson, Sarah Gehrke, Julie A Reisz, Mogens Johannsen, James R Roede, Angelo D'Alessandro, James Galligan.
      Phosphoglycerate dehydrogenase (PHGDH) is the first enzyme in de novo Ser biosynthesis. Numerous metabolic pathways rely on Ser as a precursor, most notably one-carbon metabolism, glutathione biosynthesis, and de novo nucleotide biosynthesis. To facilitate proliferation, many cancer cells shunt glycolytic flux through this pathway, placing PHGDH as a metabolic liability and feasible therapeutic target for the treatment of cancer. Herein, we demonstrate the post-translational modification (PTM) of PHGDH by lactoylLys. These PTMs are generated through a non-enzymatic acyl transfer from the glyoxalase cycle intermediate, lactoylglutathione (LGSH). Knockout of the primary LGSH regulatory enzyme, glyoxalase 2 (GLO2), results in increased LGSH and resulting lactoylLys modification of PHGDH. These PTMs reduce enzymatic activity, resulting in a marked reduction in intracellular Ser. Using stable isotope tracing, we demonstrate reduced flux through the de novo Ser biosynthetic pathway. Collectively, these data identify PHGDH as a target for modification by lactoylLys, resulting in reduced enzymatic activity and reduced intracellular Ser.
    Keywords:  3-phosphoglycerate dehydrogenase (PHGDH); cell metabolism; glycolysis; lactoylation
    DOI:  https://doi.org/10.1002/cbic.202401086
  5. Cell Stem Cell. 2025 Feb 19. pii: S1934-5909(25)00012-8. [Epub ahead of print]
    Pre-existing stem cell heterogeneity dictates clonal responses to the acquisition of leukemic driver mutations.
    Indranil Singh, Daniel Fernandez-Perez, Pedro Sanchez Sanchez, Alejo E Rodriguez-Fraticelli.
      Cancer cells display wide phenotypic variation even across patients with the same mutations. Differences in the cell of origin provide a potential explanation, but traditional assays lack the resolution to distinguish clonally heterogeneous subsets of stem and progenitor cells. To address this challenge, we developed simultaneous tracking of recombinase activation and clonal kinetics (STRACK), a method to trace clonal dynamics and gene expression before and after the acquisition of cancer mutations. Using mouse models, we studied two leukemic mutations, Dnmt3a-R878H and Npm1c, and found that their effect was highly variable across different stem cell states. Specifically, a subset of differentiation-primed stem cells, which normally becomes outcompeted with time, expands with both mutations. Intriguingly, Npm1c mutations reversed the intrinsic bias of the clone of origin, with differentiation-primed stem cells giving rise to more primitive malignant states. Thus, we highlight the relevance of single-cell lineage tracing to unravel early events in cancer evolution and posit that different cellular histories carry distinct cancer phenotypic potential.
    Keywords:  Dnmt3a; Npm1; cancer initiation; cell barcoding; cell of origin; clonal hematopoiesis; lineage tracing; myeloid leukemia; myeloid malignancies; single-cell
    DOI:  https://doi.org/10.1016/j.stem.2025.01.012
  6. J Biol Chem. 2025 Feb 25. pii: S0021-9258(25)00198-X. [Epub ahead of print] 108349
    Methionine cycle 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. Therefore, we 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 shifts the cellular metabolic profile towards oxidative stress and cell death. Mechanistically, MAT2a and AHCY regulate spare respiratory capacity, the redox buffer cystathionine, lipid and amino acid metabolism, and prevent oxidative 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 has the potential to reduce tumor growth and improve survival in patients.
    Keywords:  glioblastoma; lipid peroxidation; metabolism; metabolomics; methionine; mitochondria; oxidative stress
    DOI:  https://doi.org/10.1016/j.jbc.2025.108349
  7. Res Sq. 2025 Feb 14. pii: rs.3.rs-5961609. [Epub ahead of print]
    A Quantitative Approach to Mapping Mitochondrial Specialization and Plasticity.
    Martin Picard, Anna Monzel, Jack Devine, Darshana Kapri, Jose Enriquez, Caroline Trumpff.
      Mitochondria are a diverse family of organelles that specialize to accomplish complimentary functions 1-3. All mitochondria share general features, but not all mitochondria are created equal 4.Here we develop a quantitative pipeline to define the degree of molecular specialization among different mitochondrial phenotypes - or mitotypes. By distilling hundreds of validated mitochondrial genes/proteins into 149 biologically interpretable MitoPathway scores (MitoCarta 3.0 5) the simple mitotyping pipeline allows investigators to quantify and interpret mitochondrial diversity and plasticity from transcriptomics or proteomics data across a variety of natural and experimental contexts. We show that mouse and human multi-organ mitotypes segregate along two main axes of mitochondrial specialization, contrasting anabolic (liver) and catabolic (brain) tissues. In cultured primary human fibroblasts exhibiting robust time-dependent and treatment-induced metabolic plasticity 6-8, we demonstrate how the mitotype of a given cell type recalibrates i) over time in parallel with hallmarks of aging, and ii) in response to genetic, pharmacological, and metabolic perturbations. Investigators can now use MitotypeExplorer.org and the associated code to visualize, quantify and interpret the multivariate space of mitochondrial biology.
    DOI:  https://doi.org/10.21203/rs.3.rs-5961609/v1
  8. Methods Mol Biol. 2025 ;2882 163-178
    Determination of Nutrient Ligand-Sensor Binding Affinity.
    Xin Gu.
      Cells contain dedicated mechanisms to sense nutrient levels in the environment to regulate their growth by balancing anabolism and catabolism [1, 2]. The mechanistic Target of Rapamycin Complex 1 (mTORC1), a multi-protein kinase complex, serves as an essential growth regulator that integrates various upstream inputs including growth factors and nutrients like amino acids [1, 2] Nutrient sensors upstream of mTORC1 directly bind cognate nutrient ligands to convey their availability and thereby regulate mTORC1 signaling [1, 2]. A reliable method is needed to quantitatively determine the binding affinity (Kd) of the nutrient sensor to its ligand. In parallel, quantitative metabolomic analysis can reveal metabolite levels in fed and starved cells; which represent the physiological range of the nutrient of interest. Whether or not the binding affinity is within the physiological range serves as an indicator to determine the physiological relevance of the sensing mechanism. This chapter describes a generalizable protocol that allows reproducible determination of nutrient ligand-nutrient sensor binding affinity. Here, the S-adenosylmethionine (nutrient ligand)-SAMTOR (nutrient sensor) pair is used as an example [3]. Nutrient sensor purification, radioactive nutrient ligand incubation, and eventual scintillation counting are included, along with a description of the mathematical equation that is used to calculate the binding affinity.
    Keywords:  Affinity beads; Competitive binding assays; Nutrient sensors; Nutrients; Protein purification; Radioactive ligands; Scintillation; mTORC1
    DOI:  https://doi.org/10.1007/978-1-0716-4284-9_8
  9. Methods Mol Biol. 2025 ;2882 139-162
    Visualization of Subcellular mTOR Complex 1 Activity with a FRET-Based Sensor (TORCAR).
    Ayse Z Sahan, Sohum Metha, Jin Zhang.
      The mechanistic target of rapamycin complex 1 (mTORC1) is a nutrient-sensing complex that integrates inputs from several pathways to promote cell growth and proliferation. mTORC1 localizes to many cellular compartments, including the nucleus, lysosomes, and plasma membrane. However, little is known about the spatial regulation of mTORC1 and the specific functions of mTORC1 at these locations. To address these questions, we previously developed a Förster resonance energy transfer (FRET)-based mTORC1 activity reporter (TORCAR) to visualize the dynamic changes in mTORC1 activity within live cells. Here, we describe a detailed protocol for using subcellularly targeted TORCAR constructs to investigate subcellular mTORC1 activities via live-cell fluorescence microscopy.
    Keywords:  Biosensor; Compartmentalized signaling; Fluorescence; Location-specific
    DOI:  https://doi.org/10.1007/978-1-0716-4284-9_7
  10. Nature. 2025 Feb 26.
    Systems-level design principles of metabolic rewiring in an animal.
    Xuhang Li, Hefei Zhang, Thomas Hodder, Wen Wang, Chad L Myers, L Safak Yilmaz, Albertha J M Walhout.
      The regulation of metabolism is vital to any organism and can be achieved by transcriptionally activating or repressing metabolic genes1-3. Although many examples of transcriptional metabolic rewiring have been reported4, a systems-level study of how metabolism is rewired in response to metabolic perturbations is lacking in any animal. Here we apply Worm Perturb-Seq (WPS)-a high-throughput method combining whole-animal RNA-interference and RNA-sequencing5-to around 900 metabolic genes in the nematode Caenorhabditis elegans. We derive a metabolic gene regulatory network (mGRN) in which 385 perturbations are connected to 9,414 genes by more than 110,000 interactions. The mGRN has a highly modular structure in which 22 perturbation clusters connect to 44 gene expression programs. The mGRN reveals different modes of transcriptional rewiring from simple reaction and pathway compensation to rerouting and more complex network coordination. Using metabolic network modelling, we identify a design principle of transcriptional rewiring that we name the compensation-repression (CR) model. The CR model explains most transcriptional responses in metabolic genes and reveals a high level of compensation and repression in five core metabolic functions related to energy and biomass. We provide preliminary evidence that the CR model may also explain transcriptional metabolic rewiring in human cells.
    DOI:  https://doi.org/10.1038/s41586-025-08636-5
  11. mBio. 2025 Feb 25. e0024125
    Fission yeast metabolome dynamics during phosphate starvation and replenishment.
    Ana M Sanchez, Aye K Kyaw, Sara Nunes Violante, Angad Garg, Justin R Cross, Stewart Shuman.
      Inorganic phosphate is an essential nutrient acquired by cells from their environment and assimilated into myriad intracellular metabolites and macromolecules. Here, we characterize the metabolic responses of fission yeast to a 24 h interval of phosphate starvation, during which cells enter a state of G0 quiescence. Time-resolved profiling revealed that many key phosphometabolites were progressively depleted, including (i) NTPs, NDPs, and dNTPs; (ii) coenzyme A, NAD+, NADP+, NADH, and ADP-ribose; (iii) glycolysis pathway intermediates upstream of pyruvate; (iv) pentose phosphate pathway intermediates from 6-phosphogluconate to sedoheptulose-7-phosphate; (v) nucleotide sugars GDP-hexose, UDP-glucose/galactose, and UDP-GalNAc/GlcNAc; and (vi) phospholipid precursors glycerol-3-phosphate, CDP-choline, and glycerophosphocholine. By contrast, early Krebs cycle intermediates accumulated during phosphate starvation. Other metabolic changes included the following: (i) interdiction of de novo pyrimidine synthesis; (ii) depletion of S-adenosylmethionine and S-adenosylhomocysteine; (iii) transient accumulation of polyamine biosynthetic intermediates putrescine and 5-methylthioadenosine; (iv) accumulation of betaine (correlating with an increase in expression of atd1 mRNA encoding aldehyde dehydrogenase); and (v) depletion of aminoadipate pathway intermediates 2-oxoadipate, 2-aminoadipate, and saccharopine. Replenishing phosphate after 24 h of starvation resulted in restoration of the pre-starvation metabolome (over 2 to 12 h) as cells exited quiescence and resumed growth.
    IMPORTANCE: Fission yeast Schizosaccharomyces pombe is a valuable model system to study cellular phosphate homeostasis and the adaptive responses to chronic phosphate starvation. Previous analyses focused on changes in the fission yeast transcriptome and proteome during phosphate starvation-induced durable G0 quiescence. Here, we deployed metabolomics to survey the scope and temporal order of metabolite changes during 24 h of phosphate starvation and the kinetics of metabolic recovery after cells starved for 24 h are replenished with phosphate. These results contribute to a multi-omics understanding of how phosphate status impacts cell cycle, gene expression, metabolism, and chronological lifespan.
    Keywords:  Schizosaccharomyces pombe; phosphate metabolism; phosphate starvation
    DOI:  https://doi.org/10.1128/mbio.00241-25
  12. J Biol Chem. 2025 Feb 25. pii: S0021-9258(25)00208-X. [Epub ahead of print] 108359
    Viperin expression leads to downregulation of mitochondrial genes through misincorporation of ddhCTP by mitochondrial RNA polymerase.
    Srijoni Majhi, Pronay Roy, Minshik Jo, Jiying Liu, Rebecca Hurto, Lydia Freddolino, E Neil G Marsh.
      Increasing lines of evidence link the expression of the interferon-stimulated gene RSAD2, encoding the antiviral enzyme, viperin, to autoimmune disease. Autoimmune diseases are characterized by chronic over-production of cytokines such as interferons that upregulate the inflammatory response. Immune cells exposed to interferon selectively downregulate transcription of the mitochondrially-encoded components of the oxidative phosphorylation system, which leads to mitochondria becoming dysfunctional and impairing their ability to produce ATP. But the mechanism by which downregulation occurs has remained unknown. Here we show that 3'-deoxy-3',4'-didehydrocytidine triphosphate (ddhCTP) which is synthesized by viperin suppresses mitochondrial transcription by causing premature chain termination when misincorporated by the mitochondrial RNA polymerase (POLRMT). We show that expression of viperin in human cell lines downregulates mitochondrially encoded gene expression. A similar effect is observed across multiple cell lines when cells are exposed to ddhC, the precursor to ddhCTP. The pattern of gene downregulation fits well with a simple, quantitative model describing chain-termination. In vitro measurements with purified POLRMT demonstrate that ddhCTP competes effectively with CTP, leading to its misincorporation into RNA. These findings reveal a new molecular mechanism for mitochondrial transcriptional regulation that explains the reduction in mitochondrially-encoded transcript levels in response to chronic interferon stimulation, characteristic of inflammatory diseases.
    DOI:  https://doi.org/10.1016/j.jbc.2025.108359
  13. bioRxiv. 2025 Feb 16. pii: 2025.02.15.638423. [Epub ahead of print]
    Dietary cysteine enhances intestinal stemness via CD8 + T cell-derived IL-22.
    Fangtao Chi, Qiming Zhang, Jessica E S Shay, Johanna Ten Hoeve, Yin Yuan, Zhenning Yang, Heaji Shin, Sumeet Solanki, Yatrik M Shah, Judith Agudo, Ömer H Yilmaz.
      A critical question in physiology is understanding how tissues adapt and alter their cellular composition in response to dietary cues. The mammalian small intestine, a vital digestive organ that absorbs nutrients, is maintained by rapidly renewing Lgr5 + intestinal stem cells (ISCs) at the intestinal crypt base. While Lgr5 + ISCs drive intestinal adaptation by altering self-renewal and differentiation divisions in response to diverse diets such as high-fat diets and fasting regimens, little is known about how micronutrients, particularly amino acids, instruct Lgr5 + ISC fate decisions to control intestinal homeostasis and repair after injury. Here, we demonstrate that cysteine, an essential amino acid, enhances the ability of Lgr5 + ISCs to repair intestinal injury. Mechanistically, the effects of cysteine on ISC-driven repair are mediated by elevated IL-22 from intraepithelial CD8αβ + T cells. These findings highlight how coupled cysteine metabolism between ISCs and CD8 + T cells augments intestinal stemness, providing a dietary approach that exploits ISC and immune cell crosstalk for ameliorating intestinal damage.
    DOI:  https://doi.org/10.1101/2025.02.15.638423
  14. Nat Commun. 2025 Feb 22. 16(1): 1884
    Unveiling the cell-type-specific landscape of cellular senescence through single-cell transcriptomics using SenePy.
    Mark A Sanborn, Xinge Wang, Shang Gao, Yang Dai, Jalees Rehman.
      Senescent cells accumulate in most tissues with organismal aging, exposure to stressors, or disease progression. It is challenging to identify senescent cells because cellular senescence signatures and phenotypes vary widely across distinct cell types and tissues. Here we developed an analytical algorithm that defines cell-type-specific and universal signatures of cellular senescence across a wide range of cell types and tissues. We utilize 72 mouse and 64 human weighted single-cell transcriptomic signatures of cellular senescence to create the SenePy scoring platform. SenePy signatures better recapitulate in vivo cellular senescence than signatures derived from in vitro senescence studies. We use SenePy to map the kinetics of senescent cell accumulation in healthy aging as well as multiple disease contexts, including tumorigenesis, inflammation, and myocardial infarction. SenePy characterizes cell-type-specific in vivo cellular senescence and could lead to the identification of genes that serve as mediators of cellular senescence and disease progression.
    DOI:  https://doi.org/10.1038/s41467-025-57047-7
  15. Mol Syst Biol. 2025 Feb 24.
    Circadian clock features define novel subtypes among breast cancer cells and shape drug sensitivity.
    Carolin Ector, Jeff Didier, Sébastien De Landtsheer, Malthe S Nordentoft, Christoph Schmal, Ulrich Keilholz, Hanspeter Herzel, Achim Kramer, Thomas Sauter, Adrián E Granada.
      The circadian clock regulates key physiological processes, including cellular responses to DNA damage. Circadian-based therapeutic strategies optimize treatment timing to enhance drug efficacy and minimize side effects, offering potential for precision cancer treatment. However, applying these strategies in cancer remains limited due to a lack of understanding of the clock's function across cancer types and incomplete insights into how the circadian clock affects drug responses. To address this, we conducted deep circadian phenotyping across a panel of breast cancer cell lines. Observing diverse circadian dynamics, we characterized metrics to assess circadian rhythm strength and stability in vitro. This led to the identification of four distinct circadian-based phenotypes among 14 breast cancer cell models: functional, weak, unstable, and dysfunctional clocks. Furthermore, we demonstrate that the circadian clock plays a critical role in shaping pharmacological responses to various anti-cancer drugs and we identify circadian features descriptive of drug sensitivity. Collectively, our findings establish a foundation for implementing circadian-based treatment strategies in breast cancer, leveraging clock phenotypes and drug sensitivity patterns to optimize therapeutic outcomes.
    Keywords:  Breast Cancer; Circadian Clock; Circadian Medicine; Systems Biology
    DOI:  https://doi.org/10.1038/s44320-025-00092-7
  16. Cell Rep. 2025 Feb 18. pii: S2211-1247(25)00058-0. [Epub ahead of print]44(2): 115287
    Glycolytic reprogramming shapes the histone acetylation profile of activated CD4+ T cells in juvenile idiopathic arthritis.
    Enric Mocholi, Edward Corrigan, Theo Chalkiadakis, Can Gulersonmez, Edwin Stigter, Bas Vastert, Jorg van Loosdregt, Stefan Prekovic, Paul J Coffer.
      Juvenile idiopathic arthritis (JIA) is an autoimmune disease characterized by accumulation of activated CD4+ T cells in the synovial fluid (SF) of affected joints. JIA CD4+ T cells exhibit a unique inflammation-associated epigenomic signature, but the underlying mechanisms remain unclear. We demonstrate that CD4+ T cells from JIA SF display heightened glycolysis upon activation and JIA-specific H3K27 acetylation, driving transcriptional reprogramming. Pharmacological inhibition of glycolysis altered the expression of genes associated with these acetylated regions. Healthy CD4+ T cells exposed to JIA SF exhibited increased glycolytic activity and transcriptomic changes marked by heightened histone 3 lysine 27 acetylation (H3K27ac) at JIA-specific genes. Elevated H3K27ac was dependent on glycolytic flux, while inhibiting glycolysis or pyruvate dehydrogenase (PDH) impaired transcription of SF-driven genes. These findings demonstrate a key role of glycolysis in JIA-specific gene expression, offering potential therapeutic targets for modulating inflammation in JIA.
    Keywords:  CP: Immunology; CP: Metabolism; T cells; autoimmune disease; glucose metabolism; histone acetylation; juvenile idiopathic arthritis; pyruvate dehydrogenase
    DOI:  https://doi.org/10.1016/j.celrep.2025.115287
  17. Nat Commun. 2025 Feb 26. 16(1): 1982
    Dysregulation of mitochondrial α-ketoglutarate dehydrogenase leads to elevated lipid peroxidation in CHCHD2-linked Parkinson's disease models.
    Ge Gao, Yong Shi, Han-Xiang Deng, Dimitri Krainc.
      Dysregulation of mitochondrial function has been implicated in Parkinson's disease (PD), but the role of mitochondrial metabolism in disease pathogenesis remains to be elucidated. Using an unbiased metabolomic analysis of purified mitochondria, we identified alterations in α-ketoglutarate dehydrogenase (KGDH) pathway upon loss of PD-linked CHCHD2 protein. KGDH, a rate-limiting enzyme complex in the tricarboxylic acid cycle, was decreased in CHCHD2-deficient male mouse brains and human dopaminergic neurons. This deficiency of KGDH led to elevated α-ketoglutarate and increased lipid peroxidation. Treatment of CHCHD2-deficient dopaminergic neurons with lipoic acid, a KGDH cofactor and antioxidant agent, resulted in decreased levels of lipid peroxidation and phosphorylated α-synuclein. CHCHD10, a close homolog of CHCHD2 that is primarily linked to amyotrophic lateral sclerosis/frontotemporal dementia, did not affect the KGDH pathway or lipid peroxidation. Together, these results identify KGDH metabolic pathway as a targetable mitochondrial mechanism for correction of increased lipid peroxidation and α-synuclein in Parkinson's disease.
    DOI:  https://doi.org/10.1038/s41467-025-57142-9
  18. J Cell Biol. 2025 Apr 07. pii: e202403022. [Epub ahead of print]224(4):
    Centriole structural integrity defects are a crucial feature of hydrolethalus syndrome.
    Ana Curinha, Zhaoyu Huang, Taylor Anglen, Margaret A Strong, Colin R Gliech, Cayla E Jewett, Anoek Friskes, Thao P Phan, Zachary Nicholas, Andrew J Holland.
      Hydrolethalus syndrome (HLS) is a lethal, autosomal recessive ciliopathy caused by the mutation of the conserved centriole protein HYLS1. How HYLS1 controls centriole function is poorly understood. Here, we show that mice harboring the HYLS1 disease mutation die shortly after birth and exhibit developmental defects that recapitulate several manifestations of HLS. These phenotypes arise from a loss of centriole integrity that causes tissue-specific defects in cilia assembly and function. We show that HYLS1 is recruited to the centriole by CEP120 and stabilizes the localization of centriole inner scaffold proteins that ensure the integrity of the centriolar microtubule wall. The HLS disease mutation reduced the centriole localization of HYLS1 and caused degeneration of the centriole distal end. We propose that tissue-specific defects in centriole integrity caused by the HYLS1 mutation prevent ciliogenesis and contribute to HLS phenotypes.
    DOI:  https://doi.org/10.1083/jcb.202403022
  19. Trends Cell Biol. 2025 Feb 25. pii: S0962-8924(25)00038-8. [Epub ahead of print]
    Mitochondrial substrate oxidation regulates distinct cell differentiation outcomes.
    Woo Yong Park, Claudia Montufar, Elma Zaganjor.
      Mitochondrial metabolism, signaling, and dynamics are key regulators of cell fate. While glycolysis supports stemness, mitochondrial expansion and oxidative phosphorylation (OXPHOS) facilitate differentiation. This forum presents emerging evidence that the type of substrate, whether amino acids, carbohydrates, or fatty acids, oxidized by mitochondria significantly influences differentiation outcomes.
    Keywords:  OXPHOS; amino acids; differentiation; fatty acids; glucose; mitochondria
    DOI:  https://doi.org/10.1016/j.tcb.2025.02.004
  20. Autophagy. 2025 Feb 25.
    TAX1BP1-dependent autophagic degradation of STING1 impairs anti-tumor immunity.
    Ruoxi Zhang, Chunhua Yu, Herbert J Zeh, Guido Kroemer, Daniel J Klionsky, Daolin Tang, Rui Kang.
      The activation of STING1 can lead to the production and secretion of cytokines, initiating antitumor immunity. Here, we screened an ion channel ligand library and identified tetrandrine, a bis-benzylisoquinoline alkaloid, as an immunological adjuvant that enhances antitumor immunity by preventing the autophagic degradation of the STING1 protein. This tetrandrine effect is independent of its known function as a calcium or potassium channel blocker. Instead, tetrandrine inhibits lysosomal function, impairing cathepsin maturation, and autophagic degradation. Proteomic analysis of lysosomes identified TAX1BP1 as a novel autophagic receptor for the proteolysis of STING1. TAX1BP1 recognizes STING1 through the physical interaction of its coiled-coil domain with the cyclic dinucleotide binding domain of STING1. Systematic mutation of lysine (K) residues revealed that K63-ubiquitination of STING1 at the K224 site ignites TAX1BP1-dependent STING1 degradation. Combined treatment with tetrandrine and STING1 agonists promotes antitumor immunity by converting "cold" pancreatic cancers into "hot" tumors. This process is associated with enhanced cytokine release and increased infiltration of cytotoxic T-cells into the tumor microenvironment. The antitumor immunity mediated by tetrandrine and STING1 agonists is limited by neutralizing antibodies to the type I interferon receptor or CD8+ T cells. Thus, these findings establish a potential immunotherapeutic strategy against pancreatic cancer by preventing the autophagic degradation of STING1.
    Keywords:  Autophagy; degradation; lysosome; pancreatic cancer; tumor immunity
    DOI:  https://doi.org/10.1080/15548627.2025.2471736
  21. Nature. 2025 Feb;638(8052): 874-876
    How quickly are you ageing? What molecular 'clocks' can tell you about your health.
    Heidi Ledford.
      
    Keywords:  Ageing; Epigenetics; Medical research
    DOI:  https://doi.org/10.1038/d41586-025-00566-6
  22. Metabolites. 2025 Feb 06. pii: 101. [Epub ahead of print]15(2):
    Metabolic Objectives and Trade-Offs: Inference and Applications.
    Da-Wei Lin, Saanjh Khattar, Sriram Chandrasekaran.
      Background/Objectives: Determining appropriate cellular objectives is crucial for the system-scale modeling of biological networks for metabolic engineering, cellular reprogramming, and drug discovery applications. The mathematical representation of metabolic objectives can describe how cells manage limited resources to achieve biological goals within mechanistic and environmental constraints. While rapidly proliferating cells like tumors are often assumed to prioritize biomass production, mammalian cell types can exhibit objectives beyond growth, such as supporting tissue functions, developmental processes, and redox homeostasis. Methods: This review addresses the challenge of determining metabolic objectives and trade-offs from multiomics data. Results: Recent advances in single-cell omics, metabolic modeling, and machine/deep learning methods have enabled the inference of cellular objectives at both the transcriptomic and metabolic levels, bridging gene expression patterns with metabolic phenotypes. Conclusions: These in silico models provide insights into how cells adapt to changing environments, drug treatments, and genetic manipulations. We further explore the potential application of incorporating cellular objectives into personalized medicine, drug discovery, tissue engineering, and systems biology.
    Keywords:  archetypes; genome-scale metabolic modeling; machine learning; metabolic network; metabolic objectives; metabolomics; proteomics; transcriptomics
    DOI:  https://doi.org/10.3390/metabo15020101
  23. Nat Methods. 2025 Feb 27.
    Nellie: automated organelle segmentation, tracking and hierarchical feature extraction in 2D/3D live-cell microscopy.
    Austin E Y T Lefebvre, Gabriel Sturm, Ting-Yu Lin, Emily Stoops, Magdalena Preciado López, Benjamin Kaufmann-Malaga, Kayley Hake.
      Cellular organelles undergo constant morphological changes and dynamic interactions that are fundamental to cell homeostasis, stress responses and disease progression. Despite their importance, quantifying organelle morphology and motility remains challenging due to their complex architectures, rapid movements and the technical limitations of existing analysis tools. Here we introduce Nellie, an automated and unbiased pipeline for segmentation, tracking and feature extraction of diverse intracellular structures. Nellie adapts to image metadata and employs hierarchical segmentation to resolve sub-organellar regions, while its radius-adaptive pattern matching enables precise motion tracking. Through a user-friendly Napari-based interface, Nellie enables comprehensive organelle analysis without coding expertise. We demonstrate Nellie's versatility by unmixing multiple organelles from single-channel data, quantifying mitochondrial responses to ionomycin via graph autoencoders and characterizing endoplasmic reticulum networks across cell types and time points. This tool addresses a critical need in cell biology by providing accessible, automated analysis of organelle dynamics.
    DOI:  https://doi.org/10.1038/s41592-025-02612-7
  24. bioRxiv. 2025 Feb 16. pii: 2025.02.13.637994. [Epub ahead of print]
    Odd-chain dicarboxylic acid feeding recapitulates the biochemical phenotype of glutaric aciduria type 1 in mice.
    Adam C Richert, Yuxun Zhang, Sivakama S Bharathi, Abigail Hernandez, Tetyana Dodatko, Joanna Bons, Brandon Stauffer, Chunli Yu, Birgit Schilling, Sander M Houten, Eric S Goetzman.
      Glutaric aciduria type-1 (GA1) is an inherited mitochondrial neurometabolic disorder with a poorly understood pathogenesis and unmet medical needs. GA1 can be diagnosed via its hallmark biochemical signature consisting of glutaric aciduria, 3-hydroxyglutaric aciduria, and increased plasma glutarylcarnitine. These glutaryl-CoA-derived metabolites are thought to originate solely in the mitochondria. Here, we demonstrate that wild-type mice fed an 11-carbon odd-chain dicarboxylic acid (undecanedioic acid, DC 11 ) recreates the biochemical phenotype of GA1. Odd-chain dicarboxylic acids like DC 11 are not present in food but can arise from several endogenous processes, such as lipid peroxidation and fatty acid ω-oxidation. DC 11 is chain-shortened in peroxisomes to glutaryl (DC 5 )-CoA, which then gives rise to the GA1-like pattern of DC 5 metabolites in urine, tissues, and blood. Glutaric acid released from peroxisomes during DC 11 chain-shortening can enter mitochondria, be activated to CoA by the enzyme succinyl-CoA:glutarate-CoA transferase (SUGCT), and become substrate for glutaryl-CoA dehydrogenase (GCDH), the enzyme that is mutated in GA1. Our data provide proof-of-concept that the generation of dicarboxylic acids by ω-oxidation, which is stimulated during the same catabolic states known to trigger acute encephalopathy in GA1, may exacerbate disease by increasing the glutaryl-CoA substrate load in mitochondria.
    DOI:  https://doi.org/10.1101/2025.02.13.637994
  25. Nature. 2025 Feb 26.
    Programs, origins and immunomodulatory functions of myeloid cells in glioma.
    Tyler E Miller, Chadi A El Farran, Charles P Couturier, Zeyu Chen, Joshua P D'Antonio, Julia Verga, Martin A Villanueva, L Nicolas Gonzalez Castro, Yuzhou Evelyn Tong, Tariq Al Saadi, Andrew N Chiocca, Yuanyuan Zhang, David S Fischer, Dieter Henrik Heiland, Jennifer L Guerriero, Kevin Petrecca, Mario L Suva, Alex K Shalek, Bradley E Bernstein.
      Gliomas are incurable malignancies notable for having an immunosuppressive microenvironment with abundant myeloid cells, the immunomodulatory phenotypes of which remain poorly defined1. Here we systematically investigate these phenotypes by integrating single-cell RNA sequencing, chromatin accessibility, spatial transcriptomics and glioma organoid explant systems. We discovered four immunomodulatory expression programs: microglial inflammatory and scavenger immunosuppressive programs, which are both unique to primary brain tumours, and systemic inflammatory and complement immunosuppressive programs, which are also expressed by non-brain tumours. The programs are not contingent on myeloid cell type, developmental origin or tumour mutational state, but instead are driven by microenvironmental cues, including tumour hypoxia, interleukin-1β, TGFβ and standard-of-care dexamethasone treatment. Their relative expression can predict immunotherapy response and overall survival. By associating the respective programs with mediating genomic elements, transcription factors and signalling pathways, we uncover strategies for manipulating myeloid-cell phenotypes. Our study provides a framework to understand immunomodulation by myeloid cells in glioma and a foundation for the development of more-effective immunotherapies.
    DOI:  https://doi.org/10.1038/s41586-025-08633-8
  26. Cancer Res. 2025 Feb 24.
    Arginine Deprivation Induces Quiescence and Confers Vulnerability to Ferroptosis in Colorectal Cancer.
    Yanyun Lin, Yanhong Zhang, Tianze Huang, Junguo Chen, Guanman Li, Bin Zhang, Liang Xu, Kai Wang, Hui He, Hao Chen, Danling Liu, Shuang Guo, Xiaosheng He, Ping Lan.
      Metabolic reprogramming is a hallmark of cancer. Rewiring of amino acid metabolic processes provides the basis for amino acid deprivation therapies. In this study, we found that arginine biosynthesis is limited in colorectal cancer (CRC) due to the deficiency of ornithine transcarbamylase (OTC). Accordingly, CRC cells met the demand for arginine by increasing external uptake. The addiction to environmental arginine resulted in the susceptibility of CRC to arginine deprivation, which dramatically decreased proliferation in CRC cells and promoted these cells to enter a reversible quiescence state. Arginine deprivation induced quiescence by activating the AMPK-p53-p21 pathway. RNA sequencing data indicated that CRC cells may be vulnerable to ferroptosis during arginine deprivation, and the combination of ferroptosis inducers and arginine deprivation strongly impeded tumor growth in vivo. These findings suggest that dietary modification combined with ferroptosis induction could be a potential therapeutic strategy for CRC.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-1940
  27. Redox Biol. 2025 Feb 19. pii: S2213-2317(25)00073-4. [Epub ahead of print]81 103560
    Characterization of the glutathione redox state in the Golgi apparatus.
    Carla Miró-Vinyals, Sarah Emmert, Gina Grammbitter, Alex Jud, Tobias Kockmann, Pablo Rivera-Fuentes.
      Redox homeostasis is crucial for cell function, and, in eukaryotic cells, studying it in a compartmentalized way is essential due to the redox variations between different organelles. The redox state of organelles is largely determined by the redox potential of glutathione, EGSH, and the concentration of its reduced and oxidized species, [GS]. The Golgi apparatus is an essential component of the secretory pathway, yet little is known about the concentration or redox state of GSH in this organelle. Here, we characterized the redox state of GSH in the Golgi apparatus using a combination of microscopy and proteomics methods. Our results prove that the Golgi apparatus is a highly oxidizing organelle with a strikingly low GSH concentration (EGSH = - 157 mV, 1-5 mM). These results fill an important gap in our knowledge of redox homeostasis in subcellular organelles. Moreover, the new Golgi-targeted GSH sensors allow us to observe dynamic changes in the GSH redox state in the organelle and pave the way for further characterization of the Golgi redox state under various physiological and pathological conditions.
    Keywords:  Glutathione; Golgi apparatus; Redox homeostasis; roGFP
    DOI:  https://doi.org/10.1016/j.redox.2025.103560
  28. bioRxiv. 2025 Feb 16. pii: 2025.02.13.637960. [Epub ahead of print]
    The response of mitochondrial position to glucose stimulation in a model system of the pancreatic beta cell.
    Luis Perez, Xue Wen Ng, David W Piston, Shankar Mukherji.
      The compartmentalization of eukaryotic cells into membrane-bound organelles with specific subcellular positioning enables precise spatial and temporal control of cellular functions. While functionally significant mitochondrial localization has been demonstrated in cells such as neurons, it remains unclear how general these cell principles are. Here, we examine the spatial organization of mitochondria within MIN6 pancreatic beta cells under variable glucose conditions. We observe glucose-dependent redistributions of mitochondria, favoring peripheral localization at elevated glucose levels when insulin secretion is also elevated. Our results suggest that active mitochondrial transport along microtubules and calcium activity, but not ATP synthesis, are critical regulators of this redistribution. We derived a mathematical model that reveals a putative affinity of the mitochondria for cellular membranes competes with mitochondrial microtubule attachment to play an important role in establishing the mitochondrial spatial patterns we observe. These results suggest that mitochondrial positioning may contribute to optimizing energy delivery in response to local demand, potentially representing a general regulatory mechanism across various cell types.
    DOI:  https://doi.org/10.1101/2025.02.13.637960
  29. EMBO J. 2025 Feb 27.
    Maintenance of p-eIF2α levels by the eIF2B complex is vital for colorectal cancer.
    Ivana Paskov Škapik, Chiara Giacomelli, Sarah Hahn, Hanna Deinlein, Peter Gallant, Mathias Diebold, Josep Biayna, Anne Hendricks, Leon Olimski, Christoph Otto, Carolin Kastner, Elmar Wolf, Christina Schülein-Völk, Katja Maurus, Andreas Rosenwald, Nikolai Schleussner, Rene-Filip Jackstadt, Nicolas Schlegel, Christoph-Thomas Germer, Martin Bushell, Martin Eilers, Stefanie Schmidt, Armin Wiegering.
      Protein synthesis is an essential process, deregulated in multiple tumor types showing differential dependence on translation factors compared to untransformed tissue. We show that colorectal cancer (CRC) with loss-of-function mutation in the APC tumor suppressor depends on an oncogenic translation program regulated by the ability to sense phosphorylated eIF2α (p-eIF2α). Despite increased protein synthesis rates following APC loss, eIF2α phosphorylation, typically associated with translation inhibition, is enhanced in CRC. Elevated p-eIF2α, and its proper sensing by the decameric eIF2B complex, are essential to balance translation. Knockdown or mutation of eIF2Bα and eIF2Bδ, two eIF2B subunits responsible for sensing p-eIF2α, impairs CRC viability, demonstrating that the eIF2B/p-eIF2α nexus is vital for CRC. Specifically, the decameric eIF2B linked by two eIF2Bα subunits is critical for translating growth-promoting mRNAs which are induced upon APC loss. Depletion of eIF2Bα in APC-deficient murine and patient-derived organoids establishes a therapeutic window, validating eIF2Bα as a target for clinical intervention. In conclusion, we demonstrate how the expression of the oncogenic signature in CRC is crucially controlled at the translational level.
    Keywords:  APC; Colorectal Cancer; Translation; eIF2B; eIF2α
    DOI:  https://doi.org/10.1038/s44318-025-00381-9
  30. Int J Surg Pathol. 2025 Feb 26. 10668969251318038
    Germline Mutations in Renal Neoplasms and Their Clinicopathological Correlations.
    Meihua Chen, Yang Liu, Xianwei Yang, Yijin Gu, Lei Dong, Haimin Xu, Luting Zhou, Xiaoqun Yang.
      Introduction. Germline mutations have been described in multiple renal neoplasm entities in the fifth edition of the World Health Organization Classification of Urinary and Male Genital Systems. However, our knowledge of renal neoplasms with germline mutations remains limited. Methods. To expand our understanding, 15 tumors with germline mutations were retrieved from 284 renal neoplasms that underwent next-generation sequencing, including well-known VHL, FH, SDHB, FLCN, TSC1, and less common genes such as MUTYH, NF2, and BARD1. Results. Interesting findings included clear cell renal cell carcinoma (RCC) with FH germline mutation and succinate dehydrogenase (SDH)-deficient RCC with high-grade transformation. Patients with germline mutations of these uncommon altered genes in renal neoplasms, such as MUTYH, NF2, and BARD1 were diagnosed with different renal entities, including entities with favorable outcomes (renal cell carcinoma with fibromyomatous stroma) or adverse outcomes (collecting duct carcinoma and FH deficient renal cell carcinoma). Conclusions. Besides the well-known germline mutations in renal neoplasms, we described germline mutations in some genes that are common in other sites but uncommon in the kidney. Although they cannot be used to determine a definite renal entity, they may also contribute to the pathogenesis of renal neoplasms. Tumors need to be diagnosed based on morphology, immunohistochemistry, and other molecular evidence.
    Keywords:  germline mutation; pathology; renal neoplasm
    DOI:  https://doi.org/10.1177/10668969251318038
  31. bioRxiv. 2025 Feb 13. pii: 2025.02.10.637516. [Epub ahead of print]
    Lineage plasticity of the integrated stress response is a hallmark of cancer evolution.
    Shiqi Diao, Jia Yi Zou, Shuo Wang, Nour Ghaddar, Jason E Chan, Hyungdong Kim, Nicolas Poulain, Constantinos Koumenis, Maria Hatzoglou, Peter Walter, Nahum Sonenberg, John Le Quesne, Tuomas Tammela, Antonis E Koromilas.
      The link between the "stress phenotype"-a well-established hallmark of cancer-and its role in tumor progression and intratumor heterogeneity remains poorly defined. The integrated stress response (ISR) is a key adaptive pathway that enables tumor survival under oncogenic stress. While ISR has been implicated in promoting tumor growth, its precise role in driving tumor evolution and heterogeneity has not been elucidated. In this study, using a genetically engineered mouse models, we demonstrate that ISR activation-indicated by elevated levels of phosphorylated eIF2 (p-eIF2) and ATF4-is essential for the emergence of dedifferentiated, therapy-resistant cell states. ISR, through the coordinated actions of ATF4 and MYC, facilitates the development of tumor cell populations characterized by high plasticity, stemness, and an epithelial-mesenchymal transition (EMT)-prone phenotype. This process is driven by ISR-mediated expression of genes that maintain mitochondrial integrity and function, critical for sustaining tumor progression. Importantly, genetic, or pharmacological inhibition of the p-eIF2-ATF4 signaling axis leads to mitochondrial dysfunction and significantly impairs tumor growth in mouse models of lung adenocarcinoma (LUAD). Moreover, ISR-driven dedifferentiation is associated with poor prognosis and therapy resistance in advanced human LUAD, underscoring ISR inhibition as a promising therapeutic strategy to disrupt tumor evolution and counteract disease progression.
    DOI:  https://doi.org/10.1101/2025.02.10.637516
  32. Nat Genet. 2025 Feb 25.
    Cancer-independent somatic mutation of the wild-type NF1 allele in normal tissues in neurofibromatosis type 1.
    Thomas R W Oliver, Andrew R J Lawson, Henry Lee-Six, Anna Tollit, Hyunchul Jung, Yvette Hooks, Rashesh Sanghvi, Matthew D Young, Timothy M Butler, Pantelis A Nicola, Taryn D Treger, Stefanie V Lensing, G A Amos Burke, Kristian Aquilina, Ulrike Löbel, Isidro Cortes-Ciriano, Darren Hargrave, Mette Jorgensen, Flora A Jessop, Tim H H Coorens, Adrienne M Flanagan, Kieren Allinson, Inigo Martincorena, Thomas S Jacques, Sam Behjati.
      Cancer predisposition syndromes mediated by recessive cancer genes generate tumors via somatic variants (second hits) in the unaffected allele. Second hits may or may not be sufficient for neoplastic transformation. Here we performed whole-genome and whole-exome sequencing on 479 tissue biopsies from a child with neurofibromatosis type 1, a multisystem cancer-predisposing syndrome mediated by constitutive monoallelic NF1 inactivation. We identified multiple independent NF1 driver variants in histologically normal tissues, but not in 610 biopsies from two nonpredisposed children. We corroborated this finding using targeted duplex sequencing, including a further nine adults with the same syndrome. Overall, truncating NF1 mutations were under positive selection in normal tissues from individuals with neurofibromatosis type 1. We demonstrate that normal tissues in neurofibromatosis type 1 commonly harbor second hits in NF1, the extent and pattern of which may underpin the syndrome's cancer phenotype.
    DOI:  https://doi.org/10.1038/s41588-025-02097-2
  33. FEBS J. 2025 Feb 27.
    Human glycolysis isomerases are inhibited by weak metabolite modulators.
    Yiming Yang Jónatansdóttir, Óttar Rolfsson, Jens G Hjörleifsson.
      Modulation of enzyme activity by metabolites represents the most efficient and rapid way of controlling metabolism. Investigating enzyme-metabolite interactions can deepen our understanding of metabolic control and aid in identifying enzyme modulators with potential therapeutic applications. These interactions vary in strength, with dissociation constants (Kd) ranging from strong (nm) to weak (μm-mm). However, weak interactions are often overlooked due to the challenges in studying them. Despite this, weak modulators can reveal unknown binding modes and serve as starting points for compound optimization. In this study, we aimed to identify metabolites that weakly modulate the activity of human glucose-6-phosphate isomerase (GPI) and triosephosphate isomerase (TPI), which are potential therapeutic targets in tumor glycolysis. Through a combination of activity and binding assays, the screening revealed multiple weak inhibitors for the two targets, causing partial attenuation of their activity, with Kd and Ki in the low mm range. X-ray crystallography revealed six orthosteric ligands binding to the active sites - four inhibitors of GPI and two of TPI. Our findings underscore the role of weak interactions in enzyme regulation and may provide structural insights that could aid the design of inhibitors targeting human GPI and TPI in cancer intervention.
    Keywords:  cancer metabolism; compound screening; glycolysis; metabolic regulation; weak inhibition
    DOI:  https://doi.org/10.1111/febs.70049
  34. Nature. 2025 Feb 26.
    Macrophages recycle phagocytosed bacteria to fuel immunometabolic responses.
    Juliette Lesbats, Aurélia Brillac, Julie A Reisz, Parnika Mukherjee, Charlène Lhuissier, Mónica Fernández-Monreal, Jean-William Dupuy, Angèle Sequeira, Gaia Tioli, Celia De La Calle Arregui, Benoît Pinson, Daniel Wendisch, Benoît Rousseau, Alejo Efeyan, Leif Erik Sander, Angelo D'Alessandro, Johan Garaude.
      Macrophages specialize in phagocytosis, a cellular process that eliminates extracellular matter, including microorganisms, through internalization and degradation1,2. Despite the critical role of phagocytosis during bacterial infection, the fate of phagocytosed microbial cargo and its impact on the host cell are poorly understood. In this study, we show that ingested bacteria constitute an alternative nutrient source that skews immunometabolic host responses. By tracing stable isotope-labelled bacteria, we found that phagolysosomal degradation of bacteria provides carbon atoms and amino acids that are recycled into various metabolic pathways, including glutathione and itaconate biosynthesis, and satisfies the bioenergetic needs of macrophages. Metabolic recycling of microbially derived nutrients is regulated by the nutrient-sensing mechanistic target of rapamycin complex C1 and is intricately tied to microbial viability. Dead bacteria, as opposed to live bacteria, are enriched in cyclic adenosine monophosphate, sustain the cellular adenosine monophosphate pool and subsequently activate adenosine monophosphate protein kinase to inhibit the mechanistic target of rapamycin complex C1. Consequently, killed bacteria strongly fuel metabolic recycling and support macrophage survival but elicit decreased reactive oxygen species production and reduced interleukin-1β secretion compared to viable bacteria. These results provide a new insight into the fate of engulfed microorganisms and highlight a microbial viability-associated metabolite that triggers host metabolic and immune responses. Our findings hold promise for shaping immunometabolic intervention for various immune-related pathologies.
    DOI:  https://doi.org/10.1038/s41586-025-08629-4
  35. Cell Metab. 2025 Feb 20. pii: S1550-4131(25)00019-1. [Epub ahead of print]
    EHBP1 suppresses liver fibrosis in metabolic dysfunction-associated steatohepatitis.
    Fanglin Ma, Miriam Longo, Marica Meroni, Dipankar Bhattacharya, Erika Paolini, Shama Mughal, Syed Hussain, Sumit Kumar Anand, Neha Gupta, Yiwei Zhu, Amaia Navarro-Corcuera, Kenneth Li, Satya Prakash, Bruno Cogliati, Shuang Wang, Xin Huang, Xiaobo Wang, Arif Yurdagul, Oren Rom, Liheng Wang, Susan K Fried, Paola Dongiovanni, Scott L Friedman, Bishuang Cai.
      Excess cholesterol accumulation contributes to fibrogenesis in metabolic dysfunction-associated steatohepatitis (MASH), but how hepatic cholesterol metabolism becomes dysregulated in MASH is not completely understood. We show that human fibrotic MASH livers have decreased EH-domain-binding protein 1 (EHBP1), a genome-wide association study (GWAS) locus associated with low-density lipoprotein (LDL) cholesterol, and that EHBP1 loss- and gain-of-function increase and decrease MASH fibrosis in mice, respectively. Mechanistic studies reveal that EHBP1 promotes sortilin-mediated PCSK9 secretion, leading to LDL receptor (LDLR) degradation, decreased LDL uptake, and reduced TAZ, a fibrogenic effector. At a cellular level, EHBP1 deficiency affects the intracellular localization of retromer, a protein complex required for sortilin stabilization. Our therapeutic approach to stabilizing retromer is effective in mitigating MASH fibrosis. Moreover, we show that the tumor necrosis factor alpha (TNF-α)/peroxisome proliferator-activated receptor alpha (PPARα) pathway suppresses EHBP1 in MASH. These data not only provide mechanistic insights into the role of EHBP1 in cholesterol metabolism and MASH fibrosis but also elucidate an interplay between inflammation and EHBP1-mediated cholesterol metabolism.
    Keywords:  EHBP1; GWAS; MASH; PCSK9; TPT-260; cholesterol; liver fibrosis; metabolic-dysfunction-associated steatohepatitis; retromer; sortilin
    DOI:  https://doi.org/10.1016/j.cmet.2025.01.020
  36. Nat Med. 2025 Feb 27.
    Single-cell and spatial genomic landscape of non-small cell lung cancer brain metastases.
    Somnath Tagore, Lindsay Caprio, Amit Dipak Amin, Kresimir Bestak, Karan Luthria, Edridge D'Souza, Irving Barrera, Johannes C Melms, Sharon Wu, Sinan Abuzaid, Yiping Wang, Viktoria Jakubikova, Peter Koch, D Zack Brodtman, Banpreet Bawa, Sachin K Deshmukh, Leon Ebel, Miguel A Ibarra-Arellano, Abhinav Jaiswal, Carino Gurjao, Jana Biermann, Neha Shaikh, Priyanka Ramaradj, Yohanna Georgis, Galina G Lagos, Matthew I Ehrlich, Patricia Ho, Zachary H Walsh, Meri Rogava, Michelle Garlin Politis, Devanik Biswas, Azzurra Cottarelli, Nikhil Rizvi, Catherine A Shu, Benjamin Herzberg, Niroshana Anandasabapathy, George Sledge, Emmanuel Zorn, Peter Canoll, Jeffrey N Bruce, Naiyer A Rizvi, Alison M Taylor, Anjali Saqi, Hanina Hibshoosh, Gary K Schwartz, Brian S Henick, Fei Chen, Denis Schapiro, Parin Shah, Benjamin Izar.
      Brain metastases frequently develop in patients with non-small cell lung cancer (NSCLC) and are a common cause of cancer-related deaths, yet our understanding of the underlying human biology is limited. Here we performed multimodal single-nucleus RNA and T cell receptor, single-cell spatial and whole-genome sequencing of brain metastases and primary tumors of patients with treatment-naive NSCLC. Chromosomal instability (CIN) is a distinguishing genomic feature of brain metastases compared with primary tumors, which we validated through integrated analysis of molecular profiling and clinical data in 4,869 independent patients, and a new cohort of 12,275 patients with NSCLC. Unbiased analyses revealed transcriptional neural-like programs that strongly enriched in cancer cells from brain metastases, including a recurring, CINhigh cell subpopulation that preexists in primary tumors but strongly enriched in brain metastases, which was also recovered in matched single-cell spatial transcriptomics. Using multiplexed immunofluorescence in an independent cohort of treatment-naive pairs of primary tumors and brain metastases from the same patients with NSCLC, we validated genomic and tumor-microenvironmental findings and identified a cancer cell population characterized by neural features strongly enriched in brain metastases. This comprehensive analysis provides insights into human NSCLC brain metastasis biology and serves as an important resource for additional discovery.
    DOI:  https://doi.org/10.1038/s41591-025-03530-z
  37. Trends Immunol. 2025 Feb 26. pii: S1471-4906(25)00031-6. [Epub ahead of print]
    Extracellular vesicles transport gasdermin pores, amplifying inflammatory cell death.
    Bhesh Raj Sharma, Thirumala-Devi Kanneganti.
      Lytic cell death is crucial for antimicrobial and antitumor immunity; however, unchecked pyroptosis drives pathology in sepsis. Wright et al. demonstrate that widespread cell death following pyroptosis is propagated by extracellular vesicles (EVs) carrying gasdermin D (GSDMD) pores that become integrated into the membrane of neighboring cells, driving inflammatory cell death.
    DOI:  https://doi.org/10.1016/j.it.2025.02.004
  38. Nat Aging. 2025 Feb 24.
    What makes biological age epigenetic clocks tick.
    Mahdi Moqri, Jesse R Poganik, Steve Horvath, Vadim N Gladyshev.
      
    DOI:  https://doi.org/10.1038/s43587-025-00833-1
  39. Cell Stem Cell. 2025 Feb 17. pii: S1934-5909(25)00013-X. [Epub ahead of print]
    Mechano-oncogenic cytoskeletal remodeling drives leukemic transformation with mitochondrial vesicle-mediated STING activation.
    Zemin Song, Yali Cui, Lilan Xin, Ruijing Xiao, Jingjing Feng, Conghui Li, Zhinang Yin, Honghong Wang, Qiuzi Li, Mengxuan Wang, Baoyi Lin, Yiming Zhang, Ying Zhou, Li Huang, Yanli He, Xiaoqing Li, Xiaoyan Liu, Shangqin Liu, Fuling Zhou, Zheng Liu, Hai-Bing Zhou, Pingping Fang, Kaiwei Liang.
      Mitochondria are integrated within the cytoskeleton for structural integrity and functional regulation, yet the pathological exploitation of these interactions in cell fate decisions remains largely unexplored. Here, we identify a cytoskeleton-mitochondria remodeling mechanism underlying leukemic transformation by the core-binding factor subunit beta and smooth muscle myosin heavy-chain fusion (CBFβ-SMMHC). This chimera reconstructs a cytosolic filamentous cytoskeleton, inducing NMIIA phosphorylation and INF2-dependent filamentous actin (F-actin) assembly, which enhance cellular stiffness and tension, leading to calcium-mediated mitochondrial constriction, termed cytoskeletal co-option of mitochondrial constriction (CCMC). CCMC can also be triggered through diverse approaches independent of CBFβ-SMMHC, reconstructing a similar cytoskeleton and recapitulating acute myeloid leukemia (AML) with consistent immunophenotypes and inflammatory signatures. Notably, CCMC generates TOM20-PDH+mtDNA+ mitochondrial-derived vesicles that activate cGAS-STING signaling, with Sting knockout abrogating CCMC-induced leukemogenesis. Targeted inhibition of CCMC or STING suppresses AML propagation while sparing normal hematopoiesis. These findings establish CCMC as an intrinsic mechano-oncogenic process linking genetic mutations with cytoskeletal remodeling to oncogenic transformation, highlighting its promise as a therapeutic target.
    Keywords:  CBFβ-SMMHC; CCMC; HSPCs; MDV; cGAS-STING signaling; cytoskeletal co-option of mitochondrial constriction; cytoskeleton; hematopoietic stem and progenitor cells; mitochondrial-derived vesicle
    DOI:  https://doi.org/10.1016/j.stem.2025.01.013
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