bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2025–08–03
forty-one papers selected by
Christian Frezza, Universität zu Köln
  1. Conservation and divergence of metabolic phenotypes between patient tumours and matched xenografts.
  2. The source of dietary fat influences anti-tumour immunity in obese mice.
  3. 2-hydroxyglutarate mediates whitening of brown adipocytes coupled to nuclear softening upon mitochondrial dysfunction.
  4. VDAC2 brake release: unleashing inflammation via IFNγ.
  5. HIF-independent oxygen sensing via KDM6A regulates ferroptosis.
  6. Mitochondrial glutathione import enables breast cancer metastasis via integrated stress response signaling.
  7. Tissue-Specific Effects of Dietary Protein on Cellular Senescence Are Mediated by Branched-Chain Amino Acids.
  8. Tom40 functions as a channel for protein retrotranslocation in the mitochondria-associated degradation (MAD) pathway.
  9. An updated inventory of genes essential for oxidative phosphorylation identifies a mitochondrial origin in familial Ménière's disease.
  10. Mitochondria-derived nuclear ATP surge protects against confinement-induced proliferation defects.
  11. Gut microbiota-derived metabolite Trimethylamine N-oxide alters the host epigenome through inhibition of S-adenosylhomocysteine hydrolase.
  12. AI-directed voxel extraction and volume EM identify intrusions as sites of mitochondrial contact.
  13. Making sense of oxygen sensing.
  14. PEX39 facilitates the peroxisomal import of PTS2-containing proteins.
  15. How cancer arises: Genetics releases, plasticity creates, genetics stabilizes.
  16. Structural basis for mTORC1 regulation by the CASTOR1-GATOR2 complex.
  17. Inhibition of HDAC6 alters fumarate hydratase activity and mitochondrial structure.
  18. De novo pyrimidine biosynthesis inhibition synergizes with BCL-XL targeting in pancreatic cancer.
  19. PFKFB3 activates CAD to enhance de novo pyrimidine synthesis for cell growth.
  20. SCoTCH-seq reveals that 5-hydroxymethylcytosine encodes regulatory information across DNA strands.
  21. Nutrient sensing in intestinal stem cell: Linking dietary nutrients to cellular metabolic regulation.
  22. Hypoxia-Induced Creatine Uptake Reprograms Metabolism to Antagonize PARP1-Mediated Cell Death and Facilitate Tumor Progression in Hepatocellular Carcinoma.
  23. Mouse lemur cell atlas informs primate genes, physiology and disease.
  24. Phosphoglycerate mutase regulates Treg differentiation through control of serine synthesis and one-carbon metabolism.
  25. ACLY inhibition promotes tumour immunity and suppresses liver cancer.
  26. Transient APC/C inactivation by mTOR boosts glycolysis during cell cycle entry.
  27. DynaTag for efficient mapping of transcription factors in low-input samples and at single-cell resolution.
  28. Ageing accelerates at around age 50 - some organs faster than others.
  29. Macropinocytosis maintains CAF subtype identity under metabolic stress in pancreatic cancer.
  30. Massively parallel immunopeptidome by DNA sequencing provides insights into cancer antigen presentation.
  31. Metabolic adaptations in cancer progression.
  32. Regulation of airway fumarate by host and pathogen promotes Staphylococcus aureus pneumonia.
  33. Cryo-EM structures of amino acid sensors bound to the human GATOR2 complex.
  34. Acidosis Forces Fatty Acid Uptake and Metabolism in Cancer Cells Regardless of Genotype.
  35. A molecular cell atlas of mouse lemur, an emerging model primate.
  36. Enhancing tandem mass spectrometry-based metabolite annotation with online chemical labeling.
  37. Opantimirs: A class of antagonizing microRNAs that upregulate Opa1 and improve mitochondrial and disuse myopathies.
  38. Polyamines regulate adaptive antitumor immunity by functional specialization of regulatory T cells.
  39. Genomic convergence in hibernating mammals elucidates the genetics of metabolic regulation in the hypothalamus.
  40. The β2-adrenergic receptor (Adrb2) entrains circadian gene oscillation and CD8+ T cell differentiation in response to virus infection.
  41. Sucralose consumption ablates cancer immunotherapy response through microbiome disruption.
  1. Nat Metab. 2025 Jul 29.
    Conservation and divergence of metabolic phenotypes between patient tumours and matched xenografts.
    Aparna D Rao, Ling Cai, Marelize Snyman, Rachel E Walsdorf, Xiangyi Li, Sophia N Wix, Gabrielle Gard, Ariel B Brown, Juliana Kim, Joao Santos Patricio, Sarah Muh, Misty Martin Sandoval, Lauren G Zacharias, Kristen A Heimdal, Wen Gu, Jade Homsi, Brittny Tillman, Rohit Sharma, Travis W Vandergriff, Ashley Solmonson, Brandon Faubert, Thomas P Mathews, Sean J Morrison, Ralph J DeBerardinis, Jennifer G Gill.
      Patient-derived xenografts (PDXs) are frequently used as preclinical models, but their recapitulation of tumour metabolism in patients has not been closely examined. We developed a parallel workflow to analyse [U-13C]glucose tracing and metabolomics data from patient melanomas and matched PDXs. Melanomas from patients have substantial TCA cycle labelling, similar to levels in human brain tumours. Although levels of TCA cycle labelling in PDXs were similar to those in the original patient tumours, PDXs had higher labelling in glycolytic metabolites. Through metabolomics, we observed consistent alterations of 100 metabolites among PDXs and patient tumours that reflected species-specific differences in diet, host physiology and microbiota. Despite these differences, most of nearly 200 PDXs retained a 'metabolic fingerprint' largely durable over six passages and often traceable back to the patient tumour of origin. This study identifies both high- and low-fidelity metabolites in the PDX model system, providing a resource for cancer metabolism researchers.
    DOI:  https://doi.org/10.1038/s42255-025-01338-2
  2. Nat Metab. 2025 Jul 25.
    The source of dietary fat influences anti-tumour immunity in obese mice.
    Britta Kunkemoeller, Hannah Prendeville, Claire McIntyre, Ayantu Temesgen, Rόisín M Loftus, Conghui Yao, Lydia Dyck, Linda V Sinclair, Christina Rollings, Aaron Douglas, Gerard Pernes, Kathleen A J Mitchelson, Cathal Harmon, Mathilde Raverdeau, Ross Ward, Harry Kane, Jaclyn Kline, Katie L O'Brien, Martin Brennan, Frances Smith, Brenneth Stevens, Helen M Roche, Ed C Lavelle, David K Finlay, Doreen A Cantrell, Edward T Chouchani, Susan Kaech, Evanna L Mills, Marcia Haigis, Lydia Lynch.
      Obesity increases the risk of many cancers and impairs the anti-tumour immune response. However, little is known about whether the source or composition of dietary fat affects tumour growth or anti-tumour immunity in obesity. Here, we show that high-fat diets (HFDs) derived from lard, beef tallow or butter accelerate tumour growth in a syngeneic model of melanoma, but HFDs based on coconut oil, palm oil or olive oil do not, despite equivalent obesity. Using butter-based and palm oil-based HFDs as examples, we find that these dietary fat sources differentially regulate natural killer and CD8 T cell infiltration and function within the tumour microenvironment, governed by distinct effects on the plasma metabolome and intracellular metabolism. We identify diet-related lipid intermediates, namely long-chain acylcarnitine species, as immunosuppressive metabolites enriched in mice fed butter compared to palm oil HFD. Together, these results highlight the significance of diet in maintaining a healthy immune system and suggest that modifying dietary fat may improve cancer outcomes in obesity.
    DOI:  https://doi.org/10.1038/s42255-025-01330-w
  3. Nat Metab. 2025 Aug 01.
    2-hydroxyglutarate mediates whitening of brown adipocytes coupled to nuclear softening upon mitochondrial dysfunction.
    Harshita Kaul, Lea Isermann, Katharina Senft, Milica Popovic, Theodoros Georgomanolis, Linda Baumann, Pujyanathan Sivanesan, Andromachi Pouikli, Hendrik Nolte, Bojana Lucic, Ximena Hildebrandt, Katrin Seidel, Thorsten Gnad, Felix Gaedke, Ulrike Göbel, Franziska Peters, Maksym Cherevatenko, Joo Hyun Park, Astrid Schauss, Nieves Peltzer, Jens Claus Brüning, Jan-Wilhelm Kornfeld, Alexander Pfeifer, Thomas Langer, Marina Lusic, Sara A Wickström, Christian Frezza, Aleksandra Trifunovic.
      Mitochondria have a crucial role in regulating cellular homeostasis in response to intrinsic and extrinsic cues by changing cellular metabolism to meet these challenges. However, the molecular underpinnings of this regulation and the complete spectrum of these physiological outcomes remain largely unexplored. In this study, we elucidate the mechanisms driving the whitening phenotype in brown adipose tissue (BAT) deficient in the mitochondrial matrix protease CLPP. Here we show that CLPP-deficient BAT shows aberrant accumulation of lipid droplets, which occurs independently of defects in oxygen consumption and fatty acid oxidation. Our results indicate that mitochondrial dysfunction due to CLPP deficiency leads to the build-up of the oncometabolite D-2-hydroxyglutarate (D-2HG), which in turn promotes lipid droplet enlargement. We further demonstrate that D-2HG influences gene expression and decreases nuclear stiffness by modifying epigenetic signatures. We propose that lipid accumulation and altered nuclear stiffness regulated through 2HG are stress responses to mitochondrial dysfunction in BAT.
    DOI:  https://doi.org/10.1038/s42255-025-01332-8
  4. Trends Pharmacol Sci. 2025 Jul 29. pii: S0165-6147(25)00144-0. [Epub ahead of print]
    VDAC2 brake release: unleashing inflammation via IFNγ.
    Swapneel J Patel, Zhijian J Chen.
      Identification of therapeutic vulnerabilities in cancer remains a high priority for cancer research. A recent CRISPR/Cas9 screen identified that VDAC2 deletion in tumors enhanced their sensitivity to interferon-γ (IFNγ) through the release of mitochondrial DNA (mtDNA) and activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway. These data suggest that VDAC2 inhibition could enhance antitumor therapies.
    Keywords:  STING; VDAC; cGAS; cancer; inflammation
    DOI:  https://doi.org/10.1016/j.tips.2025.07.001
  5. Mol Cell. 2025 Jul 15. pii: S1097-2765(25)00580-5. [Epub ahead of print]
    HIF-independent oxygen sensing via KDM6A regulates ferroptosis.
    Alexander M Minikes, Pei Liu, Hua Wang, Jiachen Hu, Hanan Alwaseem, Yueming Li, Xuejun Jiang.
      Ferroptosis, a metabolic cell death process driven by iron-dependent phospholipid peroxidation, is implicated in various pathologies, including cancer. While metabolic factors such as glucose, lipids, and multiple amino acids have all been demonstrated to modulate ferroptosis, the role of oxygen, another fundamental metabolic component, in ferroptosis is not fully understood. Here, we show that cells acclimated to a low oxygen environment develop marked resistance to ferroptosis, and this resistance is independent of canonical oxygen-sensing pathway mediated by prolyl hydroxylases (PHDs) and HIF transcription factors. Instead, hypoxia suppresses ferroptosis by inhibiting KDM6A, a tumor suppressor and oxygen-dependent histone demethylase, leading to reduced expression of its transcriptional targets, including lipid metabolic enzymes ACSL4 and ETNK1, thus rewiring cellular phospholipid profile to a ferroptosis-resistant state. Relevant to cancer, pharmacological inhibition of the oncogenic histone methyltransferase EZH2, which opposes KDM6A activity, restored ferroptosis sensitivity of xenograft bladder tumor tissues harboring KDM6A mutation.
    Keywords:  ACSL4; ETNK1; KDM6A; KMT2D; bladder cancer; cancer therapy; ferroptosis; hypoxia; lipid metabolism; oxygen sensing
    DOI:  https://doi.org/10.1016/j.molcel.2025.07.001
  6. Cancer Discov. 2025 Jul 31.
    Mitochondrial glutathione import enables breast cancer metastasis via integrated stress response signaling.
    Hsi-Wen Yeh, Nicole Lauren DelGaudio, Beste Uygur, Alon Millet, Artem Khan, Gokhan Unlu, Michael Xiao, Rebecca C Timson, Caifan Li, Kerem Ozcan, Karl W Smith, Luiza Martins Nascentes Melo, Gabriele Allies, Olca Basturk, Albert Sickmann, Erol C Bayraktar, Richard Possemato, Alpaslan Tasdogan, Kivanc Birsoy.
      Cancer cells require substantial metabolic adaptations to metastasize to distant organs, but the metabolites essential for successful colonization remain poorly defined. Here, we used a mitochondrial metabolomics approach to compare primary and metastatic breast cancer cells. This analysis revealed accumulation of mitochondrial glutathione (GSH) during lung metastasis, driven by elevated expression of SLC25A39, a mitochondrial GSH transporter. Loss of SLC25A39 impairs metastatic colonization in genetic screens, cell line models, and patient-derived xenografts, without affecting primary tumor growth. Mitochondrial GSH import is specifically required during early colonization and functions independently of its canonical antioxidant role. CRISPR activation screens identified ATF4, a stress-induced transcription factor, as a bypass mechanism that restores metastatic potential in SLC25A39-deficient cells. Mechanistically, SLC25A39 is required for optimal ATF4 activation during metastasis and under hypoxia, linking mitochondrial GSH availability to integrated stress response signaling. These findings identify mitochondrial GSH as a necessary and limiting metabolite for metastatic progression.
    DOI:  https://doi.org/10.1158/2159-8290.CD-24-1556
  7. Aging Cell. 2025 Jul 28. e70176
    Tissue-Specific Effects of Dietary Protein on Cellular Senescence Are Mediated by Branched-Chain Amino Acids.
    Mariah F Calubag, Ismail Ademi, Isaac D Grunow, Lucia E Breuer, Reji Babygirija, Penelope Lialios, Sandra M Le, Michelle M Sonsalla, Julia A Illiano, Bailey A Knopf, Fan Xiao, Dennis Minton, Adam R Konopka, David A Harris, Dudley W Lamming.
      Dietary protein is a key regulator of healthy aging in both mice and humans. In mice, reducing dietary levels of the branched-chain amino acids (BCAAs) recapitulates many of the benefits of a low protein diet; BCAA-restricted diets extend lifespan, reduce frailty, and improve metabolic health, while BCAA supplementation shortens lifespan, promotes obesity, and impairs glycemic control. Recently, high protein diets have been shown to promote cellular senescence, a hallmark of aging implicated in many age-related diseases, in the liver of mice. Here, we test the hypothesis that the effects of high protein diets on metabolic health and on cellular senescence are mediated by BCAAs. We find that reducing dietary levels of BCAAs protects male mice from the negative metabolic consequences of both normal and high protein diets. Further, we identify tissue-specific effects of BCAAs on cellular senescence, with restriction of all three BCAAs-but not individual BCAAs-protecting from hepatic cellular senescence while potentiating cellular senescence in white adipose tissue. We also find that these effects are sex-specific. We find that the effects of BCAAs on hepatic cellular senescence are cell-autonomous, with lower levels of BCAAs protecting cultured cells from antimycin-A induced senescence. Our results demonstrate a direct effect of a specific dietary component on a hallmark of aging and suggest that cellular senescence may be highly susceptible to dietary interventions.
    DOI:  https://doi.org/10.1111/acel.70176
  8. Commun Biol. 2025 Jul 29. 8(1): 1122
    Tom40 functions as a channel for protein retrotranslocation in the mitochondria-associated degradation (MAD) pathway.
    Pin-Chao Liao, Tzu-Ying Lin, Catherine A Tsang, Chen-Jing Huang, Katherine Filpo, Istvan Boldogh, Liza A Pon.
      The mitochondria-associated degradation pathway (MAD) mediates removal and elimination of damaged, unfolded mitochondrial proteins by the ubiquitin-proteasome system (UPS). Previous studies revealed that MAD is critical for mitochondrial protein quality control and that MAD function extends beyond mitochondrial outer membrane (MOM) to proteins within the organelle. Here, we reconstitute retrotranslocation of MAD substrates from the mitochondrial matrix across mitochondrial inner and outer membranes in cell-free systems. This retrotranslocation is ATP-dependent but membrane potential-independent. We also identify a role for the TOM complex, the protein import channel in the MOM, in this process. Inhibition of protein translocation across the Tom40p channel reduces the retrotranslocation of MAD substrates. Our studies support the model that the TOM complex is a bidirectional protein channel in the MOM: it mediates retrotranslocation of damaged mitochondrial proteins across the MOM in the MAD pathway for mitochondrial protein quality control in addition to its function in import of proteins into the organelle.
    DOI:  https://doi.org/10.1038/s42003-025-08549-z
  9. Cell Rep. 2025 Jul 25. pii: S2211-1247(25)00840-X. [Epub ahead of print]44(8): 116069
    An updated inventory of genes essential for oxidative phosphorylation identifies a mitochondrial origin in familial Ménière's disease.
    Marcell Harhai, Mads M Foged, Christine Zarges, Juan C Landoni, Sylvain Chollet, Michele Simonelli, Emeline Recazens, Miriam Lisci, Nora Laban, Suliana Manley, Jan Riemer, Jose Antonio Lopez-Escamez, Anna Lysakowski, Alexis A Jourdain.
      Mitochondrial disorders (MDs) are among the most common inborn errors of metabolism, and dysfunction in oxidative phosphorylation (OXPHOS) is a hallmark. Their complex mode of inheritance and diverse clinical presentations render the diagnosis of MDs challenging, and, to date, most lack a cure. Here, we build on previous efforts to identify genes necessary for OXPHOS and report a highly complementary galactose-sensitized CRISPR-Cas9 "growth" screen, presenting an updated inventory of 481 OXPHOS genes, including 157 linked to MDs. We further focus on FAM136A, a gene associated with Ménière's disease, and demonstrate that it supports intermembrane space protein homeostasis and OXPHOS in cell lines, mice, and patients. Our study identifies a mitochondrial basis in familial Ménière's disease, provides a comprehensive resource of OXPHOS-related genes, and sheds light on the pathways involved in MDs, with the potential to guide future diagnostics and treatments for MDs.
    Keywords:  CLPB; CP: Metabolism; FAM136A; HAX1; Ménière; OXPHOS; functional genomics; intermembrane space; mitochondria; mitochondrial disease; proteostasis
    DOI:  https://doi.org/10.1016/j.celrep.2025.116069
  10. Nat Commun. 2025 Jul 30. 16(1): 6613
    Mitochondria-derived nuclear ATP surge protects against confinement-induced proliferation defects.
    Ritobrata Ghose, Fabio Pezzano, Rémi Badia, Savvas Kourtis, Ilir Sheraj, Shubhamay Das, Antoni Gañez Zapater, Upamanyu Ghose, Sara Musa-Afaneh, Lorena Espinar, Albert Coll-Manzano, Katja Parapatics, Saška Ivanova, Paula Sànchez-Fernàndez-de-Landa, Dragana Radivojevikj, Valeria Venturini, Stefan Wieser, Antonio Zorzano, André C Müller, Verena Ruprecht, Sara Sdelci.
      The physical tissue microenvironment regulates cell state and behaviour. How mechanical confinement rewires the subcellular localisation of organelles and affects cellular metabolism is largely unknown. In this study, proteomics analysis revealed that cellular confinement induced a strong enrichment of mitochondrial proteins in the nuclear fraction. Quantitative live cell microscopy confirmed that mechanical cell confinement leads to a rapid re-localisation of mitochondria to the nuclear periphery in vitro, reflecting a physiologically relevant phenomenon in patient-derived tumours. This nucleus-mitochondria proximity is mediated by an endoplasmic reticulum-based net that entraps the mitochondria in an actin-dependent manner. Functionally, the nucleus-mitochondria proximity results in a nuclear ATP surge, which can be regulated by the genetic and pharmacological modulation of mitochondrial ATP production or via alterations of the actin cytoskeleton. The confinement-induced nuclear ATP surge has physiologically significant long-term effects on cell fitness, driven by changes in chromatin state, enhanced DNA damage repair, and cell cycle progression during mechanical cell deformation. Together, our data describe a confinement-induced metabolic adaptation that is required to enable prompt DNA damage repair and cell proliferation under mechanical confinement stress by facilitating chromatin state transitions.
    DOI:  https://doi.org/10.1038/s41467-025-61787-x
  11. J Biol Chem. 2025 Jul 25. pii: S0021-9258(25)02372-5. [Epub ahead of print] 110521
    Gut microbiota-derived metabolite Trimethylamine N-oxide alters the host epigenome through inhibition of S-adenosylhomocysteine hydrolase.
    Jessica H Han, Federico E Rey, John M Denu.
      The gut microbiota profoundly influences host metabolism through the production of bioactive metabolites that modulate cellular pathways. Among these, trimethylamine N-oxide (TMAO) has emerged as an enigmatic molecule linking dietary factors to cellular dysfunction in cardiovascular, neurological, and oncologic disorders. Here, we investigate the cellular and systemic impact of TMAO on metabolic pathways and epigenetic landscapes. Using cultured cells and a mouse model that simulates endogenous TMAO production, we demonstrate that TMAO disrupts the methionine cycle and dynamically remodels chromatin states via histone post-translational methylation and acetylation. Compared to liver, brain cortex and hippocampus show greater sensitivity to TMAO levels. Mechanistically, TMAO noncompetitively inhibits S-adenosylhomocysteine hydrolase (AHCY), leading to accumulation of S-adenosylhomocysteine (SAH) and subsequent reduction in global methylation capacity. In vitro overexpression of SAM synthase, MAT2A, rescues many of these epigenetic defects by boosting SAM/SAH, highlighting the tissue/cell-specific importance of balancing SAM synthesis and SAH clearance. These mechanistic findings reveal that TMAO targets AHCY and disrupts the methionine cycle, expanding our understanding of how gut-derived metabolites modulate chromatin states and identifying potential avenues to mitigate TMAO-associated disease.
    Keywords:  Gut microbiome; S-adenosylhomocysteine hydrolase; Trimethylamine N-oxide; epigenetics; one-carbon metabolism; post-translational modification
    DOI:  https://doi.org/10.1016/j.jbc.2025.110521
  12. J Cell Biol. 2025 Oct 06. pii: e202411138. [Epub ahead of print]224(10):
    AI-directed voxel extraction and volume EM identify intrusions as sites of mitochondrial contact.
    Benjamin S Padman, Runa S J Lindblom, Michael Lazarou.
      Membrane contact sites (MCSs) establish organelle interactomes in cells to enable communication and exchange of materials. Volume EM (vEM) is ideally suited for MCS analyses, but semantic segmentation of large vEM datasets remains challenging. Recent adoption of artificial intelligence (AI) for segmentation has greatly enhanced our analysis capabilities. However, we show that organelle boundaries, which are important for defining MCS, are the least confident predictions made by AI. We outline a segmentation strategy termed AI-directed voxel extraction (AIVE), which refines segmentation results and boundary predictions derived from any AI-based method by combining those results with electron signal values. We demonstrate the precision conferred by AIVE by applying it to the quantitative analysis of organelle interactomes from multiple FIB-SEM datasets. Through AIVE, we discover a previously unknown category of mitochondrial contact that we term the mitochondrial intrusion. We hypothesize that intrusions serve as anchors that stabilize MCS and promote organelle communication.
    DOI:  https://doi.org/10.1083/jcb.202411138
  13. EMBO J. 2025 Aug 01.
    Making sense of oxygen sensing.
    Peter J Ratcliffe, Thomas P Keeley.
      
    DOI:  https://doi.org/10.1038/s44318-025-00513-1
  14. Nat Cell Biol. 2025 Jul 30.
    PEX39 facilitates the peroxisomal import of PTS2-containing proteins.
    Walter W Chen, Tony A Rodrigues, Daniel Wendscheck, Ana G Pedrosa, Chendong Yang, Tânia Francisco, Till Möcklinghoff, Alexandros Zografakis, Bernardo Nunes-Silva, Reut E Avraham, Ana R Silva, Maria J Ferreira, Hirak Das, Janet Koster, Simone Neuwirth, Julian Bender, Silke Oeljeklaus, Varun Sondhi, Christos Gatsogiannis, Maya Schuldiner, Einat Zalckvar, Kay Hofmann, Hans R Waterham, Ralph J DeBerardinis, Jorge E Azevedo, Bettina Warscheid.
      Peroxisomes are metabolic organelles essential for human health. Defects in peroxisomal biogenesis proteins (also known as peroxins (PEXs)) cause devastating disease. PEX7 binds proteins containing a type 2 peroxisomal targeting signal (PTS2) to enable their import from the cytosol into peroxisomes, although many aspects of this process remain enigmatic. Utilizing in vitro assays, yeast and human cells, we show that PEX39, a previously uncharacterized protein, is a cytosolic peroxin that facilitates the import of PTS2-containing proteins by binding PEX7 and stabilizing its interaction with cargo proteins containing a PTS2. PEX39 and PEX13, a peroxisomal membrane translocon protein, both possess an (R/K)PWE motif necessary for PEX7 binding. Handover of PEX7 from PEX39 to PEX13 via these motifs provides a new paradigm for peroxisomal protein import and biogenesis. Collectively, this work reveals how PEX39 and (R/K)PWE motifs facilitate the import of PTS2-containing proteins and advances our understanding of peroxisomal disease.
    DOI:  https://doi.org/10.1038/s41556-025-01711-z
  15. Proc Natl Acad Sci U S A. 2025 Aug 05. 122(31): e2505377122
    How cancer arises: Genetics releases, plasticity creates, genetics stabilizes.
    Steven A Frank.
      Cancer is the origin of a novel tissue that attracts resources, spreads beyond boundaries, avoids normal controls, and escapes immunity. How does a novel tissue arise? The puzzle is that two seemingly different processes appear to be the primary driving force. On the one hand, overwhelming evidence links (epi)genetic driver mutations to the origin and progression of tumors. Common oncogenic mutations such as KRAS accelerate cell division, and common knockouts of tumor suppressors such as TP53 abrogate cell death or checks on cell division. On the other hand, cancerous tissues create complex traits that require intricate changes in cells and multiple interactions between different cell types. Such novelty often arises by hijacking the developmental plasticity that normally creates the diverse cells and tissues of our bodies from a single original zygotic cell. How can we reconcile the simple genetic changes in carcinogenesis with the complex developmental plasticity that creates novel tissues? This perspective advocates a new model. (Epi)genetic mutations release developmental plasticity. That developmental plasticity creates novel cellular interactions and complex tissues. Initially, novel traits created by developmental plasticity may not be stably heritable, thus subsequent (epi)genetic changes must stabilize the phenotypic novelty. Recent studies show how classic oncogenic and tumor suppressor driver mutations, such as KRAS and TP53, may primarily act in early carcinogenesis as broad releasers of developmental plasticity rather than as stimulators of cell division or knockout of limitations on cellular clonal expansion. In the new model, genetics releases, plasticity creates, and genetics stabilizes.
    Keywords:  cancer evolution; cell state; developmental plasticity; single-cell technology
    DOI:  https://doi.org/10.1073/pnas.2505377122
  16. Nat Struct Mol Biol. 2025 Jul 25.
    Structural basis for mTORC1 regulation by the CASTOR1-GATOR2 complex.
    Rachel M Jansen, Clément Maghe, Karla Tapia, Selina Wu, Serim Yang, Xuefeng Ren, Roberto Zoncu, James H Hurley.
      Mechanistic target of rapamycin complex 1 (mTORC1) is a nutrient-responsive master regulator of metabolism. Amino acids control the recruitment and activation of mTORC1 at the lysosome through the nucleotide loading state of the heterodimeric Rag GTPases. Under low nutrients, including arginine, the GTPase-activating protein complex GATOR1 promotes GTP hydrolysis on RagA/B, inactivating mTORC1. GATOR1 is regulated by the cage-like GATOR2 complex and cytosolic amino acid sensors. To understand how the arginine sensor CASTOR1 binds to GATOR2 to disinhibit GATOR1 under low cytosolic arginine, we determined the cryo-electron microscopy structure of human GATOR2 bound to CASTOR1 in the absence of arginine. Two MIOS WD40 domain β-propellers of the GATOR2 cage engage with both subunits of a single CASTOR1 homodimer. Each propeller binds to a negatively charged MIOS-binding interface on CASTOR1 that is distal to the arginine pocket. The structure shows how arginine-triggered loop ordering in CASTOR1 blocks the MIOS-binding interface, switches off its binding to GATOR2 and, thus, communicates to downstream mTORC1 activation.
    DOI:  https://doi.org/10.1038/s41594-025-01635-0
  17. Nat Commun. 2025 Jul 28. 16(1): 6923
    Inhibition of HDAC6 alters fumarate hydratase activity and mitochondrial structure.
    Andrew Roe, Catríona M Dowling, Cian D'Arcy, Daniel Alencar Rodrigues, Yu Wang, Matthew Hiller, Carl Keogh, Kate E R Hollinshead, Massimiliano Garre, Brenton Cavanagh, Kieran Wynne, Tianyan Liu, Zhixing Chen, Emma Kerr, Marie McIlroy, Jochen H M Prehn, Ingmar Schoen, Tríona Ní Chonghaile.
      Fumarate hydratase (FH), a key node of mitochondrial metabolism, is also a tumour suppressor. Despite its prominent roles in tumourigenesis and inflammation, its regulation remains poorly understood. Herein, we show that histone deacetylase 6 (HDAC6) regulates FH activity. In triple-negative breast cancer cells, HDAC6 inhibition or knockdown results in alterations to mitochondrial cristae structure, as detected by live-cell super-resolution STED nanoscopy and electron microscopy, along with the release of mitochondrial DNA. Mass-spectrometry immunoprecipitation reveals multiple mitochondrial HDAC6-interactors, with FH emerging as a top hit. Super-resolution 3D-STORM shows HDAC6 interactions with FH in mitochondrial networks, which increases after perturbation of HDAC6 activity with BAS-2. Treatment with BAS-2 leads to fumarate accumulation by 13C glucose labelling, along with downstream succination of proteins and cell death. Together, these results identify HDAC6 inhibition as a regulator of endogenous FH activity in tumour cells, and highlight it as a promising candidate for indirectly targeting tumour metabolism.
    DOI:  https://doi.org/10.1038/s41467-025-61897-6
  18. Nat Commun. 2025 Jul 30. 16(1): 6987
    De novo pyrimidine biosynthesis inhibition synergizes with BCL-XL targeting in pancreatic cancer.
    Huan Zhang, Naiara Santana-Codina, Qijia Yu, Clara Poupault, Claudia Campos, Xingping Qin, Nicole Sindoni, Marina Ciscar, Aparna Padhye, Miljan Kuljanin, Junning Wang, Matthew J Dorman, Peter Bross, Andrew J Aguirre, Stephanie K Dougan, Kristopher A Sarosiek, Joseph D Mancias.
      Oncogenic KRAS induces metabolic rewiring in pancreatic ductal adenocarcinoma (PDAC) characterized, in part, by dependency on de novo pyrimidine biosynthesis. Pharmacologic inhibition of dihydroorotate dehydrogenase (DHODH), an enzyme in the de novo pyrimidine synthesis pathway, delays pancreatic tumor growth; however, limited monotherapy efficacy suggests that compensatory pathways may drive resistance. Here, we use an integrated metabolomic, proteomic and in vitro and in vivo DHODH inhibitor-anchored genetic screening approach to identify compensatory pathways to DHODH inhibition (DHODHi) and targets for combination therapy strategies. We demonstrate that DHODHi alters the apoptotic regulatory proteome thereby enhancing sensitivity to inhibitors of the anti-apoptotic BCL2L1 (BCL-XL) protein. Co-targeting DHODH and BCL-XL synergistically induces apoptosis in PDAC cells and patient-derived organoids. The combination of DHODH inhibition with Brequinar and BCL-XL degradation by DT2216, a proteolysis targeting chimera (PROTAC), significantly inhibits PDAC tumor growth. These data define mechanisms of adaptation to DHODHi and support combination therapy targeting BCL-XL in PDAC.
    DOI:  https://doi.org/10.1038/s41467-025-61242-x
  19. Cell Rep. 2025 Jul 29. pii: S2211-1247(25)00842-3. [Epub ahead of print]44(8): 116071
    PFKFB3 activates CAD to enhance de novo pyrimidine synthesis for cell growth.
    Qingen Da, Yongfeng Cai, Qian Ma, Qiuhua Yang, Yapeng Cao, Yaqi Zhou, Dingwei Zhao, Zhiping Liu, Jiean Xu, Junming Quan, Liang Zhang, Rui Wang, Xuejun Jiang, Xiao Liu, Kunfu Ouyang, Zhen Han, Jikui Liu, Tao Wang, Chunxiang Zhang, Neal L Weintraub, David J R Fulton, Jun Zhao, Mei Hong, Zigang Li, Yuqing Huo.
      Aerobic glycolysis, termed the Warburg effect, is one of the aberrant metabolic pathways in highly proliferating cells. Glycolysis provides glycolytic metabolites to support the generation of biomass, such as nucleotides, amino acids, and lipids. Research on the direct interactions between glycolysis and other metabolic pathways is an emerging field that has garnered significant interest. Phosphofructokinase-2/fructose-2,6-bisphosphatase 3 (PFKFB3) activates glycolysis by synthesizing fructose-2,6-bisphosphate (F2,6BP), which allosterically activates the rate-limiting enzyme 6-phosphofructo-1-kinase (PFK-1). In this study, we found that PFKFB3 directly interacts with and regulates the phosphorylation of carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD), the enzyme catalyzing the first three steps of de novo pyrimidine synthesis. PFKFB3 inactivation reduced de novo pyrimidine synthesis, RNA and DNA production, and cell proliferation. Thus, the glycolytic activator PFKFB3 bridges glycolysis with pyrimidine synthesis, unites both glucose metabolism and nucleic acid metabolism, and contributes to cell proliferation under pathological conditions.
    Keywords:  CAD; CP: Metabolism; CP: Molecular biology; PFKFB3; Warburg effect; de novo pyrimidine synthesis; glycolysis; kinase activity
    DOI:  https://doi.org/10.1016/j.celrep.2025.116071
  20. Proc Natl Acad Sci U S A. 2025 Aug 05. 122(31): e2512204122
    SCoTCH-seq reveals that 5-hydroxymethylcytosine encodes regulatory information across DNA strands.
    Jack S Hardwick, Somdutta Dhir, Angie Kirchner, Angela Simeone, Sean M Flynn, James M Edgerton, Rafael de Cesaris Araujo Tavares, Isabel Esain-Garcia, David Tannahill, Paula Golder, Jack M Monahan, Walraj S Gosal, Shankar Balasubramanian.
      In mammalian genomes, cytosine modifications form a layer of regulatory information alongside the genetic code. Decoding this information is crucial to our understanding of biology and disease. Established sequencing methods cannot simultaneously resolve cytosine's three most common forms-cytosine (C), 5-methylcytosine (mC), and 5-hydroxymethylcytosine (hmC)-across both strands of the DNA double helix. Thus, how epigenetic information is distributed in DNA remains unclear. Here, we present Strand-Coupled Tandem Cytosine Hydroxymethylation and methylation sequencing (SCoTCH-seq): an accurate and quantitative, base-resolution approach to sequence genomes, together with mC and hmC, in both strands of the same DNA fragment. We show that different forms of cytosine combine across the double helix at CpG sites to form discrete information states in the mouse epigenome. These CpG states have distinct genomic distributions-including at promoters, enhancers, and gene bodies-and have different relationships with transcription. We show that while all possible forms of hydroxymethylation occur, hmC is predominantly asymmetric and that different forms of asymmetric hmC are not equivalent. Our findings demonstrate that 5-hydroxymethylcytosine combines with different cytosine variants across the DNA double helix to form distinct states of regulatory information.
    Keywords:  5-hydroxymethylcytosine; 5-methylcytosine; DNA sequencing; epigenetics
    DOI:  https://doi.org/10.1073/pnas.2512204122
  21. World J Stem Cells. 2025 Jul 26. 17(7): 107770
    Nutrient sensing in intestinal stem cell: Linking dietary nutrients to cellular metabolic regulation.
    Wen-Hao Li, Xin-Yi Yuan, Zhe Wang, Rong Lin.
      Diet and nutrition significantly influence health, largely by regulating intestinal nutrient absorption. The intestinal epithelium, as the primary site for nutrient uptake, undergoes continuous renewal driven by precise regulation of intestinal stem cells (ISCs). Nutrient sensing and metabolism are key determinants of ISC fate, making ISCs a central link between nutrient metabolism and the regulation of intestinal tissue renewal and homeostasis. Understanding how ISCs respond or make adaptations to nutritional signals is therefore vital for maintaining intestinal homeostasis. Recent studies have spotlighted the origin and identity of ISCs and broadened our insight into the plasticity and function of ISCs under different conditions. Mitochondria, the central hubs of energy production and metabolic signals provided by dietary components and metabolic substrates, such as glucose, amino acids, and lipids, govern the intricate balance between self-renewal and differentiation of ISCs. This review highlights the importance of nutrient sensing, metabolic regulation, and mitochondrial function in the specification of ISC fate. A thorough understanding of these mechanisms paves the way for the development of stem cell-based therapy for the mucosal healing of gastrointestinal diseases and diet intervention to foster body health.
    Keywords:  Intestinal organoids; Intestinal stem cell; Metabolic regulation; Mitochondria; Nutrient sensing
    DOI:  https://doi.org/10.4252/wjsc.v17.i7.107770
  22. Cancer Res. 2025 Jul 31.
    Hypoxia-Induced Creatine Uptake Reprograms Metabolism to Antagonize PARP1-Mediated Cell Death and Facilitate Tumor Progression in Hepatocellular Carcinoma.
    Rui-Zhe Li, Guo-Qiang Pan, Chen Xiong, Zi-Niu Ding, Tuan-Song Zhang, Lun-Jie Yan, Dongxu Wang, Xiaolu Zhang, Xiao-Feng Dong, Yu-Chuan Yan, Yu Zhou, Rui Dong, Zhao-Ru Dong, Tao Li.
      Recently, a PARP1-dependent cell-death process termed "parthanatos" that is driven by DNA damage has emerged as a crucial regulator of tissue homeostasis and tumorigenesis. Hypoxia is a hallmark of solid tumors and profoundly affects the malignant phenotypes of cancer cells. Here, we investigated the crosstalk between parthanatos and hypoxia. Despite causing DNA damage, hypoxia failed to induce parthanatos in hepatocellular carcinoma (HCC). The creatine transporter SLC6A8 promoted parthanatos antagonism and malignant phenotypes in hypoxic HCC cells. Hypoxia-induced creatine accumulation drove metabolic reprogramming and antagonized parthanatos. Mechanistically, creatine elevated SERPINE1 expression through MPS1-mediated Smad2/3 phosphorylation and formed a creatine/SERPINE1/HIF-1α positive feedback loop. SERPINE1 facilitated USP10-mediated deubiquitination and stabilization of PKLR by forming a SERPINE1-USP10-PKLR complex. USP10 contained a strong PAR-binding motif, and SERPINE1 reversed the attenuated deubiquitination activity of USP10 caused by the direct binding of PAR under hypoxia. The SLC6A8 inhibitor RGX-202 exerted potent antitumor activity alone and in combination with lenvatinib in patient-derived xenografts and primary HCC mouse models. Overall, this study identified intracellular creatine accumulation as a mechanism that allows hypoxic cancer cells to circumvent parthanatos and as a therapeutic target in HCC.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-0301
  23. Nature. 2025 Jul 30.
    Mouse lemur cell atlas informs primate genes, physiology and disease.
    Tabula Microcebus Consortium
      Mouse lemurs (Microcebus spp.) are an emerging primate model organism, but their genetics, cellular and molecular biology remain largely unexplored. In an accompanying paper1, we performed large-scale single-cell RNA sequencing of 27 organs from mouse lemurs. We identified more than 750 molecular cell types, characterized their transcriptomic profiles and provided insight into primate evolution of cell types. Here we use the generated atlas to characterize mouse lemur genes, physiology, disease and mutations. We uncover thousands of previously unidentified lemur genes and hundreds of thousands of new splice junctions including over 85,000 primate splice junctions missing in mice. We systematically explore the lemur immune system by comparing global expression profiles of key immune genes in health and disease, and by mapping immune cell development, trafficking and activation. We characterize primate-specific and lemur-specific physiology and disease, including molecular features of the immune program, lemur adipocytes and metastatic endometrial cancer that resembles the human malignancy. We present expression patterns of more than 400 primate genes missing in mice, many with similar expression patterns to humans and some implicated in human disease. Finally, we provide an experimental framework for reverse genetic analysis by identifying naturally occurring nonsense mutations in three primate immune genes missing in mice and by analysing their transcriptional phenotypes. This work establishes a foundation for molecular and genetic analyses of mouse lemurs and prioritizes primate genes, isoforms, physiology and disease for future study.
    DOI:  https://doi.org/10.1038/s41586-025-09114-8
  24. Elife. 2025 Jul 28. pii: RP104423. [Epub ahead of print]14
    Phosphoglycerate mutase regulates Treg differentiation through control of serine synthesis and one-carbon metabolism.
    Wesley H Godfrey, Judy J Lee, Shruthi Shanmukha, Kaho Cho, Xiaojing Deng, Chandra Shekar R Ambati, Vasanta Putluri, Abu Hena Mostafa Kamal, Paul M Kim, Nagireddy Putluri, Michael D Kornberg.
      The differentiation and suppressive functions of regulatory CD4 T cells (Tregs) are supported by a broad array of metabolic changes, providing potential therapeutic targets for immune modulation. In this study, we focused on the regulatory role of glycolytic enzymes in Tregs and identified phosphoglycerate mutase (PGAM) as being differentially overexpressed in Tregs and associated with a highly suppressive phenotype. Pharmacologic or genetic inhibition of PGAM reduced Treg differentiation and suppressive function while reciprocally inducing markers of a pro-inflammatory, T helper 17 (Th17)-like state. The regulatory role of PGAM was dependent on the contribution of 3-phosphoglycerate (3 PG), the PGAM substrate, to de novo serine synthesis. Blocking de novo serine synthesis from 3 PG reversed the effect of PGAM inhibition on Treg polarization, while exogenous serine directly inhibited Treg polarization. Additionally, altering serine levels in vivo with a serine/glycine-free diet increased peripheral Tregs and attenuated autoimmunity in a murine model of multiple sclerosis. Mechanistically, we found that serine limits Treg polarization by contributing to one-carbon metabolism and methylation of Treg-associated genes. Inhibiting one-carbon metabolism increased Treg polarization and suppressive function both in vitro and in vivo in a murine model of autoimmune colitis. Our study identifies a novel physiologic role for PGAM and highlights the metabolic interconnectivity between glycolysis, serine synthesis, one-carbon metabolism, and epigenetic regulation of Treg differentiation and suppressive function.
    Keywords:  PGAM; T cell biology; Treg; glycolysis; immunology; immunometabolism; inflammation; mouse; phosphoglycerate mutase; serine synthesis
    DOI:  https://doi.org/10.7554/eLife.104423
  25. Nature. 2025 Jul 30.
    ACLY inhibition promotes tumour immunity and suppresses liver cancer.
    Jaya Gautam, Jianhan Wu, James S V Lally, Jamie D McNicol, Russta Fayyazi, Elham Ahmadi, Daniela Carmen Oniciu, Spencer Heaton, Roger S Newton, Sonia Rehal, Dipankar Bhattacharya, Fiorella Di Pastena, Binh Nguyen, Celina M Valvano, Logan K Townsend, Suhrid Banskota, Battsetseg Batchuluun, Maria Joy Therese Jabile, Alice Payne, Junfeng Lu, Eric M Desjardins, Naoto Kubota, Evangelia E Tsakiridis, Bejal Mistry, Alex Aganostopoulos, Vanessa Houde, Ann Dansercoer, Koen H G Verschueren, Savvas N Savvides, Joanne A Hammill, Ksenia Bezverbnaya, Paola Muti, Theodoros Tsakiridis, Wenting Dai, Lei Jiang, Yujin Hoshida, Mark Larché, Jonathan L Bramson, Scott L Friedman, Kenneth Verstraete, Dongdong Wang, Gregory R Steinberg.
      Immunosuppressive tumour microenvironments are common in cancers such as metabolic dysfunction-associated steatohepatitis (MASH)-driven hepatocellular carcinoma (HCC) (MASH-HCC)1-3. Although immune cell metabolism influences effector function, the effect of tumour metabolism on immunogenicity is less understood4. ATP citrate lyase (ACLY) links substrate availability and mitochondrial metabolism with lipid biosynthesis and gene regulation5-7. Although ACLY inhibition shows antiproliferative effects in various tumours, clinical translation has been limited by challenges in inhibitor development and compensatory metabolic pathways8-12. Here, using a mouse model of MASH-HCC that mirrors human disease, genetic inhibition of ACLY in hepatocytes and tumours reduced neoplastic lesions by over 70%. To evaluate the therapeutic potential of this pathway, a novel small-molecule ACLY inhibitor, EVT0185 (6-[4-(5-carboxy-5-methyl-hexyl)-phenyl]-2,2-dimethylhexanoic acid), was identified via phenotypic screening. EVT0185 is converted to a CoA thioester in the liver by SLC27A2 and structural analysis by cryo-electron microscopy reveals that EVT0185-CoA directly interacts with the CoA-binding site of ACLY. Oral delivery of EVT0185 in three mouse models of MASH-HCC dramatically reduces tumour burden as monotherapy and enhances efficacy of current standards of care including tyrosine kinase inhibitors and immunotherapies. Transcriptomic and spatial profiling in mice and humans linked reduced tumour ACLY with increases in the chemokine CXCL13, tumour-infiltrating B cells and tertiary lymphoid structures. The depletion of B cells blocked the antitumour effects of ACLY inhibition. Together, these findings illustrate how targeting tumour metabolism can rewire immune function and suppress cancer progression in MASH-HCC.
    DOI:  https://doi.org/10.1038/s41586-025-09297-0
  26. Nature. 2025 Jul 30.
    Transient APC/C inactivation by mTOR boosts glycolysis during cell cycle entry.
    Debasish Paul, Derek L Bolhuis, Hualong Yan, Sudipto Das, Xia Xu, Christina C Abbate, Lisa M M Jenkins, Michael J Emanuele, Thorkell Andresson, Jing Huang, John G Albeck, Nicholas G Brown, Steven D Cappell.
      Mammalian cells entering the cell cycle favour glycolysis to rapidly generate ATP and produce the biosynthetic intermediates that are required for rapid biomass accumulation1. Simultaneously, the ubiquitin-ligase anaphase-promoting complex/cyclosome and its coactivator CDH1 (APC/CCDH1) remains active, allowing origin licensing and blocking premature DNA replication. Paradoxically, glycolysis is reduced by APC/CCDH1 through the degradation of key glycolytic enzymes2, raising the question of how cells coordinate these mutually exclusive events to ensure proper cell division. Here we show that cells resolve this paradox by transiently inactivating the APC/C during cell cycle entry, which allows a transient metabolic shift favouring glycolysis. After mitogen stimulation, rapid mTOR-mediated phosphorylation of the APC/C adapter protein CDH1 at the amino terminus causes it to partially dissociate from the APC/C. This partial inactivation of the APC/C leads to the accumulation of PFKFB3, a rate-limiting enzyme for glycolysis, promoting a metabolic shift towards glycolysis. Delayed accumulation of phosphatase activity later removes CDH1 phosphorylation, restoring full APC/C activity, and shifting cells back to favouring oxidative phosphorylation. Thus, cells coordinate the simultaneous demands of cell cycle progression and metabolism through an incoherent feedforward loop, which transiently inhibits APC/C activity to generate a pulse of glycolysis that is required for mammalian cell cycle entry.
    DOI:  https://doi.org/10.1038/s41586-025-09328-w
  27. Nat Commun. 2025 Jul 28. 16(1): 6585
    DynaTag for efficient mapping of transcription factors in low-input samples and at single-cell resolution.
    Pascal Hunold, Giulia Pizzolato, Nadia Heramvand, Laura Kaiser, Giulia Barbiera, Olivia van Ray, Roman Thomas, Julie George, Martin Peifer, Robert Hänsel-Hertsch.
      Systematic discovery of transcription factor (TF) landscapes in low-input samples and at single cell level is a major challenge in the fields of molecular biology, genetics, and epigenetics. Here, we present cleavage under Dynamic targets and Tagmentation (DynaTag), enabling robust mapping of TF-DNA interactions using a physiological salt solution during sample preparation. DynaTag uncovers occupancy alterations for 15 TFs in stem cell and cancer tissue models. We highlight changes in TF-DNA binding for NANOG, MYC, and OCT4, during stem-cell differentiation, at both bulk and single-cell resolutions. DynaTag surpasses CUT&RUN and ChIP-seq in signal-to-background ratio and resolution. Furthermore, using tumours of a small cell lung cancer model derived from a single female donor, DynaTag reveals increased chromatin occupancy of FOXA1, MYC, and the mutant p53 R248Q at enriched gene pathways (e.g. epithelial-mesenchymal transition), following chemotherapy treatment. Collectively, we believe that DynaTag represents a significant technological advancement, facilitating precise characterization of TF landscapes across diverse biological systems and complex models.
    DOI:  https://doi.org/10.1038/s41467-025-61797-9
  28. Nature. 2025 Jul 25.
    Ageing accelerates at around age 50 - some organs faster than others.
    Heidi Ledford.
      
    Keywords:  Ageing; Medical research; Proteomics
    DOI:  https://doi.org/10.1038/d41586-025-02333-z
  29. Cancer Cell. 2025 Jul 15. pii: S1535-6108(25)00271-5. [Epub ahead of print]
    Macropinocytosis maintains CAF subtype identity under metabolic stress in pancreatic cancer.
    Yijuan Zhang, Li Ling, Rabi Murad, Swetha Maganti, Ambroise Manceau, Hannah A Hetrick, Madelaine Neff, Cheska Marie Galapate, Shea F Grenier, Florent Carrette, Karen Duong-Polk, Anindya Bagchi, David A Scott, Yoav Altman, Jennifer L Hope, Andrew M Lowy, Linda M Bradley, Cosimo Commisso.
      Pancreatic ductal adenocarcinoma (PDAC) tumors are glutamine deficient, and both tumor cells and cancer-associated fibroblasts (CAFs) rely on this amino acid to maintain fitness and induce macropinocytosis as an adaptive response. CAFs play a critical role in sculpting the tumor microenvironment, yet how adaptations to metabolic stress impact the stromal architecture remains elusive. In this study, we find that macropinocytosis sustains the myCAF phenotype under glutamine limitation by preventing inflammatory reprogramming. Our data demonstrate that metabolic stress induces an intrinsic inflammatory CAF (iCAF) program through MEK-ERK signaling. We find that blocking macropinocytosis in vivo promotes myCAF-to-iCAF transitions, remodeling the tumor stroma. Importantly, stromal remodeling driven by macropinocytosis inhibition-including iCAF enrichment, collagen reduction, immune cell infiltration, and vascular expansion-sensitizes PDAC tumors to immunotherapy and chemotherapy. Our findings reveal that inhibiting macropinocytosis promotes an inflammatory, less fibrotic tumor microenvironment that can be leveraged to improve therapeutic responses in PDAC.
    Keywords:  CAF heterogeneity; chemotherapy; drug delivery; immunotherapy; macropinocytosis; metabolic stress; pancreatic cancer; plasticity; stromal architecture; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.ccell.2025.06.021
  30. Nat Genet. 2025 Jul 28.
    Massively parallel immunopeptidome by DNA sequencing provides insights into cancer antigen presentation.
    Quanming Shi, Elana P Simon, Cansu Cimen Bozkus, Anna Kaminska, Leandra Velazquez, Mansi Saxena, Zilin Zhang, Julia A Belk, Shuo Wang, Nuoya Yang, Yaowen Zhang, Ashley Kwong, Yonglu Che, Robert R Stickels, Charles R Crain, Laura Schmidt-Hong, Cheryl F Lichti, Gaurav D Gaiha, Theodore L Roth, Nina Bhardwaj, Ansuman T Satpathy, Bingfei Yu, Howard Y Chang.
      Human leukocyte antigens (HLAs) are encoded by the most polymorphic genes in the human genome. HLA class I alleles control antigen presentation for T cell recognition, which is pivotal for autoimmunity, infectious diseases and cancer. Current knowledge of HLA-bound peptides is limited, skewed and falls short of population-wide HLA binding profiles for high-value targets. Here we present ESCAPE-seq (enhanced single-chain antigen presentation sequencing), a massively parallel platform for comprehensive screening of class I HLA-peptide combinations for antigen presentation via deep DNA sequencing. ESCAPE-seq demonstrates programmability, high throughput, sensitivity and nominated viral and cancer epitopes. We simultaneously assessed over 75,000 peptide-HLA combinations, revealing broadly presented epitopes from oncogenic driver mutations and fusions across diverse HLA-A, HLA-B and HLA-C alleles that cover 90% of the human population. We further identified epitopes that are differentially presented, comparing oncogenic hotspot mutations versus wild type. ESCAPE-seq enables one-shot population-wide antigen presentation discovery, offering insights into HLA specificity and immune recognition of genomic mutations.
    DOI:  https://doi.org/10.1038/s41588-025-02268-1
  31. Physiol Rev. 2025 Jul 28.
    Metabolic adaptations in cancer progression.
    Yiming Peng-Winkler, Sarah-Maria Fendt.
      Cancer cells reprogram their metabolism as they travel to distant organs to establish metastases, the leading cause of cancer-related mortality. While the metabolic state of primary tumors has been extensively studied, the specific metabolic alterations associated with metastases have only recently garnered significant attention. The metabolic dependencies that arise during the metastatic cascade, along with the adaptive metabolic shifts required for growth in a new microenvironment, present promising therapeutic targets. In this review, we provide an overview of cancer metabolism, followed by a detailed exploration of the metabolic changes occurring at each stage of metastasis and within common organs of metastatic spread. Lastly, we examine the potential and challenges of targeting metabolic pathways in cancer therapy.
    Keywords:  Cancer; Metabolism; Metabolism-based therapy; Metastasis; Organ microenvironment
    DOI:  https://doi.org/10.1152/physrev.00037.2024
  32. Nat Commun. 2025 Aug 01. 16(1): 7050
    Regulation of airway fumarate by host and pathogen promotes Staphylococcus aureus pneumonia.
    Ying-Tsun Chen, Zihua Liu, Dario Fucich, Stefano G Giulieri, Zhe Liu, Ridhima Wadhwa, Gustavo Rios, Henning Henschel, Nupur Tyagi, Françios A B Olivier, Ian R Monk, Shivang S Shah, Shwetha H Sridhar, Marija Drikic, Colleen Bianco, Gaurav K Lohia, Ayesha Z Beg, Paul J Planet, Ian A Lewis, Robert Sebra, Ana Traven, Abderrahman Hachani, Timothy P Stinear, Benjamin P Howden, Jeffrey M Boyd, Sebastian A Riquelme, Chu Wang, Alice Prince, Tania Wong Fok Lung.
      Staphylococcus aureus is a leading cause of healthcare-associated pneumonia, contributing significantly to morbidity and mortality worldwide. As a ubiquitous colonizer of the upper respiratory tract, S. aureus must undergo substantial metabolic adaptation to achieve persistent infection in the distinctive microenvironment of the lung. We observed that fumC, which encodes the enzyme that converts fumarate to malate, is highly conserved with low mutation rates in S. aureus isolates from chronic lung infections. Fumarate, a pro-inflammatory metabolite produced by macrophages during infection, is regulated by the host fumarate hydratase (FH) to limit inflammation. Here, we demonstrate that fumarate, which accumulates in the chronically infected lung, is detrimental to S. aureus, blocking primary metabolic pathways such as glycolysis and oxidative phosphorylation (OXPHOS). This creates a metabolic bottleneck that drives staphylococcal FH (FumC) activity for airway adaptation. FumC not only degrades fumarate but also directs its utilization into critical pathways including the tricarboxylic acid (TCA) cycle, gluconeogenesis and hexosamine synthesis to maintain metabolic fitness and form a protective biofilm. Itaconate, another abundant immunometabolite in the infected airway enhances FumC activity, in synergy with fumarate. In a mouse model of pneumonia, a ΔfumC mutant displays significant attenuation compared to its parent and complemented strains, particularly in fumarate- and itaconate-replete conditions. Our findings underscore the pivotal role of immunometabolites in promoting S. aureus pulmonary adaptation.
    DOI:  https://doi.org/10.1038/s41467-025-62453-y
  33. Cell Rep. 2025 Jul 29. pii: S2211-1247(25)00859-9. [Epub ahead of print]44(8): 116088
    Cryo-EM structures of amino acid sensors bound to the human GATOR2 complex.
    Ming-Yuan Su, Fei Teng, Shan Wang, Xinyi Mai, Huan Zeng, Juan Li, Xiaoxiao Song, Xi Wang, Goran Stjepanovic.
      Mammalian cells regulate growth by integrating environmental cues through the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway. The human GATOR2 complex, comprising WDR59, WDR24, Mios, Sec13, and Seh1l, is key to mTORC1 regulation. Under amino acid deprivation, GATOR2 is inhibited through interactions with cytosolic leucine sensor Sestrin2 and arginine sensor cytosolic arginine sensor for mTORC1 subunit 1 (CASTOR1). Amino acid abundance relieves this inhibition, allowing GATOR2 to antagonize the repressor GATOR1. Despite its importance, GATOR2's inhibition mechanisms were unclear. Here, we present cryo-electron microscopy (cryo-EM) structures of GATOR2 in three inhibitory states: CASTOR1 bound, Sestrin2 bound, and dual bound. CASTOR1 engages the Mios WD40 β-propellers, while Sestrin2 interacts with the WDR24-Seh1l subcomplex, inducing conformational movements. Hydrogen-deuterium exchange mass spectrometry (HDX-MS) reveals dynamic motions in apo-GATOR2 and its complexes with amino acid sensors, as well as the effects of amino acid supplementation. These findings unravel the interactions between GATOR2 and amino acid sensors, providing a perspective on the regulation of the mTORC1 pathway by nutrient-sensing machinery.
    Keywords:  CASTOR1; CP: Metabolism; CP: Molecular biology; GATOR1; GATOR2; HDX-MS; Sestrin2; amino acid sensing; cryo-EM; mTOR complex 1
    DOI:  https://doi.org/10.1016/j.celrep.2025.116088
  34. Adv Sci (Weinh). 2025 Jul 29. e05436
    Acidosis Forces Fatty Acid Uptake and Metabolism in Cancer Cells Regardless of Genotype.
    Sébastien Ibanez, Maria Virginia Giolito, Sultan Al-Siyabi, Kristian Serafimov, Florine Laloux, Emeline Dierge, Léo Aubert, Céline Guilbaud, Selena Kaye, Paula Varon, Dorothée Marchand, Hanne Vlieghe, Emmanuel Hermans, Caroline Bouzin, Davide Brusa, Christiani Andrade Amorim, Barabara Pachikian, Yvan Larondelle, Cyril Corbet, Chantal Dessy, Olivier Feron.
      While proteins facilitate fatty acid (FA) partitioning into plasma membranes, movement between membrane leaflets occurs through a "flip-flop" mechanism. This study provides evidence that biological acidosis, as encountered in tumors and ischemic diseases, promotes FA protonation, thereby enhancing neutral, non-ionized FA uptake. This positions the altered lipid metabolism in acid-exposed cells as a consequence, rather than a cause, of preferential FA uptake. Cancer cell vulnerability, independent of their genetic background, directly stems from this paradigm shift, as detoxifying the overload of very long-chain FA (VLCFA) becomes highly dependent on peroxisomal activity. Inhibition of peroxisomal function in acid-exposed cancer cells leads to the rerouting of these fatty acids into triglycerides within lipid droplets, but also into phospholipids, contributing to membrane alterations, triggering ER stress, and ultimately supporting cytotoxicity. Using patient-derived tumor organoids and sera from human volunteers supplemented with polyunsaturated FA (PUFA), it is shown that inhibiting peroxisomal ACOX1 selectively kills acid-exposed cancer cells, an effect exacerbated by pharmacological stimulation of glycolysis. Similar acid-driven FA uptake is observed in endothelial cells and cardiac myocytes, opening new therapeutic avenues not only cancer but also cardiovascular diseases.
    Keywords:  acidosis; cancer; fatty acid; lipid metabolism; peroxisome
    DOI:  https://doi.org/10.1002/advs.202505436
  35. Nature. 2025 Jul 30.
    A molecular cell atlas of mouse lemur, an emerging model primate.
    Tabula Microcebus Consortium
      Mouse lemurs are the smallest and fastest reproducing primates, as well as one of the most abundant, and they are emerging as a model organism for primate biology, behaviour, health and conservation. Although much has been learnt about their ecology and phylogeny in Madagascar and their physiology, little is known about their cellular and molecular biology. Here we used droplet-based and plate-based single-cell RNA sequencing to create Tabula Microcebus, a transcriptomic atlas of 226,000 cells from 27 mouse lemur organs opportunistically obtained from four donors clinically and histologically characterized. Using computational cell clustering, integration and expert cell annotation, we define and biologically organize more than 750 lemur molecular cell types and their full gene expression profiles. This includes cognates of most classical human cell types, including stem and progenitor cells, and differentiating cells along the developmental trajectories of spermatogenesis, haematopoiesis and other adult tissues. We also describe dozens of previously unidentified or sparsely characterized cell types. We globally compare expression profiles to define the molecular relationships of cell types across the body, and explore primate cell and gene expression evolution by comparing lemur transcriptomes to those of human, mouse and macaque. This reveals cell-type-specific patterns of primate specialization and many cell types and genes for which the mouse lemur provides a better human model than mouse1. The atlas provides a cellular and molecular foundation for studying this model primate and establishes a general approach for characterizing other emerging model organisms.
    DOI:  https://doi.org/10.1038/s41586-025-09113-9
  36. Nat Commun. 2025 Jul 26. 16(1): 6911
    Enhancing tandem mass spectrometry-based metabolite annotation with online chemical labeling.
    Giovanni Andrea Vitale, Shu-Ning Xia, Kai Dührkop, Mohammad Reza Zare Shahneh, Heike Brötz-Oesterhelt, Yvonne Mast, Corinna Brungs, Sebastian Böcker, Robin Schmid, Mingxun Wang, Chambers C Hughes, Daniel Petras.
      Metabolite identification in non-targeted mass spectrometry-based metabolomics remains a major challenge due to limited spectral library coverage and difficulties in predicting metabolite fragmentation patterns. Here, we introduce Multiplexed Chemical Metabolomics (MCheM), which employs orthogonal post-column derivatization reactions integrated into a unified mass spectrometry data framework. MCheM generates orthogonal structural information that substantially improves metabolite annotation through in silico spectrum matching and open-modification searches, offering a powerful new toolbox for the structure elucidation of unknown metabolites at scale.
    DOI:  https://doi.org/10.1038/s41467-025-61240-z
  37. Cell Rep Med. 2025 Jul 16. pii: S2666-3791(25)00321-0. [Epub ahead of print] 102248
    Opantimirs: A class of antagonizing microRNAs that upregulate Opa1 and improve mitochondrial and disuse myopathies.
    Andre Djalalvandi, Keisuke Takeda, Francesca Grespi, Hualin Fan, Tiago Branco Fonseca, Leonardo Nogara, Saman Sharifi, Carlotta Barison, Martina Semenzato, Akiko Omori, Raffaele Cerutti, Davide Steffan, Lorenza Tsansizi, Valeria Balmaceda, Lukas Alan, Camilla Bean, Bert Blaauw, Carlo Viscomi, Luca Scorrano.
      Alterations in mitochondrial ultrastructure and reduced levels of the crista-shaping protein Opa1 are key features of mitochondrial myopathies and aging. We identify and characterize a biological therapy that improves mitochondrial and disuse myopathy models by boosting Opa1 levels. In silico analysis identifies microRNAs (miRNAs) 128-3p and 148/152-3p family as conserved modulators of OPA1 transcription and elevated in various muscle disorders. These miRNAs target the 3' UTR of murine and human OPA1, reducing its mRNA and protein levels, causing mitochondrial fragmentation and crista disorganization. Genetic experiments confirm that their mitochondrial effects rely on 3' UTR binding. In mitochondrial disease patient cells and murine models, elevated OPA1-specific miRNA levels are reduced by antagonistic miRNAs (Opantimirs), which restore mitochondrial ultrastructure, morphology, and function. In vivo, Opantimirs correct mitochondrial ultrastructure and fiber size in muscles of denervated and Cox15-ablated mice, improving strength in the latter. Thus, biopharmacological correction of the mitochondrial ultrastructure can ameliorate mitochondrial myopathies.
    Keywords:  OPA1; antimiRs; cristae remodeling; disuse myopathies; miR-128-3p; miR-148/152-3p family; microRNAs; mitochondrial myopathies; mitochondrial ultrastructure
    DOI:  https://doi.org/10.1016/j.xcrm.2025.102248
  38. Immunity. 2025 Jul 25. pii: S1074-7613(25)00316-4. [Epub ahead of print]
    Polyamines regulate adaptive antitumor immunity by functional specialization of regulatory T cells.
    Georg Bündgen, Alexander Ulges, Jan Pietruschka, Natalia Truong-Andrievici, Matthias Klein, Karolina Romaniuk, Fabian Schmitt, Mathias Hagen, Joachim G Seebass, Lenart Zezlina, Lara Stein, Hans Christian Probst, Ute Distler, Stefan Tenzer, Michael Lohoff, Addi J Romero-Olmedo, Henrik Mei, Toszka Bohn, Michael Delacher, Thierry Schmidlin, Matthias M Gaida, Ivan Dikic, Charles Imbusch, Hansjörg Schild, Tobias Bopp.
      In cancer, metabolic changes and uncontrolled tumor growth alter nutrient availability, impacting antitumor immune responses. Regulatory T (Treg) cells are a subset of T cells with immunosuppressive properties that can also influence tissue homeostasis and repair. However, it is not known how these functions are molecularly controlled and whether they are influenced by tumor metabolism. Here, we report that excessive release of polyamines in the tumor microenvironment directs the functional polarization of Treg cells toward immunosuppression in a protein kinase CK2 (CK2)-dependent manner. Polyamine deprivation as well as genetic or pharmacological inhibition of CK2 activity in Treg cells induced tissue reparative properties in Treg cells that orchestrated efficient antitumor type 2 immune responses and coordinated tissue repair mechanisms to support tumor eradication. These findings suggest that targeted modulation of Treg cell functions could be leveraged as a potential avenue for cancer therapy.
    Keywords:  FOXP3; cancer; immune evasion; immunometabolism; kinase; metabolism; polyamines; regulatory T cells; tissue repair; tumor immunology
    DOI:  https://doi.org/10.1016/j.immuni.2025.07.007
  39. Science. 2025 Jul 31. 389(6759): 494-500
    Genomic convergence in hibernating mammals elucidates the genetics of metabolic regulation in the hypothalamus.
    Elliott Ferris, Josue D Gonzalez Murcia, Adriana Cristina Rodriguez, Susan Steinwand, Cornelia Stacher Hörndli, Dimitri Traenkner, Pablo J Maldonado-Catala, Christopher Gregg.
      Extreme metabolic adaptations can elucidate genetic programs that govern mammalian metabolism. Here, we used convergent evolutionary changes in hibernating lineages to define conserved cis-regulatory elements (CREs) and metabolic programs. We characterized mouse hypothalamus gene expression and chromatin dynamics across fed, fasted, and refed states and then used comparative genomics of hibernating versus nonhibernating lineages to identify cis elements with convergent changes in hibernators. Multi-omics approaches pinpointed CREs, hub genes, regulatory programs, and cell types underlying lineage divergence. Hibernators accumulated loss-of-function effects for CREs regulating hypothalamic responses, and the refeeding period after fasting served as a key phase for molecular processes with convergent evolutionary changes. This work provides a genetic framework for harnessing hibernator adaptations to understand human metabolic control.
    DOI:  https://doi.org/10.1126/science.adp4025
  40. Sci Adv. 2025 Aug;11(31): eady2643
    The β2-adrenergic receptor (Adrb2) entrains circadian gene oscillation and CD8+ T cell differentiation in response to virus infection.
    Drashya Sharma, Kira A Kohlbach, Robert Maples, J David Farrar.
      Adaptive immune cells are regulated by circadian rhythms both under steady state conditions and during responses to infection. Cytolytic CD8+ T cells display variable responses to infection depending upon the time of day of exposure. However, the neuronal signals that entrain these cyclic behaviors remain unknown. Immune cells express various neurotransmitter receptors, and we demonstrate that selective deletion of the β2-adrenergic receptor (Adrb2) gene perturbs the normal diurnal oscillation of clock gene expression in CD8+ T cells, such as Per2 and Bmal1. Consequently, their time-of-day-dependent response to vesicular stomatitis virus was dysregulated, and the diurnal development of CD8+ T cells into variegated populations of memory/effectors was altered in the absence of ADRB2 signaling. The diurnal fluctuations in T cell phenotypes were a distinct developmental process, independent of migration kinetics within the spleen. Thus, Adrb2 directly entrains core clock gene oscillation and regulates T cell developmental responses to virus infection as a function of time of day of pathogen exposure.
    DOI:  https://doi.org/10.1126/sciadv.ady2643
  41. Cancer Discov. 2025 Jul 30.
    Sucralose consumption ablates cancer immunotherapy response through microbiome disruption.
    Kristin M Morder, Madison Nguyen, Drew N Wilfahrt, Zakaria Larbi Dahmani, Ansen Bp Burr, Bingxian Xie, Michael Morikone, Hector Nieves-Rosado, William G Gunn, Drew E Hurd, Hong Wang, Steven J Mullett, Kaitlin Bossong, Stacy L Gelhaus, Dhivyaa Rajasundaram, Lawrence P Kane, Greg M Delgoffe, Jishnu Das, Diwakar Davar, Abigail E Overacre-Delgoffe.
      Gut microbiota composition is directly associated with response to immunotherapies in cancer. How the diet impacts the gut microbiota and downstream immune responses to cancer remains unclear. Here, we show that consumption of a common non-nutritive sweetener, sucralose, modifies microbiome composition, restricts T cell metabolism and function, and limits immunotherapy response in preclinical models of cancer and advanced cancer patients treated with anti-PD-1 based immune checkpoint inhibitors (ICIs). Sucralose consumption is associated with a reduction in microbiota-accessible arginine, and amino acid supplementation or fecal microbiome transfer (FMT) from anti-PD-1 responder mice completely restores T cell function and immunotherapy response. Overall, sucralose consumption destabilizes the gut microbiota, resulting in compromised T cell function and ablated ICI response in cancer.
    DOI:  https://doi.org/10.1158/2159-8290.CD-25-0247
This page is being maintained by Thomas Krichel. It was last updated on 2025‒08‒03 at 5:39.