bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2025–11–30
fifty papers selected by
Christian Frezza, Universität zu Köln
  1. Mitochondrial NAD+ drives liver regeneration.
  2. Mitochondria redistribution organizes the immunosuppressive tumor ecosystem.
  3. A metabolic atlas of mouse aging.
  4. Macropinocytosis enables metabolic recycling of extracellular DNA in cancer cells.
  5. Inhibition of oligomeric BAX by an anti-apoptotic dimer.
  6. Age distinguishes selection from causation in cancer genomes.
  7. NADH dehydrogenase reverses dietary and clock metabolic syndrome.
  8. Imaging Cellular Metabolic Rewiring with SuMMIT-SRS.
  9. Carbohydrate adaptation drives liver-brain axis maturation.
  10. The proton motive force maintains mtDNA euploidy by balancing mtDNA replication with cell proliferation.
  11. The histone modification regulator, SIN3, plays a role in the cellular response to changes in glycolytic flux.
  12. Burning fat with cysteine depletion.
  13. Loss of IDH1 and IDH2 mutations during the evolution of metastatic chondrosarcoma.
  14. Hypoxia Rewires Histone Methylation in Glioblastoma Cells via Enzyme Reprogramming Despite Disruption of One-Carbon Metabolism.
  15. Many circulating indole and phenol metabolites are host derived.
  16. Acetyl-CoA carboxylase maintains energetic balance for functional oogenesis.
  17. Intrinsic errors in mitochondrial translation trigger a decline in cell fitness.
  18. Mitochondrial movement in pancreatic alpha cells requires Miro2 and is regulated by glucose.
  19. pH-dependent regulation in SLC38A9.
  20. PANK2-mediated de novo CoA synthesis is required for metabolic switching to fatty acid oxidation.
  21. Mitochondrial metabolic rewiring sensitizes mTORC1 inhibitor persister cells to cuproptosis.
  22. MTHFD2: A Retrospective and a Glance into the Future.
  23. Spectrum and Impact of Mitochondrial DNA Mutations in Ovarian Cancer.
  24. Fasting hijacks proximal tubule circadian control mechanisms to regulate glucose reabsorption via the Nrf1/Sglt2 pathway in mice.
  25. Molecular Architecture of the human Citrate Synthase-Malate Dehydrogenase 2 metabolon.
  26. Interplay between cancer cell lipotypes and disease states.
  27. Cell size modulates ferroptosis susceptibility.
  28. Dietary sulfur amino acid restriction improves glucose homeostasis through hepatic de novo serine synthesis.
  29. All-Optical Multimodal Mapping of Single Cell-Type-Specific Metabolic Activities via REDCAT.
  30. Arginine Metabolism Supports De Novo Pyrimidine Biosynthesis to Block DNA Damage and Maintain Epstein-Barr Virus Latency.
  31. Targeting prohibitins activates the ISR through DELE1-HRI by impairing protein import into the mitochondrial matrix.
  32. Localized Wnt-signaling promotes asymmetric NuMA-dependent oriented divisions and unequal apportioning of mitochondria.
  33. Spatial Partitioning of Core Glycolysis Enables Tissue-Specific Metabolic Programs In Vivo.
  34. We are all mosaics: vast genetic diversity found between cells in a single person.
  35. Vitamin B6 preserves the stemness-like phenotypes and antitumor ability of CD8+ T cells.
  36. Smart spatial omics (S2-omics) optimizes region of interest selection to capture molecular heterogeneity in diverse tissues.
  37. Chronic sensing of host-derived lipids is an all-in-one signal that primes and activates NLRP3.
  38. Single-cell 3D architecture maps the drivers of lung adenocarcinoma.
  39. NAD+ restores proteostasis through splicing-dependent autophagy.
  40. Lifting regenerative barriers promotes epithelial cell fate plasticity supporting lineage conversion.
  41. Propionate metabolism dysregulation promotes drug-tolerant persister cell survival in non-small cell lung cancer.
  42. Electron microscopy visualization of cell-free mitochondrial DNA-containing extracellular vesicles in human plasma, serum, and saliva.
  43. MITF, TFEB, and TFE3 drive distinct adaptive gene expression programs and immune infiltration in melanoma.
  44. Mechanical confinement induces ferroptosis through mitochondrial dysfunction.
  45. Iron homeostasis and cell clonality drive cancer-associated intestinal DNA methylation drift in aging.
  46. MAPK-driven epithelial cell plasticity drives colorectal cancer therapeutic resistance.
  47. Targeting serine dehydratase supports amino acid homeostasis and skin repair.
  48. Polyamines sustain epithelial regeneration in aged intestines by modulating protein homeostasis.
  49. Very long-chain fatty acids drive 1-deoxySphingolipid toxicity.
  50. ER-to-Golgi Trafficking is a Nutrient-Sensitive Checkpoint Linking Glucose Starvation to Cell Surface Remodeling.
  1. Nat Metab. 2025 Nov 24.
    Mitochondrial NAD+ drives liver regeneration.
      
    DOI:  https://doi.org/10.1038/s42255-025-01414-7
  2. bioRxiv. 2025 Nov 13. pii: 2025.11.11.687895. [Epub ahead of print]
    Mitochondria redistribution organizes the immunosuppressive tumor ecosystem.
    Azusa Terasaki, Alexis T Weiner, Yuhao Tan, Viktoria Szeifert, Keshav Bhatnagar, Cara C Rada, Vishnu Shankar, Courtney Kernick, Mahnoor Mahmood, Lukas Wiggers, Viviana R Rodrigues, Payam A Gammage, Theodore Roth, Jeffrey D Axelrod, Edgar Engleman, Bo Li, Derick Okwan-Duodu.
      Hostile conditions in the tumor microenvironment restrict cellular respiration, yet mitochondrial metabolism remains indispensable for tumor growth and the activity of immunosuppressive cells. How tumor ecosystems sustain mitochondrial output has been unclear. Here, we show that cancer cells resolve this paradox by acting as hubs of intercellular mitochondrial redistribution. Using mitochondrial reporter systems, we demonstrate that cancer cells import host-derived mitochondria, integrate them into their endogenous network, and subsequently relay these hybrid organelles to neighboring immune cells. Mitochondria redistribution reprograms recipient neutrophils, macrophages, and CD4+ T cells into highly suppressive states but drives CD8+ T cell exhaustion. Within cancer cells, fusion of incoming mitochondria induces filamentous P5CS assembly, enhances biosynthetic output, and enables the refurbishment of damaged organelles into fully functional units. Disrupting mitochondrial redistribution collapses the immunosuppressive ecosystem and impairs tumor growth. Thus, cancer cells do not hoard resources but orchestrate a redistribution program that fortifies their own metabolic resilience, derails anti-tumor immunity, and sustains immunosuppressive partners.
    HIGHLIGHTS: Tumor cells regulate their ecosystem by redistributing mitochondriaRedistributed mitochondria expand immunosuppressive cells but exhausts CD8+ T cellsMitochondria fusion within cancer cells, which precedes redistribution, optimizes metabolic output by triggering conformational changes in P5CSMitochondria fusion allows cancer cells to incorporate and refurbish seemingly incompetent host-derived mitochondria, improving efficiency in the tumor ecosystem.
    DOI:  https://doi.org/10.1101/2025.11.11.687895
  3. Cell Metab. 2025 Nov 25. pii: S1550-4131(25)00476-0. [Epub ahead of print]
    A metabolic atlas of mouse aging.
    Steven E Pilley, Dominik Awad, Djakim Latumalea, Connie New, Edgar Esparza, Shuo Wang, Xuanyi Shi, Li Zhang, Maximilian Unfried, Jasinda H Lee, Ernst Schmid, Ipsita Mohanty, Jenna L E Blum, Shivaanishaa Raventhiran, Esther Wong, Preeti R Iyengar, Racheal Mulondo, Sriraksha Bharadwaj Kashyap, Darius Moaddeli, Peter Sajjakulnukit, Damien Sutton, Harrison K A Wong, Yaqi Gao, George Wang, Aeowynn J Coakley, Gilberto Garcia, Ryo Higuchi-Sanabria, Anja Karlstaedt, Timothy L Frankel, Marina Pasca di Magliano, Whitaker Cohn, Sophia Liu, Bingfei Yu, Pieter C Dorrestein, Ernest Fraenkel, Shawn M Davidson, William B Tu, Brian K Kennedy, Costas A Lyssiotis, Peter J Mullen.
      Humans are living longer and experiencing more age-related diseases, many of which involve metabolic dysregulation, but how metabolism changes in multiple organs during aging is not known. Answering this could reveal new mechanisms of aging and therapeutics. Here, we profile metabolic changes in 12 organs in male and female mice at 5 different ages. We also develop organ-specific metabolic aging clocks that identify metabolic drivers of aging, including alpha-ketoglutarate, previously shown to extend lifespan in mice. We also use the clocks to uncover that carglumic acid is a potential driver of aging and show that it is synthesized by human cells. Finally, we validate that hydroxyproline decreases with age in the human pancreas, emphasizing that our approach reveals insights across species. This study reveals fundamental insights into the aging process and identifies new therapeutic targets to maintain organ health.
    Keywords:  LC-MS/MS; MALDI-MSI; aging; aging clocks; healthspan; human tissue; hydroxyproline; metabolism; scRNA-seq; sex
    DOI:  https://doi.org/10.1016/j.cmet.2025.10.016
  4. bioRxiv. 2025 Oct 23. pii: 2025.10.22.684010. [Epub ahead of print]
    Macropinocytosis enables metabolic recycling of extracellular DNA in cancer cells.
    Wen-Hsuan Yang, Olivia T Stamatatos, Evdokia Michalopoulou, Ava Sann, Paolo Cifani, Linda Van Aelst, Justin R Cross, Tse-Luen Wee, Michael J Lukey.
      Avid nutrient consumption is a metabolic hallmark of cancer and leads to regional depletion of key metabolites within the tumor microenvironment (TME). Cancer cells consequently employ diverse strategies to acquire the fuels needed for growth, including bulk uptake of the extracellular medium by macropinocytosis. Here, we show that breast and pancreatic cancer cells macropinocytically internalize extracellular DNA (exDNA), an abundant component of the TME, and deliver it to lysosomes for degradation. This provides a supply of nucleotides that sustains growth when de novo biosynthesis is impaired by glutamine restriction or pharmacological blockade. Mechanistically, this process is dependent on the non-redundant lysosomal equilibrative nucleoside transporter SLC29A3 (ENT3), which mediates the export of nucleosides from the lysosomal lumen into the cytosol. Accordingly, genetic ablation of SLC29A3 or pharmacological disruption of lysosomal function prevents exDNA scavenging and potently sensitizes breast tumors to antimetabolite chemotherapy in vivo . These findings reveal a previously unrecognized nutrient acquisition pathway through which cancer cells recycle exDNA into metabolic building blocks and highlight SLC29A3 as a mediator of metabolic flexibility and a potential target to improve chemotherapy response.
    DOI:  https://doi.org/10.1101/2025.10.22.684010
  5. Cell. 2025 Nov 21. pii: S0092-8674(25)01242-5. [Epub ahead of print]
    Inhibition of oligomeric BAX by an anti-apoptotic dimer.
    Catherine E Newman, Micah A Gygi, Haleh Alimohamadi, Thomas M DeAngelo, Christina M Camara, Julian Mintseris, Ezra Yu, Edward P Harvey, Zachary J Hauseman, Lixin Fan, Yun-Xing Wang, Elizabeth W-C Luo, Marina Godes, Jacob Gehtman, Ann M Cathcart, Steven P Gygi, John R Engen, Gregory H Bird, Gerard C L Wong, Thomas E Wales, Loren D Walensky.
      BAX is a pro-apoptotic BCL-2 protein that resides in the cytosol as a monomer until triggered by cellular stress to form an oligomer that permeabilizes mitochondria and induces apoptosis. The paradigm for apoptotic blockade involves heterodimeric interactions between pro- and anti-apoptotic monomers. Here, we find that full-length BCL-w forms a distinctive, symmetric dimer (BCL-wD) that dissociates oligomeric BAX (BAXO), inhibits mitochondrial translocation, promotes retrotranslocation, blocks membrane-porating activity, and influences apoptosis induction of cells. Structure-function analyses revealed discrete conformational changes upon BCL-w dimerization and reciprocal structural impacts upon BCL-wD and BAXO interaction. Small-angle X-ray scattering (SAXS) analysis demonstrated that BAXO disrupts membranes by inducing negative Gaussian curvature, which is reversed by positive Gaussian curvature exerted by BCL-wD. Systematic truncation and mutagenesis dissected the core features of BCL-wD activity-dimerization, BAXO engagement, and membrane interaction. Our studies reveal a downstream layer of apoptotic control mediated by protein and membrane interactions of higher-order BCL-2 family multimers.
    Keywords:  BAX; BCL-2 family proteins; BCL-w; anti-apoptotic; apoptosis; cell death; chemical crosslinking mass spectrometry; dimer; hydrogen deuterium exchange mass spectrometry; membrane curvature; mitochondria; mitochondrial retrotranslocation; mitochondrial translocation; oligomer; pro-apoptotic; small-angle X-ray scattering
    DOI:  https://doi.org/10.1016/j.cell.2025.10.037
  6. bioRxiv. 2025 Oct 06. pii: 2025.10.06.680730. [Epub ahead of print]
    Age distinguishes selection from causation in cancer genomes.
    David Cheek, Martin Blohmer, Martin Nowak, Tibor Antal, Kamila Naxerova.
      Cancer genome sequencing efforts have revealed hundreds of genes under positive selection, many of which are now being developed as therapeutic targets. However, positively selected mutations also populate our aging tissues in the absence of cancer. For most mutations, it is currently unknown whether they are recurrently found in cancer genomes because they cause cancer or because they expand during normal tissue evolution and are passively inherited. Here, we develop a mathematical and statistical framework that distinguishes these two factors. We discover - across thousands of cancer and normal tissue genomes - that mutations that most strongly increase cancer risk are enriched in younger patients' cancers, whereas mutations that are positively selected in normal tissue without causing cancer are enriched in older patients. Focusing on a particularly data-rich cancer type, acute myeloid leukemia, we show that genetic differences between young- and adult-onset cancers can largely be explained by the cumulative effects of normal tissue evolution, contradicting the long-standing notion that childhood cancers require a distinct set of causal mutations. Our framework establishes patient age as a powerful resource for clarifying whether positively selected mutations in cancer genomes are truly disease-promoting.
    DOI:  https://doi.org/10.1101/2025.10.06.680730
  7. bioRxiv. 2025 Oct 23. pii: 2025.10.22.684030. [Epub ahead of print]
    NADH dehydrogenase reverses dietary and clock metabolic syndrome.
    Chelsea Hepler, Nathan J Waldeck, Benjamin J Weidemann, Biliana Marcheva, You-Jia Chen, Jacqueline Hecker, Ziming Zhu, Rino Nozawa, Joseph V Mastroni, Anneke K Thorne, Colleen R Reczek, Jonathan Cedernaes, Kathryn M Ramsey, Clara B Peek, Grant D Barish, Navdeep S Chandel, Joseph Bass.
      Circadian clocks are internal timing systems that enable organisms to anticipate and adapt to daily environmental changes. These rhythms arise from a transcription-translation feedback loop in which CLOCK/BMAL1 regulate the expression of thousands of genes, including their repressors PER/CRY 1 . Disruption of circadian rhythms contributes to obesity, metabolic disease, and cancer 2-4 , yet how the clock maintains metabolic homeostasis remains limited. Here we report that the clock regulates oxidative metabolism through diurnal respiration of mitochondrial respiratory chain complex I. Genetic loss of the clock and high fat diet feeding in male mice led to reduced complex I respiration within adipocytes, leading to suppression of PPAR and insulin signaling pathways. In contrast, preserving complex I function maintained adipogenic and metabolic gene networks and protected against diet- and circadian-induced metabolic dysfunction independently of weight gain. These findings reveal that circadian disruption impairs metabolic health through mitochondrial complex I dysfunction, establishing clock control of complex I as a key regulator of transcriptional and metabolic homeostasis.
    DOI:  https://doi.org/10.1101/2025.10.22.684030
  8. bioRxiv. 2025 Oct 13. pii: 2025.10.10.681769. [Epub ahead of print]
    Imaging Cellular Metabolic Rewiring with SuMMIT-SRS.
    Yajuan Li, Zhi Li, Yuhan Li, Kevin Rhine, Sural Ranamukhaarachchi, Shuo Qin, Hongje Jang, Jorge Villazon, Zhiliang Bai, Stephanie I Fraley, Gene W Yeo, Rong Fan, Lingyan Shi.
      Cells dynamically rewire their metabolic pathways in response to physiological and pathological cues. Such plasticity is particularly critical in neurons, stem cells, cancer cells, and immune cells, where biosynthetic demands can shift rapidly. However, current metabolic imaging techniques using isotope labeling typically track only one metabolite at a time, limiting their ability to capture the rapid dynamics of complex metabolic networks including coordinated precursor utilization, crosstalk, and turnover. Here, we present Subcellular Multiplexed Metabolic Isotope Tracing Stimulated Raman Scattering microscopy (SuMMIT-SRS), a platform that enables simultaneous visualization of multiple metabolic dynamics at subcellular resolution. By exploiting the distinct vibrational signatures of carbon-deuterium bonds derived from multiple deuterated amino acids, lipids, and monosaccharide tracers, SuMMIT-SRS maps co-regulated DNA, RNA, protein, and lipid synthesis at the same time and resolves various individual amino acid-mediated metabolic pathways within intact cells and tissues. We demonstrate SuMMIT's broad utility across Drosophila fat body tissue and developing brain, tumor organoids, aged human neurons, and mouse liver, capturing cell type-specific metabolic rewiring under genetic and pathological perturbations. This approach extends SRS to multiplexed isotope tracing, offering a powerful tool to uncover dynamic and complex biosynthesis programs in development, health, and disease.
    Keywords:  Metabolic rewiring; SRS; lipid; metabolism; multiplex; optical imaging; protein
    DOI:  https://doi.org/10.1101/2025.10.10.681769
  9. bioRxiv. 2025 Nov 06. pii: 2025.11.05.685548. [Epub ahead of print]
    Carbohydrate adaptation drives liver-brain axis maturation.
    Hongmei Cui, Zheng Wu, Yuannyu Zhang, Hieu S Vu, Hongli Chen, Xiaofei Gao, Yan Jin, Donghong Cai, Sarada Achyutuni, Phong Nguyen, Chunxiao Pan, Hui Cao, Camenzind G Robinson, Jeffery D Steinberg, Laura J Janke, Sara M Nowinski, Jian Xu, Ralph J DeBerardinis, Min Ni.
      Mammalian postnatal life requires adaptation to a carbohydrate-rich diet, yet how metabolic programs are coordinated within and across organs is unclear. Using time-resolved transcriptomic and metabolomic analyses from the neonatal period through adulthood, we show that mouse liver rapidly acquires oxidative and detoxification capacity after weaning. This transition enables the brain to establish energy-sufficient, low-toxicity metabolic environment for neuronal function. This maturation process is marked by progressive activation of the hepatic electron transport chain (ETC), with the mitochondrial RNA endoribonuclease LACTB2 acting as a key regulator. LACTB2 prevents the accumulation of mitochondrial RNAs and sustains expression of mtDNA-encoded ETC subunits, thereby preserving mitochondrial competence for oxidative metabolism. LACTB2 is postnatally induced in hepatocytes, and its loss causes defective glucose utilization, systemic metabolic toxicity, and impaired brain metabolism and myelination, leading to prepubertal lethality, particularly in males. Restoring ETC function through liver-targeted expression of yeast NADH dehydrogenase NDI1, inhibiting the integrated stress response or ammonia scavenging improved survival. Our findings identify LACTB2-dependent hepatic mitochondrial maturation as a central mechanism that aligns carbohydrate adaptation with the liver-brain metabolic coordination to support early-life development.
    DOI:  https://doi.org/10.1101/2025.11.05.685548
  10. bioRxiv. 2025 Oct 27. pii: 2025.10.27.684790. [Epub ahead of print]
    The proton motive force maintains mtDNA euploidy by balancing mtDNA replication with cell proliferation.
    Sneha P Rath, Vamsi K Mootha.
      Human mitochondrial DNA (mtDNA) encodes 13 essential components of the electron transport chain (ETC) 1 . A typical cell contains ∼1000s of copies of mtDNA, but how this copy number is stably maintained is unclear. Here, we track mtDNA copy number (mtCN) recovery in K562 cells following transient, chemically induced depletion to uncover principles of mtCN stability. Below a critical mtCN, ETC activity fails to sustain the proton motive force (PMF) and de novo pyrimidine synthesis-both required for mtDNA replication. PMF-dependent processes like Fe-S cluster biogenesis are also disrupted and stress responses are activated that impair cell proliferation and limit further mtCN dilution by cell division. Nonetheless, mtDNA replication and recovery remain possible via mtDNA-independent PMF, generated by complex V reversal, and uridine salvage. Once mtCN is restored, the ETC and forward complex V activity re-engage, stress responses subside, and proliferation recommences. Each cell division then dilutes mtDNA, serving as a built- in brake on mtCN. Our findings suggest that mtCN homeostasis emerges from the balance of two opposing PMF-driven processes - mtDNA replication and cell proliferation - revealing a bioenergetic logic that preserves mtDNA euploidy through repeated cell divisions.
    DOI:  https://doi.org/10.1101/2025.10.27.684790
  11. PLoS One. 2025 ;20(11): e0335411
    The histone modification regulator, SIN3, plays a role in the cellular response to changes in glycolytic flux.
    Imad Soukar, Anindita Mitra, Linh Vo, Melanie Rofoo, Miriam L Greenberg, Lori A Pile.
      Epigenetic regulation and metabolism are connected. Epigenetic regulators, like the SIN3 complex, affect the expression of a wide range of genes, including those encoding metabolic enzymes essential for central carbon metabolism. The idea that epigenetic modifiers can sense and respond to metabolic flux by regulating gene expression has long been proposed. In support of this cross-talk, we provide data linking SIN3 regulatory action on a subset of metabolic genes with the cellular response to changes in metabolic flux. Furthermore, we show that loss of SIN3 is linked to decreases in mitochondrial respiration and the cellular response to mitochondrial and glycolytic stress. Data presented here provide evidence that SIN3 is important for the cellular response to metabolic flux change.
    DOI:  https://doi.org/10.1371/journal.pone.0335411
  12. Cell Stress. 2025 ;9 216-221
    Burning fat with cysteine depletion.
    Brittney Adams, Stanislaw Walkowiak, Mohammed K Hankir.
      Removing certain essential amino acids from the diet is known to promote weight loss in rodents via effects on food intake and energy expenditure. Two complementary articles by Varghese et al [Nature 643(8072)] and Lee et al [Nature Metabolism 7(6)] now show that cysteine depletion through combined dietary and genetic means in mice evokes a unique stress response in the liver to amplify these metabolic outcomes and offer a potentially new treatment option for obesity.
    Keywords:  adipose tissue thermogenesis; cysteine; essential amino acids; integrated stress response; obesity; oxidative stress response
    DOI:  https://doi.org/10.15698/cst2025.11.313
  13. Genome Biol. 2025 Nov 26. 26(1): 404
    Loss of IDH1 and IDH2 mutations during the evolution of metastatic chondrosarcoma.
    PEACE consortium
      Driver mutations in IDH1 and IDH2 are initiating events in the evolution of chondrosarcoma and several other cancer types. Here, we present evidence that mutant IDH1 is recurrently lost in metastatic central chondrosarcoma. This may reflect either relaxed positive selection for the mutant IDH1 locus, or negative selection for the hypermethylation phenotype later in tumor evolution. This finding highlights the challenge for therapeutic intervention by mutant IDH1 inhibitors in chondrosarcoma.
    Keywords:   IDH1 ; IDH2 ; Bone tumor; Cancer evolution; Chondrosarcoma; Metastasis
    DOI:  https://doi.org/10.1186/s13059-025-03812-2
  14. Biochemistry. 2025 Nov 26.
    Hypoxia Rewires Histone Methylation in Glioblastoma Cells via Enzyme Reprogramming Despite Disruption of One-Carbon Metabolism.
    Hui Tang, Pei Xu, Jason Herring, Kangling Zhang.
      Hypoxia is a hallmark of the tumor microenvironment that profoundly alters the cellular metabolism and epigenetic regulation. In this study, we investigated how oxygen limitation reprograms histone methylation in glioblastoma cells by integrating stable isotope tracing with high-resolution proteomics and epigenomics. Using deuterium-labeled serine and the RQMID-MS platform, we demonstrated that hypoxia impairs methyl group transfer from serine to histones due to the downregulation of the vitamin B12 transporter TCN2, which is critical for homocysteine remethylation and SAM synthesis. Despite this blockade in one-carbon metabolism, global histone methylation patterns were not uniformly suppressed. Instead, we observed site-specific changes driven by altered expression of methyltransferases and demethylases, particularly decreased KMT1F (H3K9 methylation) and KMT2B (H3K4 methylation) and increased KDM2A (H3K36 demethylation), KDM3A (H3K9 demethylation), and KMT5A/SETD8 (H4K20 monomethylation). These findings reveal that the histone methylation landscape under hypoxia is governed by a compensatory interplay between one-carbon metabolism and chromatin-modifying enzyme regulation.
    DOI:  https://doi.org/10.1021/acs.biochem.5c00632
  15. bioRxiv. 2025 Oct 06. pii: 2025.10.05.680522. [Epub ahead of print]
    Many circulating indole and phenol metabolites are host derived.
    Jenna E AbuSalim, Kellen Olszewski, Salma Youssef, Craig J Hunter, Michael R MacArthur, Alessa Henneberg, Rolf-Peter Ryseck, Christiane A Opitz, Mohamed S Donia, Joshua D Rabinowitz.
      Indole and phenol metabolites are typically thought to be products of bacterial digestion of tryptophan (indoles) and phenylalanine or tyrosine (phenols). Interest in controlling gut microbial production of these metabolites has continually grown as they have important physiological impacts, with indoles agonizing AhR signaling, and phenols being associated with healthy body weight. While there is a growing wealth of research into which bacteria produce these metabolites, host contribution to their circulating pools has not been adequately characterized. Here, through stable isotope tracing in cell culture and mice, we show that mammalian cells can make aryl-pyruvates, -lactates, -acetates, and -carboxylic acids. Levels of these metabolites in mice and human patients are insensitive to perturbations of the microbiome. In contrast, bacterial metabolism is required to synthesize aryl-propionates and free indole, phenol, and cresol. Overall, we show that host metabolism is a primary contributor to circulating indole and phenol metabolite pools.
    DOI:  https://doi.org/10.1101/2025.10.05.680522
  16. Nat Commun. 2025 Nov 27. 16(1): 10677
    Acetyl-CoA carboxylase maintains energetic balance for functional oogenesis.
    Oyundari Amartuvshin, Chi-Hung Lin, Yi-Ting Ke, Han-Jung Lee, Kreeti Kajal, Tsai-Ling Huang, Wen-Der Wang, Tsai-Ming Lu, Ling-Huei Yih, Chen-Yuan Tseng, Hwei-Jan Hsu.
      Reproduction is tightly linked to nutrient availability and metabolic homeostasis, yet how specific metabolic pathways coordinate with cellular signaling to control oogenesis remains unclear. Through a targeted RNAi screen in the Drosophila germline, we identify Acetyl-CoA Carboxylase (Acc), the rate-limiting enzyme in fatty acid synthesis (FAS), as an essential regulator of germline stem cell (GSC) maintenance and oocyte development. Acc loss shifts cellular metabolism toward fatty acid oxidation (FAO), fueling the TCA cycle and electron transport chain, which elevates ATP levels and hyperactivates TOR signaling. This metabolic reprogramming induces excessive protein synthesis, disrupting endosomal trafficking and fusome branching, a germline-specific organelle essential for synchronized cell divisions and oocyte selection. These defects are rescued by inhibiting FAO, suppressing TOR activity, reducing protein synthesis, or restricting dietary protein intake. Our study establishes a direct metabolic-signaling-structural axis in the female germline and highlights Acc as a key metabolic checkpoint that safeguards energy balance, intracellular trafficking, and oocyte fate.
    DOI:  https://doi.org/10.1038/s41467-025-65708-w
  17. bioRxiv. 2025 Oct 15. pii: 2025.10.13.682189. [Epub ahead of print]
    Intrinsic errors in mitochondrial translation trigger a decline in cell fitness.
    Güleycan Lutfullahoglu Bal, Kah Ying Ng, Eli Berzell, Ani Akpinar, Alex E Ekvik, Lidiia Koludarova, Seyedehshima Naddafi, Clemens Raths, Tania Vane-Tempest, Jordyn J VanPortfliet, Sarah O'Keefe, Arafath K Najumudeen, Tuula A Nyman, James B Stewart, A Phillip West, Brendan J Battersby.
      Defects in the faithful expression of the human mitochondrial genome underlies disease states, from rare inherited disorders to common pathologies and the aging process itself. The ensuing decrease in the capacity for oxidative phosphorylation alone cannot account for the phenotype complexity associated with disease. Here, we address how aberrations in mitochondrial nascent chain synthesis per se exert a decline in cell fitness using a classic model of mitochondrial induced premature aging. We identify how intrinsic errors during mitochondrial nascent chain synthesis destabilize organelle gene expression, triggering intracellular stress responses that rewire cellular metabolism and cytokine secretion. Further, we show how these mechanisms extend to pathogenic variants associated with inherited human disorders. Together, our findings reveal how aberrations in mitochondrial protein synthesis can sensitize a cell to metabolic challenges associated with disease and pathogen infection independent of oxidative phosphorylation.
    Teaser/One-Sentence Summary: Aberrations in mitochondrial translation elongation trigger activation of intracellular stress responses associated with disease and aging.
    DOI:  https://doi.org/10.1101/2025.10.13.682189
  18. J Biol Chem. 2025 Nov 25. pii: S0021-9258(25)02836-4. [Epub ahead of print] 110984
    Mitochondrial movement in pancreatic alpha cells requires Miro2 and is regulated by glucose.
    Maia H Ekstrand, Sameena Nawaz, Anne Clark, Benoit Hastoy, Jakob G Knudsen.
      Under normal physiological conditions, glucagon is released from pancreatic alpha cells to elevate circulating glucose levels in response to hypoglycaemia. In type 2 diabetic patients, glucagon secretion is dysregulated, but the underlying mechanisms remain unclear. Several hypotheses have been suggested to explain the coupling of blood glucose sensing to electrical activity and glucagon secretion from alpha cells. Here, we show that glucose rapidly regulates mitochondrial motility and localisation in alpha cells. Under conditions of low glucose, mitochondria are arrested in positions further from the nucleus, correlating with increased ATP/ADP in the sub-plasma membrane space. We also find that knock down (KD) of Mitochondrial Rho GTPase 2 (Miro2), but not Miro1, reduces mitochondrial motility in alpha cells and impairs glucose-induced inhibition of glucagon secretion without effects on insulin secretion or mitochondrial motility in non-alpha islet cells. These findings highlight the significance of mitochondrial motility for alpha cell function and reveal fundamental differences between alpha and beta cells.
    Keywords:  Glucagon; alpha cells; beta cells; cell metabolism; insulin; mitochondria; mitochondrial transport
    DOI:  https://doi.org/10.1016/j.jbc.2025.110984
  19. bioRxiv. 2025 Oct 25. pii: 2025.10.24.684471. [Epub ahead of print]
    pH-dependent regulation in SLC38A9.
    Xuelang Mu, Ampon Sae Her, Tamir Gonen.
      Cells rely on precise metabolic control to adapt to environmental cues. The mechanistic target of rapamycin complex 1 (mTORC1) senses nutrient availability, with amino acids serving as key signals. Lysosomes, which act as nutrient recycling centers, maintain amino acid homeostasis by breaking down macromolecules and releasing amino acids for cellular use. SLC38A9, a lysosomal amino acid transporter, functions as both a transporter and a sensor in the mTORC1 pathway. Here, we investigated whether SLC38A9 activity is regulated by pH. We show that arginine uptake by SLC38A9 is pH-dependent, and that the histidine residue His544 serves as the pH sensor. Mutating His544 abolishes the pH dependence of arginine uptake without impairing overall transport activity, indicating that His544 is not directly involved in substrate binding. Instead, protonation or deprotonation of His544 appears to influence transport through SLC38A9. To explore this mechanism, we compared two structures of SLC38A9 that we determined, one at high pH and one at low pH, and proposed a working model for pH-induced activation. These findings highlight the role of local ionic changes in modulating lysosomal transporters and underscore the intricate regulatory mechanisms that govern SLC38A9 function and, ultimately, mTORC1 signaling.
    DOI:  https://doi.org/10.1101/2025.10.24.684471
  20. bioRxiv. 2025 Nov 18. pii: 2025.10.07.680981. [Epub ahead of print]
    PANK2-mediated de novo CoA synthesis is required for metabolic switching to fatty acid oxidation.
    Sandra M Nordlie, Robert Schafer, Adam Rauckhorst, Ana M Santos-Exposito, Andres Prieto-Rodriguez, Bryce A Wilson, Idil A Evans, Una Hadziamehtovic, Frances Nowlen, Carlos Santos-Ocaña, Eric B Taylor, Michael C Kruer, Sergio Padilla-Lopez.
      Humans have 3 different PANK enzymes (PANK1-3) that catalyze the first step in the de novo synthesis of Coenzyme A (CoA). All PANKs are feedback inhibited by acyl-CoAs but only PANK2 can overcome this inhibition by binding palmitoyl-carnitine. Previous studies, conducted under glucose-replete conditions, have failed to detect a PANK2-mediated contribution to CoA synthesis. We found that exposure to BSA-conjugated palmitate (PAL-BSA) led to activation of fatty acid oxidation (FAO) and the accumulation of both palmitoyl-carnitine and palmitoyl-CoA in HEK293T cells, suggesting that PANK2 is active under these conditions. Isotope tracing experiments with 13 C 15 N-pantothenate showed that PANK2 uniquely sustains de novo CoA synthesis and high production of Acetyl-CoA in the presence of long-chain fatty acids, indicating that FAO is limited by CoA availability in these conditions. Consistent with this mechanism, fibroblasts from PKAN patients exhibited impaired oxidation of palmitoyl-carnitine, confirming the functional relevance of our results in a disease context.
    DOI:  https://doi.org/10.1101/2025.10.07.680981
  21. JCI Insight. 2025 Nov 24. pii: e187448. [Epub ahead of print]10(22):
    Mitochondrial metabolic rewiring sensitizes mTORC1 inhibitor persister cells to cuproptosis.
    Heng Du, Heng-Jia Liu, Magdalena Losko, Yu Chi Yang, Min Yuan, Elizabeth P Henske, John M Asara, Mallika Singh, David J Kwiatkowski.
      Therapeutics blocking PI3K/mTOR complex 1 (mTORC1) are commonly used for tumor treatment, and at times achieve major responses, yet minimal residual disease (MRD) persists, leading to tumor relapse. We developed multiple MRD models both in vitro (rapamycin persistent, RP) and in vivo after mTORC1 inhibition. All 11 RP/MRD cell lines showed complete growth and signaling insensitivity to rapamycin but variable sensitivity to bi-steric mTORC1 inhibitors, with MtorS2035 mutations identified in 4 of 7 RP cell lines. Multiomic analyses identified a pronounced shift toward oxidative phosphorylation and away from glycolysis with increased mitochondrial number in all RP/MRD models. MYC and SWI/SNF expression was significantly enhanced. Both the SWI/SNF inhibitor AU-15330 and the mitochondrial complex I oxidative phosphorylation inhibitor IACS-010759 showed pronounced synergy with bi-steric mTORC1 inhibitors to cause cuproptotic cell death in RP/MRD cells, suggesting these combinations as a potential patient treatment strategy for rapalog resistance.
    Keywords:  Cancer; Epigenetics; Metabolism; Mitochondria; Oncology
    DOI:  https://doi.org/10.1172/jci.insight.187448
  22. Int J Mol Sci. 2025 Nov 14. pii: 11025. [Epub ahead of print]26(22):
    MTHFD2: A Retrospective and a Glance into the Future.
    Costas Koufaris, Vicky Nicolaidou.
      The 1985 confirmation by Mejia and MacKenzie of mammalian NAD-dependent methylenetetrahydrofolate dehydrogenase activity launched four decades of research on methylenetetrahydrofolate dehydrogenase (NAD+-dependent), methenyltetrahydrofolate cyclohydrolase 2 (MTHFD2). This review provides a retrospective on four decades of advancements on MTHFD2 that have revealed its key roles in the folate pathway, amino acid and redox homeostasis, and the metabolism of cancer and immune cells. We trace the initial biochemical characterization of the enzyme, highlight pivotal discoveries regarding MTHFD2's metabolic and non-canonical roles, and discuss the current state of knowledge and future prospects.
    Keywords:  MTHFD2; one-carbon metabolism; retrospective
    DOI:  https://doi.org/10.3390/ijms262211025
  23. Int J Mol Sci. 2025 Nov 19. pii: 11180. [Epub ahead of print]26(22):
    Spectrum and Impact of Mitochondrial DNA Mutations in Ovarian Cancer.
    Samantha Su Ping Low, Laura Greaves, Ryan Silk, Colin A Semple, Charlie Gourley.
      Mitochondrial DNA (mtDNA) mutations are prevalent across cancer genomes, and growing evidence implicates their multifaceted role in energy metabolism with tumorigenesis. Ovarian cancer, in particular, demonstrates high mtDNA copy numbers and increased incidences of truncating and missense mtDNA mutations, with heteroplasmy levels predictive of prognosis. This review provides a comprehensive description of published mtDNA sequencing data in ovarian cancer, the majority being high-grade serous samples, encompassing both coding and non-coding regions. MtDNA mutations within non-coding regions, such as the D-loop control region, can affect mtDNA replication and transcription, hence affecting overall mtDNA copy numbers, while mtDNA mutations within coding regions can directly impact respiratory complex function and downstream metabolic pathways. MtDNA mutations may serve as clinically valuable diagnostic biomarkers for ovarian cancer and predictors for chemoresistance. We also explore ongoing efforts to deepen our understanding of mitochondrial oncogenetics through the creation of novel cancer models enabled by mitochondrial gene editing techniques. Developing robust human ovarian cancer cell models will be critical to elucidate mechanistic and phenotypic consequences of mtDNA mutations, assess drug response and resistance and identify new therapeutic targets to advance precision oncology in this emerging field.
    Keywords:  gene editing; heteroplasmy; mitochondrial DNA; ovarian cancer; somatic mutations
    DOI:  https://doi.org/10.3390/ijms262211180
  24. Nat Commun. 2025 Nov 25. 16(1): 10447
    Fasting hijacks proximal tubule circadian control mechanisms to regulate glucose reabsorption via the Nrf1/Sglt2 pathway in mice.
    Xiaoyue Pan, Cyrus Mowdawalla, Samantha Bagnato, Jeffrey Pessin, Volker Vallon, M Mahmood Hussain.
      The kidneys contribute to glucose homeostasis by gluconeogenesis and glucose reabsorption. Herein, we identified previously unknown fasting-induced, glucagon-mediated inhibitory effect of the circadian clock gene basic helix-loop-helix ARNT like 1 (Bmal1) on the expression of the main proximal tubule glucose transporter solute carrier family 5 member 2 (Sglt2) in mice. During fasting, glucagon induces Bmal1, which increases expression of nuclear receptor subfamily 1, group D, member 1 (Rev-erbα). Rev-erbα represses nuclear respiratory factor 1, a transcriptional activator of Sglt2, and diminishes Sglt2 expression and thereby kidney glucose reabsorption capacity. During refeeding (lower glucagon) this process is attenuated, thereby inducing glucose reabsorption. The physiological role of this mechanism appears to ensure optimal temporal retrieval of filtered glucose during fasting/refeeding. Thus, this study demonstrates that during fasting and refeeding, glucagon regulates renal glucose reabsorption by utilizing the local cellular circadian machinery.
    DOI:  https://doi.org/10.1038/s41467-025-65402-x
  25. bioRxiv. 2025 Oct 14. pii: 2025.10.13.681887. [Epub ahead of print]
    Molecular Architecture of the human Citrate Synthase-Malate Dehydrogenase 2 metabolon.
    Angela J Kayll, Umanga Rupakheti, Renee St John, Joseph J Provost, Christopher E Berndsen.
      Metabolons are transient biomolecular complexes that enhance the efficiency of metabolic pathways through substrate channeling. These complexes are difficult to study because of the transient nature, thus limiting our understanding of how they are formed and regulated. The citric acid cycle is proposed to contain many such complexes although few have been characterized structurally. Here, we provide direct structural evidence for the complex of human Citrate Synthase and human mitochondrial Malate Dehydrogenase 2, which is part of the larger proposed citric acid cycle metabolon. Our structural model supports previous crosslinking studies and suggests that hMDH2 can interact with each subunit of the hCS dimer, forming up to a hexameric complex. However, this complex appears transient as titration of hMDH2 into hCS in activity assays does not saturate. We further show that the interaction site with hCS is non-specific, as hCS could also stimulate oxaloacetate formation by cytosolic and plant MDH enzymes. This structural model will provide a base for understanding the structure and regulation of the broader citric acid cycle metabolon.
    DOI:  https://doi.org/10.1101/2025.10.13.681887
  26. Trends Cancer. 2025 Nov 25. pii: S2405-8033(25)00260-2. [Epub ahead of print]
    Interplay between cancer cell lipotypes and disease states.
    Xi Wang, Yilong Zou.
      While the initial transformation of cancer cells is driven by genetic alterations, tumor cell behaviors and functional states are dynamically regulated by cell-intrinsic factors including proteins, metabolites and lipids, and extrinsic microenvironmental factors. Emerging multi-omics technologies highlighted that cancer cells exhibit distinct lipidome compositions and employ specific lipid metabolic circuits for chemical conversions - collectively defined as 'lipotypes'. We review the interplay between cancer lipotypes and cellular states, focusing on interpreting how being at different positions along the spectra of representative lipid metabolic axes influences cancerous traits. We aim to instill a system biology perspective to integrate 'lipotypes' into the established 'genotype-phenotype' framework in cancer.
    Keywords:  cancer progression and metastasis; lipid biosynthesis; lipid metabolism; lipidomics; lipotypes; storage and degradation; tumor microenvironment; uptake
    DOI:  https://doi.org/10.1016/j.trecan.2025.10.009
  27. bioRxiv. 2025 Oct 26. pii: 2025.10.25.684524. [Epub ahead of print]
    Cell size modulates ferroptosis susceptibility.
    Evgeny Zatulovskiy, Magdalena B Murray, Shuyuan Zhang, Scott J Dixon, Jan M Skotheim.
      Size is a fundamental property of cells that influences many aspects of their physiology. This is because cell size sets the scale for all subcellular components and drives changes in the composition of the proteome. Given that large and small cells differ in their biochemical composition, we hypothesize that they should also differ in how they respond to signals and make decisions. Here, we investigated how cell size affects the susceptibility to cell death. We found that large cells are more resistant to ferroptosis induced by system x c - inhibition. Ferroptosis is a type of cell death characterized by the iron-dependent accumulation of toxic lipid peroxides. This process is opposed by cysteine-dependent lipid peroxide detoxification mechanisms. We found that larger cells exhibit higher concentrations of the cysteine-containing metabolite glutathione and lower concentrations of membrane lipid peroxides, compared to smaller cells. Mechanistically, this can be explained by the fact that larger cells had lower concentrations of an enzyme that enriches cellular membranes with peroxidation-prone polyunsaturated fatty acids, ACSL4, and increased concentrations of the iron-chelating protein ferritin and the glutathione-producing enzymes glutamate-cysteine ligase and glutathione synthetase. Taken together, our results highlight the significant impact of cell size on cellular function and survival, revealing a size-dependent vulnerability to ferroptosis that could influence therapeutic strategies based on this cell death pathway.
    DOI:  https://doi.org/10.1101/2025.10.25.684524
  28. bioRxiv. 2025 Oct 17. pii: 2025.10.16.682938. [Epub ahead of print]
    Dietary sulfur amino acid restriction improves glucose homeostasis through hepatic de novo serine synthesis.
    Andres F Ortega, Cha Mee Vang, Ferrol I Rome, Kaitlyn M Andreoni, Aiden M Phoebe, Alisa B Nelson, Peter A Crawford, James J Galligan, Stanley Ching-Cheng Huang, Curtis C Hughey.
      Dietary sulfur amino acid restriction (SAAR) improves whole-body glucose homeostasis, elevates liver insulin action, and lowers liver triglycerides. These adaptations are associated with an increased expression of hepatic de novo serine synthesis enzymes, phosphoglycerate dehydrogenase (PHGDH) and phosphoserine aminotransferase 1 (PSAT1). This study tested the hypothesis that enhanced hepatic serine synthesis is necessary for glucose and lipid adaptations to SAAR. Hepatocyte-specific PSAT1 knockout (KO) mice and wild type (WT) littermates were fed a high-fat control or SAAR diet. In WT mice, SAAR increased liver PSAT1 protein (~70-fold), serine concentration (~2-fold), and 13C-serine (~20-fold) following an intravenous infusion of [U-13C]glucose. The elevated liver serine and partitioning of circulating glucose to liver serine by SAAR were attenuated in KO mice. This was accompanied by a blunted improvement in glucose tolerance in KO mice fed a SAAR diet. Interestingly, SAAR decreased liver lysine lactoylation, a SAA-supported post-translational modification known to inhibit PHGDH enzymatic activity. This suggests dietary SAAR may increase serine synthesis, in part, by lowering lysine lactoylation. Beyond glucose metabolism, dietary SAAR reduced body weight, adiposity, and liver triglycerides similarly in WT and KO mice. Collectively, these results demonstrate that hepatic PSAT1 is necessary for glucose, but not lipid, adaptations to SAAR.
    DOI:  https://doi.org/10.1101/2025.10.16.682938
  29. bioRxiv. 2025 Oct 11. pii: 2024.11.07.622511. [Epub ahead of print]
    All-Optical Multimodal Mapping of Single Cell-Type-Specific Metabolic Activities via REDCAT.
    Yajuan Li, Zhaojun Zhang, Archibald Enninful, Negin Farzad, Presha Rajbhandari, Jungmin Nam, Xiaoyu Qin, Jorge Villazon, Anthony A Fung, Hongje Jang, Zhiliang Bai, Nancy R Zhang, Brent R Stockwell, Rong Fan, Mina L Xu, Zongming Ma, Lingyan Shi.
      Metabolism underlies cell growth, survival, and function, yet its activities vary widely across cell types and tissue environments. Spatially resolving these processes in situ at single-cell resolution is essential to advance our understanding of cellular function and tissue physiology in health and disease. However, existing approaches are limited by either destructive workflows, insufficient spatial resolution and biochemical specificity, or lack of direct linkage to cell identity. Here, we present Raman Enhanced Delineation of Cell Atlases in Tissues (REDCAT), a multimodal all-optical platform that integrates stimulated Raman scattering, autofluorescence redox imaging, second harmonic generation, and high-plex immunofluorescence to co-map metabolic activities and cell types within the same tissue section. REDCAT achieves subcellular resolution profiling of protein, lipid, redox, and nuclear acid metabolism, together with extracellular matrix composition, in both FFPE and fresh-frozen human tissues. Applied to normal lymph nodes, REDCAT delineated distinct redox and lipid remodeling programs across germinal center B-cell zones and immune subsets, highlighting cell-type-specific metabolic specialization. In lymphoma, it revealed profound metabolic reprogramming, including extensive lipid accumulation, nuclear metabolic heterogeneity, and a transitional metabolic state associated with transformation from chronic lymphocytic leukemia to diffuse large B-cell lymphoma, thereby illuminating tumor evolution in situ . In human liver, REDCAT resolved cell-type-specific lipid droplet diversity and zonation-dependent nuclear metabolic gradients, uncovering new principles of spatial metabolic organization. By directly linking cell identity with spatial metabolic states at single-cell or subcellular resolution, REDCAT establishes a broadly applicable framework for studying immune function, tumor progression, and tissue physiology, and offers a new path to deciphering the metabolic basis of health and disease.
    DOI:  https://doi.org/10.1101/2024.11.07.622511
  30. bioRxiv. 2025 Oct 21. pii: 2025.10.21.683727. [Epub ahead of print]
    Arginine Metabolism Supports De Novo Pyrimidine Biosynthesis to Block DNA Damage and Maintain Epstein-Barr Virus Latency.
    Shaowen White, Yifei Liao, Eric M Burton, John M Asara, Benjamin E Gewurz.
      Incompletely understood mechanisms serve to maintain Epstein-Barr virus (EBV) latency in most B-cell states, in which viral oncogene(s) are expressed but lytic antigens are repressed. Shortly after EBV's discovery and even before it was named, early pioneers Werne and Gertrude Henle identified that restriction of extracellular arginine de-represses EBV lytic antigens within Burkitt lymphoma tumor cells. However, for nearly 60 years, it has remained unknown how arginine metabolism supports EBV latency. To gain insights, we performed an amino acid restriction screen in Burkitt cell lines. This confirmed that arginine restriction was sufficient to trigger EBV reactivation in Burkitt B-cells and gastric carcinoma models. Arginine restriction strongly impaired de novo pyrimidine biosynthesis, and CRISPR or chemical genetic blockade of pyrimidine biosynthesis enzymes induced EBV immediate early and early lytic gene expression. However, arginine restriction blocked EBV lytic DNA replication and consequently also late gene expression, suggesting an abortive lytic cycle. Arginine restriction triggered DNA damage, which was an important driver of arginine restriction-driven EBV reactivation. Arginine restriction and DNA hypomethylation synergistically increased EBV reactivation. Together, our results highlight arginine and pyrimidine metabolism as potential targets for EBV lytic antigen induction therapy in B and epithelial cell contexts.
    Keywords:  DNA damage; de novo pyrimidine synthesis; double-stranded DNA virus; epigenetic; lytic cycle; metabolism; nucleotide biosynthesis; nucleotide metabolism; reactivation; viral latency
    DOI:  https://doi.org/10.1101/2025.10.21.683727
  31. Cell Death Differ. 2025 Nov 25.
    Targeting prohibitins activates the ISR through DELE1-HRI by impairing protein import into the mitochondrial matrix.
    Ismael Sánchez-Vera, Ana M Cosialls, Nekane Maritorena-Hualde, Max-Hinderk Schuler, Rodolfo Lavilla, Gabriel Pons, Lucas T Jae, Daniel Iglesias-Serret, Joan Gil.
      Prohibitins (PHBs) are predominantly located at the inner mitochondrial membrane, displaying significant roles in tumor progression, invasion, and apoptotic resistance, often overexpressed in primary tumors. Importantly, we developed a synthetic molecule, fluorizoline, that induces apoptosis by selectively targeting PHBs in various cancer cell lines and primary samples from different hematological neoplasms. Fluorizoline induces apoptosis by activating the pro-apoptotic branch of the integrated stress response (ISR) pathway in HeLa and HAP1 cells, specifically via the ATF4-CHOP-NOXA axis. We identified compensatory mechanisms for four ISR-related kinases, with HRI emerging as the primary kinase responsible for the activation of the ISR and apoptosis induction, implicating mitochondrial stress in ISR activation. Here, we investigate the mitochondrial stress response signaling pathway responsible for activating HRI after targeting PHBs either by fluorizoline treatment or by PHBs downregulation in HeLa and HAP1 cancer cell lines. In this study, we describe how PHBs regulate the localization of the mitochondrial stress sensor DELE1, leading to ISR activation and apoptosis induction in HeLa and HAP1 cells. Our findings demonstrate that DELE1 promotes ISR activation upon fluorizoline treatment and PHBs downregulation. Although fluorizoline treatment activates the cleavage of long DELE1 (L-DELE1) to its cleaved form (S-DELE1), OMA1 was found to be dispensable for activating the ISR upon fluorizoline treatment. Furthermore, our findings indicate a potential impairment of the mitochondrial protein import machinery upon targeting PHBs, as the import of other mitochondrial proteins beyond DELE1 is also disrupted. These findings reveal a previously unknown physiological role of PHBs in preserving the mitochondrial protein import pre-sequence pathway, possibly due to the interaction between PHBs and DNAJC19. This novel insight underscores the potential of targeting PHBs, such as with fluorizoline, to overwhelm mitochondrial stress in cancer.
    DOI:  https://doi.org/10.1038/s41418-025-01618-0
  32. Nat Commun. 2025 Nov 27. 16(1): 10690
    Localized Wnt-signaling promotes asymmetric NuMA-dependent oriented divisions and unequal apportioning of mitochondria.
    Susanna Eli, Greta Rauso, Paola Ghezzi, James L A Szczerkowski, Michela Bruzzi, Francesca Rizzelli, Fabiola Iommazzo, Alessia Loffreda, Francesco Castagna, Federico Donà, Chiara Gaddoni, Ambra Dondi, Mattia Marenda, Simona Rodighiero, Pierre Tournier, Zeno Lavagnino, Dario Parazzoli, Nils C Gauthier, Simone Tamburri, Diego Pasini, Shukry James Habib, Marina Mapelli.
      In multicellular organisms, the execution of developmental and homeostatic programs often relies on asymmetric cell divisions. These divisions require the alignment of the mitotic spindle axis to cortical polarity cues, and the unequal partitioning of cellular components between progeny cells. Asymmetric divisions are orchestrated by signals from the niche frequently presented in a directional manner, such as Wnt signals. Here we employ bioengineered Wnt-niches to demonstrate that in metaphase NuMA/dynein microtubule motors form a complex with activated LRP6 and β-catenin at the cortical sites of Wnt activation to orient cell division perpendicularly. We show that engagement of LRP6 co-receptors by Wnt ligands locally stabilizes actomyosin contractility through the accumulation of myosin1C. Additionally, we describe a proteomic-based approach to identify mitotic protein complexes enriched at the Wnt-contact site, revealing that mitochondria polarize toward localized Wnt3a sources and are asymmetrically apportioned to the Wnt-proximal daughter cell during Wnt-mediated asymmetric cell division of embryonic stem cells. Mechanistically, we show that CENP-F is required for mitochondria polarization towards localized sites of Wnt3a activation, and that deletion of the Wnt-co-receptor LRP6 impairs the asymmetric apportioning of mitochondria. Our findings enhance the understanding of mitotic Wnt-signaling and elucidate fundamental principles underlying Wnt-dependent mitochondrial polarization.
    DOI:  https://doi.org/10.1038/s41467-025-65775-z
  33. bioRxiv. 2025 Nov 10. pii: 2025.11.09.687253. [Epub ahead of print]
    Spatial Partitioning of Core Glycolysis Enables Tissue-Specific Metabolic Programs In Vivo.
    Ian J Gonzalez, Aaron D Wolfe, Benjamin Clark, Michael Hanna, Quishi Sun, Snusha Ravikumar, Anastasia Tsives, Sarah E Emerson, Stephan Siebel, Richard Kibbey, Daniel Colón-Ramos.
      Tissues exhibit metabolic heterogeneity that tailors metabolism to their physiological demands. How the conserved pathways of metabolism achieve metabolic heterogeneity is not well understood, particularly in vivo. We established a system in Caenorhabditis elegans to investigate tissue-specific requirements for glucose 6-phosphate isomerase (GPI-1), a conserved glycolytic enzyme that also regulates the pentose phosphate pathway (PPP). Using CRISPR-Cas9 genome editing, we found that gpi-1 knockout animals display germline defects consistent with impaired PPP, and somatic defects consistent with impaired glycolysis. We discovered that two GPI-1 isoforms are differentially expressed and localized: GPI-1A is expressed in most tissues, where it displays cytosolic localization, whereas GPI-1B is primarily expressed in the germline, where it localizes to subcellular foci near the endoplasmic reticulum. GPI-1B expression alone is sufficient to maintain wild type levels of reproductive fitness, but insufficient to reconstitute wild-type glycolytic dynamics. Our findings uncover isoform-specific, spatially-compartmentalized functions of GPI-1 that underpin tissue-specific anabolic and catabolic metabolism in vivo , underscoring roles for subcellular localization in achieving tissue-specific metabolic flux.
    DOI:  https://doi.org/10.1101/2025.11.09.687253
  34. Nature. 2025 Nov 25.
    We are all mosaics: vast genetic diversity found between cells in a single person.
    Heidi Ledford.
      
    Keywords:  Ageing; Cancer; DNA sequencing; Genetics
    DOI:  https://doi.org/10.1038/d41586-025-03768-0
  35. Dev Cell. 2025 Nov 27. pii: S1534-5807(25)00691-4. [Epub ahead of print]
    Vitamin B6 preserves the stemness-like phenotypes and antitumor ability of CD8+ T cells.
    Jun Wu, Gen Li, Jiawen Zhou, Xuan Sun, Haoyu Wang, Haipeng Gong, Peng Jiang.
      Tumor-infiltrating lymphocytes are usually dysfunctional but demonstrate stem cell-like behavior through unclear mechanisms. Here, we report that administration of vitamin B6 or its active form, pyridoxal phosphate (PLP), endows mouse and human CD8+ T cells with improved persistence, stemness-like phenotypes, and tumor clearance capabilities. Lowering PLP by pyridoxal kinase (PDXK) heterozygosity results in reduced T cell stemness-like properties and increased exhaustion phenotypes in tumors. Mechanistically, PLP preserves T cell function by directly binding to and inhibiting p70S6 kinase (p70S6K). Through limiting p70S6K-mediated BTB domain and CNC homolog 2 (BACH2) phosphorylation, PLP increases nuclear retention and functional activation of BACH2, promoting stemness gene expression while dampening exhaustion gene expression. In preclinical tumor models, PLP treatment improves the efficacy of anti-programmed death receptor 1 (PD-1) antibody therapy. Thus, our study reveals a pathway that preserves T cell functional stemness-like phenotypes to drive the acquisition of antitumor immunity, highlighting the clinical potential of vitamin B6/PLP-enhanced T cell function strategies in cancer immunotherapy.
    Keywords:  T cell differentiation; antitumor immunity; metabolite signaling; p70S6K; vitamin B6
    DOI:  https://doi.org/10.1016/j.devcel.2025.10.017
  36. Nat Cell Biol. 2025 Nov 26.
    Smart spatial omics (S2-omics) optimizes region of interest selection to capture molecular heterogeneity in diverse tissues.
    Musu Yuan, Kaitian Jin, Hanying Yan, Amelia Schroeder, Chunyu Luo, Sicong Yao, Bernhard Dumoulin, Jonathan Levinsohn, Tianhao Luo, Jean R Clemenceau, Inyeop Jang, Minji Kim, Yunhe Liu, Minghua Deng, Emma E Furth, Parker Wilson, Anupma Nayak, Idania Lubo, Luisa Maren Solis Soto, Linghua Wang, Jeong Hwan Park, Katalin Susztak, Tae Hyun Hwang, Mingyao Li.
      Spatial omics technologies have transformed biomedical research by enabling high-resolution molecular profiling while preserving the native tissue architecture. These advances provide unprecedented insights into tissue structure and function. However, the high cost and time-intensive nature of spatial omics experiments necessitate careful experimental design, particularly in selecting regions of interest (ROIs) from large tissue sections. Currently, ROI selection is performed manually, which introduces subjectivity, inconsistency and a lack of reproducibility. Previous studies have shown strong correlations between spatial molecular patterns and histological features, suggesting that readily available and cost-effective histology images can be leveraged to guide spatial omics experiments. Here we present Smart Spatial omics (S2-omics), an end-to-end workflow that automatically selects ROIs from histology images with the goal of maximizing molecular information content in the ROIs. Through comprehensive evaluations across multiple spatial omics platforms and tissue types, we demonstrate that S2-omics enables systematic and reproducible ROI selection and enhances the robustness and impact of downstream biological discovery.
    DOI:  https://doi.org/10.1038/s41556-025-01811-w
  37. bioRxiv. 2025 Oct 30. pii: 2025.10.29.685328. [Epub ahead of print]
    Chronic sensing of host-derived lipids is an all-in-one signal that primes and activates NLRP3.
    Océane Dufies, Marco Di Gioia, Roberto Spreafico, Piao J Tan, James R Springstead, Sean A Prell, Junning Case, Ce Gao, Kevin Wei, Hao Wu, Ivan Zanoni.
      Activation of the NLRP3 inflammasome leads to the production of bioactive interleukin (IL)-1β fostering atherosclerosis. The current dogma is that NLRP3 must be first primed by microbial stimuli, known as pathogen-associated molecular patterns (PAMPs), and then activated by either microbial or host-derived inflammatory cues. The mechanism that controls NLRP3 functioning in the context of non-communicable diseases lacking overt microbial infections remains debated. Here, we show that chronic exposure to atherosclerosis-associated oxidized phospholipids (oxPLs) simultaneously primes and activates NLRP3 independently of microbial cues. Mechanistically, chronic exposure to host-derived oxPLs activate the transcription factor NRF2, which is necessary and sufficient to prime and activate NLRP3 in a PAMP-independent manner. NRF2 chronic activation drives oxidized mitochondrial DNA to activate NLRP3. Ex vivo analyses of atherosclerotic plaques in mice and humans identify a population of monocytes-derived macrophages which activates NRF2 and expresses IL-1β. Overall, our data point to oxPL-dependent NRF2 activation as an all-in-one signal necessary and sufficient to prime and activate NLRP3, sustaining atherogenesis.
    DOI:  https://doi.org/10.1101/2025.10.29.685328
  38. Nat Genet. 2025 Nov 27.
    Single-cell 3D architecture maps the drivers of lung adenocarcinoma.
    Guido Barzaghi, Aristotelis Tsirigos.
      
    DOI:  https://doi.org/10.1038/s41588-025-02414-9
  39. Autophagy. 2025 Nov 28.
    NAD+ restores proteostasis through splicing-dependent autophagy.
    Ruixue Ai, Evandro F Fang.
      Autophagy preserves neuronal integrity by clearing damaged proteins and organelles, but its efficiency declines with aging and neurodegeneration. Depletion of the oxidized form of nicotinamide adenine dinucleotide (NAD+) is a hallmark of this decline, yet how metabolic restoration enhances autophagic control has remained obscure. Meanwhile, alternative RNA splicing errors accumulate in aging brains, compromising proteostasis. Here, we identify a metabolic - transcriptional mechanism linking NAD+ metabolism to autophagic proteostasis through the NAD+ -EVA1C axis. Cross-species analyses in C. elegans, mice, and human samples reveal that NAD+ supplementation corrects hundreds of age- or Alzheimer-associated splicing errors, notably restoring balanced expression of EVA1C isoforms. Loss of EVA1C impairs the memory and proteostatic benefits of NAD+, underscoring its essential role in neuronal resilience. Mechanistically, NAD+ rebalances EVA1C isoforms that interact with chaperones BAG1 and HSPA/HSP70, reinforcing their network to facilitate chaperone-assisted selective autophagy and proteasomal degradation of misfolded proteins such as MAPT/tau. Thus, NAD+ restoration coordinates RNA splicing fidelity with downstream proteostatic systems, establishing a metabolic - transcriptional checkpoint for neuronal quality control. This finding expands the paradigm of autophagy regulation, positioning metabolic splice-switching as a crucial mechanism to maintain proteostasis and suggesting new strategies to combat aging-related neurodegenerative diseases.
    Keywords:  Aging; NAD+ precursors; alzheimer disease; machine learning; rna splicing; tauopathy
    DOI:  https://doi.org/10.1080/15548627.2025.2596679
  40. Nat Commun. 2025 Nov 27.
    Lifting regenerative barriers promotes epithelial cell fate plasticity supporting lineage conversion.
    Maria T Bejar, Paula Jimenez-Gomez, Ilias Moutsopoulos, Harikrishnan Ajith, Bartomeu Colom, Jamie McGinn, Seungmin Han, Greta Skrupskelyte, Fernando J Calero-Nieto, Berthold Göttgens, Irina I Mohorianu, Benjamin D Simons, Maria P Alcolea.
      The ability of adult epithelial cells to rewire their cell fate programme in response to injury has emerged as a new paradigm in stem cell biology. This plasticity supersedes the concept of strict stem cell hierarchies, granting cells access to a wider repertoire of fate choices. Yet, in order to prevent a disordered cellular response, this process must be finely regulated. Here we investigate the little-known regulatory processes that restrict fate permissibility in adult cells, and keep plasticity in check. Using a 3D regenerative culture system, that enables co-culturing epithelium and stroma of different origins, we demonstrate that oesophageal cells exposed to the ectopic signals of the dermis are capable of switching their identity towards skin. Lineage tracing experiments and histological analysis, however, reveal that the oesophageal-to-skin lineage conversion process is highly inefficient, pointing to the existence of barriers limiting cell fate re-specification. Single-cell RNA sequencing capturing the temporality of this process shows that cells transitioning towards skin identity resist the natural progression towards tissue maturation by remaining in a persistent regenerative state marked by a particularly strong hypoxic signature. Gain and loss of function experiments demonstrate that the HIF1a-SOX9 axis acts as a key modulator of epithelial cell fate plasticity, restricting changes in identity during tissue regeneration. Taken together, our results reveal the existence of lineage conversion barriers that must be resolved for cells to respond to signals instructing alternative fate choices, shedding light on the principles underlying the full regenerative capacity of adult epithelial cells.
    DOI:  https://doi.org/10.1038/s41467-025-66446-9
  41. bioRxiv. 2025 Oct 15. pii: 2025.10.15.682658. [Epub ahead of print]
    Propionate metabolism dysregulation promotes drug-tolerant persister cell survival in non-small cell lung cancer.
    Bobak Parang, Liron Yoffe, Rabia Khan, Zhongchi Li, Michal J Nagiec, Eric E Gardner, Yiwey Shieh, Rachel S Heise, Ashish Saxena, Nasser Altorki, John Blenis.
      Recent studies show that genetic sequencing can not fully explain drug resistance in non-small cell lung cancer (NSCLC), suggesting undiscovered non-genetic mechanisms that can enable cancer cell survival. Propionate metabolism is the pathway by which odd-chain fatty acids, branched chain amino acids, and cholesterol are metabolized. We have previously shown that methylmalonic acid (MMA), a byproduct of propionate metabolism that accumulates when the pathway is disrupted, can activate epithelial-to-mesenchymal transition (EMT) in cell lines. But the clinical significance of propionate metabolism in cancer patients is not known. Here we show, for the first time, that propionate metabolism is dysregulated in patients with non-small cell lung cancer. MMA is elevated in lung tumors and in the serum of patients with metastatic NSCLC. Metabolism of cobalamin associated B (MMAB), a key regulatory gene of propionate metabolism, is downregulated in NSCLC and drug-tolerant persister cells, leading to MMA accumulation and EMT activation. We show that restoring expression of MMAB in NSCLC enhances targeted therapy and suppresses TGFB signaling. These findings reveal propionate metabolism dysregulation as a non-genetic mechanism of drug resistance and highlight propionate metabolism as a potential therapeutic target.
    DOI:  https://doi.org/10.1101/2025.10.15.682658
  42. medRxiv. 2025 Oct 17. pii: 2025.10.15.25338094. [Epub ahead of print]
    Electron microscopy visualization of cell-free mitochondrial DNA-containing extracellular vesicles in human plasma, serum, and saliva.
    Alexandra Volos, Soah Grace Franklin, Jeremy Michelson, Shannon Rausser, Jonathan R Brestoff, Martin Picard.
      Human biofluids contain cell-free mitochondrial DNA (cf-mtDNA) and extracellular mitochondria (ex-Mito), creating the challenge of defining their origins, destinations, mechanisms of regulation, and purposes. To expand our understanding of cf-mtDNA biology, we present a descriptive electron microscopy analysis of circulating particles from cf-mtDNA-enriched plasma (citrate, heparin, and EDTA), serum (red and gold top), and saliva collected from ten healthy people (5 females, 5 males, mean age 44.9 years). Ex-mito and extracellular vesicles (EVs) were isolated by centrifugation followed by size-exclusion chromatography, imaged by transmission electron microscopy, and morphometrically analyzed. In parallel, cf-mtDNA was quantified in each biofluid. The resulting catalog of the most common circulating particles in plasma, serum, and saliva show that circulating double-membrane extracellular particles- consistent with mitochondrial ultrastructure-are present across human biofluids, along with EVs and other particle types. Combining imaging with cf-mtDNA quantification, we show that individuals with higher plasma cf-mtDNA concentrations tend to contain more double-membrane, ex-Mito-like particles. These preliminary results challenge the notion that, under normal conditions, the majority of cf-mtDNA exists as naked and potentially pro-inflammatory forms. Instead, these results are consistent with the concept of mitochondria transfer or signaling between cells and tissues. The image inventory provided here expands our knowledge of cell-free mitochondrial biology and provides a resource to inform biofluid selection and technical considerations in future studies quantifying ex-Mito and cf-mtDNA.
    DOI:  https://doi.org/10.1101/2025.10.15.25338094
  43. Cell Rep. 2025 Nov 21. pii: S2211-1247(25)01270-7. [Epub ahead of print]44(12): 116499
    MITF, TFEB, and TFE3 drive distinct adaptive gene expression programs and immune infiltration in melanoma.
    Diogo Dias, Erica Oliveira, Román Martí-Díaz, Sarah Andrews, Ana Chocarro-Calvo, Alice Bellini, Laura Mosteo, Yurena Vivas García, Jagat Chauhan, Linxin Li, José Manuel García-Martinez, José Neptuno Rodriguez-López, Silvya Stuchi Maria-Engler, Colin Kenny, Javier Martínez-Useros, Custodia García-Jiménez, Luis Sanchez-Del-Campo, Pakavarin Louphrasitthiphol, Colin R Goding.
      Cells can contain multiple related transcription factors targeting the same sequences, leading to potential regulatory cooperativity, redundancy, competition, or temporally regulated factor exchange. Yet, the differential biological functions of co-targeting transcription factors are poorly understood. In melanoma, three highly related transcription factors are co-expressed: the mammalian target of rapamycin complex 1 (mTORC1)-regulated TFEB and TFE3 (both key effectors of a wide range of metabolic and microenvironmental cues assumed to perform similar functions) and the microphthalmia-associated transcription factor (MITF), which controls melanoma phenotypic identity. Here, we reveal the functional specialization of MITF, TFE3, and TFEB and their impact on melanoma progression. Notably, although all bind the same sequences, each regulates different and frequently opposing gene expression programs to coordinate differentiation, metabolism, and protein synthesis and qualitatively and quantitatively impacts tumor immune infiltration. The results uncover a hierarchical cascade whereby microenvironmental stresses, including glucose limitation, lead MITF, TFEB, and TFE3 to drive distinct biologically important transcription programs that underpin phenotypic transitions in cancer.
    Keywords:  CP: cancer; CP: genomics; MITF; TFE3; TFEB; melanoma; melanoma gene regulation; tumor immune infiltration
    DOI:  https://doi.org/10.1016/j.celrep.2025.116499
  44. Nat Commun. 2025 Nov 28.
    Mechanical confinement induces ferroptosis through mitochondrial dysfunction.
    Fang Zhou, Robert J Ju, Chenlu Kang, Jiayi Li, Ao Yang, Alexandre Libert, Yujie Sun, Ling Liang, Youwei Ai, Xiaoqing Hu, Samantha J Stehbens, Congying Wu.
      Cells in highly crowded environments are exposed to fluctuating mechanical forces. While cells can activate the cortical migration machinery to escape from undesirable compressive stress, the consequence to less motile cells and of prolonged extensive confinement is yet to be uncovered. Here, we demonstrate that nuclear deformation generated by axial confinement triggers a specific form of regulated cell death - ferroptosis. We show that axial confinement is sensed by the nucleus and results in Drp1-dependent mitochondrial fragmentation and mitochondrial ROS accumulation. Meanwhile, we detect cPLA2 translocation to mitochondria. These mitochondrial ROS accumulation and arachidonic acid production concertedly lead to lipid peroxidation and evoke ferroptosis. Interestingly, we find in osteoarthritis, a disease intimately associated with mechanical overloading and inflammation, characteristics of confinement-induced ferroptosis including mitochondrial localization of cPLA2 and high ROS. Together, our findings unveil a pivotal role of cell nucleus and mitochondria in linking mechanical confinement with cell death, highlighting the orchestration of Drp1 and cPLA2 in confinement-induced ferroptosis.
    DOI:  https://doi.org/10.1038/s41467-025-66353-z
  45. Nat Aging. 2025 Nov 26.
    Iron homeostasis and cell clonality drive cancer-associated intestinal DNA methylation drift in aging.
    Anna Krepelova, Mahdi Rasa, Francesco Annunziata, Jing Lu, Chiara Giannuzzi, Omid Omrani, Elisabeth Wyart, Paolo Ettore Porporato, Ihab Ansari, Dor Bilenko, Yehudit Bergman, Francesco Neri.
      Epigenetic drift is a key feature of aging and is associated with age-related diseases including cancer, yet the underlying molecular mechanisms remain unclear. Here, by analyzing DNA methylation and gene expression data from healthy and cancerous human colon samples, we identify an aging and colon cancer-associated DNA methylation (DNAm) drift. We find evidence that this drift is conserved in the mouse intestinal epithelium, where we demonstrate its origin within intestinal stem cells and identify its cell-intrinsic and non-mitotic characteristics, finding that its expansion is regulated via crypt clonality and fission. Mechanistically, we find that this drift is driven by age-related inflammation and reduced Wnt signaling, which dysregulate iron metabolism and impair TET activity. Despite CpG-level heterogeneity, we find that DNAm changes are consistent at the gene level, suggesting potential functionality. Our findings shed light on the epigenetic mechanisms of aging and provide a mechanistic basis for the hypermethylation observed in cancer.
    DOI:  https://doi.org/10.1038/s43587-025-01021-x
  46. Nature. 2025 Nov 24.
    MAPK-driven epithelial cell plasticity drives colorectal cancer therapeutic resistance.
    Mark White, Megan L Mills, Laura M Millett, Kathryn Gilroy, Yourae Hong, Lucas B Zeiger, Rosalin J Simpson, Shania M Corry, Amelia Ligeza, Tamsin R M Lannagan, Susanti Susanti, Rachel A Ridgway, Ayse S Yazgili, Lucile Grzesiak, Raheleh Amirkhah, Catriona A Ford, Nikola Vlahov, Hannah Tovell, Leah Officer-Jones, Catherine Ficken, Rachel Pennie, Arafath K Najumudeen, Alexander Raven, Nadia Nasreddin, Ekansh Chauhan, Andrew S Papanastasiou, Colin Nixon, Vivienne Morrison, Rene Jackstadt, Janet S Graham, Crispin J Miller, Sarah J Ross, Simon T Barry, Valeria Pavet, Richard H Wilson, John Le Quesne, Philip D Dunne, Sabine Tejpar, Simon Leedham, Andrew D Campbell, Owen J Sansom.
      The colorectal epithelium is rapidly renewing, with remarkable capacity to regenerate following injury. In colorectal cancer (CRC), this regenerative capacity can be co-opted to drive epithelial plasticity. While oncogenic MAPK signalling in CRC is common, with frequent mutations of both KRAS (40-50%) and BRAF (10%)1, inhibition of this pathway typically drives resistance clinically. Given the development of KRAS inhibitors, and licensing of BRAF inhibitor combinations2-4, we have interrogated key mechanisms of resistance to these agents in advanced preclinical CRC models. We show that oncogenic MAPK signalling induces epithelial state changes in vivo, driving adoption of a regenerative/revival stem like population, while inhibition leads to rapid transcriptional remodeling of both Kras- and Braf-mutant tumours, favoring a Wnt-associated, canonical stem phenotype. This drives acute therapeutic resistance in Kras- and delayed resistance in Braf-driven models. Importantly, where plasticity is restrained, such as in early metastatic disease, or through targeting ligand-dependent Wnt-pathway Rnf43 mutations, marked therapeutic responses are observed. This explains the super response to BRAF+EGFR targeted therapies previously observed in a BRAF/RNF43 co-mutant patient population, highlighting the criticality of cellular plasticity in therapeutic response. Together, our data provides clear insight into the mechanisms underpinning resistance to MAPK targeted therapies in CRC. Moreover, strategies that aim to corral stem cell fate, restrict epithelial plasticity or intervene when tumours lack heterogeneity may improve therapeutic efficacy of these agents.
    DOI:  https://doi.org/10.1038/s41586-025-09916-w
  47. bioRxiv. 2025 Oct 24. pii: 2025.10.23.683531. [Epub ahead of print]
    Targeting serine dehydratase supports amino acid homeostasis and skin repair.
    Emeline Joulia, Ethan L Ashley, Patrick Tseng, Citlalic Arechiga, Yuqiong Liang, Aurélie Laguerre, Maureen L Ruchhoeft, Joseph Rainaldi, Michal K Handzlik, Regis J Fallon, Hyun Young Kim, Prashant Mali, David A Brenner, Tatiana Kisseleva, Ye Zheng, Marin L Gantner, Christian M Metallo.
      Serine and glycine are altered in patients with metabolic disorders, and this dysregulation can lead to diverse pathologies 1-6 . Modulation of serine levels via diet can influence relevant phenotypes in mouse models of metabolic syndrome 7,8 . Here we identify serine dehydratase (Sds), a gluconeogenic hepatic enzyme involved in serine and threonine catabolism, as a key regulator of systemic serine and sphingolipid metabolism. We show that SDS is expressed and active in human liver tissue. Furthermore, Sds abundance strongly correlates with hepatic serine. This enzyme is highly active in BKS-db/db mice, which show amino acid alterations reminiscent of type 2 diabetes. Hepatic Sds overexpression increases serine and threonine degradation and promotes the accumulation of toxic 1-deoxysphingolipids (doxSLs). Conversely, Sds deletion dramatically increases systemic serine, glycine, and threonine while altering canonical and non-canonical sphingolipids. Finally, Sds deletion in BKS-db/db mice reduces skin doxSLs and accelerates wound healing. Our results demonstrate that Sds constrains serine levels in circulation and suggest therapeutic approaches for targeting this enzyme to improve chronic disorders.
    DOI:  https://doi.org/10.1101/2025.10.23.683531
  48. Nat Cell Biol. 2025 Nov 24.
    Polyamines sustain epithelial regeneration in aged intestines by modulating protein homeostasis.
    Alberto Minetti, Omid Omrani, Christiane Brenner, Feyza Cansiz, Shinya Imada, Jonas Rösler, Saleh Khawaled, Gabriele Allies, Sven W Meckelmann, Nadja Gebert, Ivonne Heinze, Norman Rahnis, Jing Lu, Katrin Spengler, Mahdi Rasa, Emilio Cirri, Regine Heller, Ömer Yilmaz, Alpaslan Tasdogan, Francesco Neri, Alessandro Ori.
      Ageing dampens the regenerative potential of intestinal epithelium across species including humans, yet the underlying causes remain elusive. Here we characterized the temporal dynamics of regeneration following injury induced by 5-fluorouracil, a commonly used chemotherapeutic agent, using proteomic and metabolomic profiling of intestinal tissues together with functional assays. The comparison of regeneration dynamics in mice of different ages revealed the emergence of proteostasis stress and increased levels of polyamines following injury exclusively in old epithelia. We show that delayed regeneration is an intrinsic feature of aged epithelial cells that display reduced protein synthesis and the accumulation of ubiquitylated proteins. The inhibition of the polyamine pathway in vivo further delays regeneration in old mice, whereas its activation by dietary intervention or supplementation of polyamines is sufficient to enhance the regenerative capacity of aged intestines. Our findings highlight the promising epithelial targets for interventions aimed at tackling the decline in tissue repair mechanisms associated with ageing.
    DOI:  https://doi.org/10.1038/s41556-025-01804-9
  49. Nat Commun. 2025 Nov 26.
    Very long-chain fatty acids drive 1-deoxySphingolipid toxicity.
    Adam Majcher, Gergely Karsai, Elkhan Yusifov, Martina Schaettin, Ermanno Malagola, Peter Horvath, Jinmei Li, Sofía Rodriguez-Gallardo, Kuniyoshi Shimizu, Gai Zhibo, Raghvendra Dubey, Tim Peterson, Takeshi Harayama, Thorsten Hornemann.
      1-Deoxysphingolipids (1-deoxySLs) are atypical sphingolipids formed when serine palmitoyltransferase incorporates L-alanine instead of L-serine. Elevated 1-deoxySLs are associated with hereditary sensory neuropathy type 1 and diabetic neuropathy, but the molecular basis of their toxicity remains unclear. Here we show that toxicity is mediated by very long-chain (VLC) 1-deoxy-dihydroceramides (1-deoxyDHCer), particularly nervonyl-1-deoxyDHCer (m18:0/24:1) and lignoceryl-1-deoxyDHCer (m18:0/24:0). Using a CRISPR interference screen, we identify ELOVL1 and CERS2 as essential enzymes driving the formation of these toxic species. Genetic modulation or pharmacological inhibition of ELOVL1 prevents VLC 1-deoxyDHCer accumulation, rescuing the toxicity in cellular and neuronal models. Mechanistic studies reveal that m18:0/24:1 disrupts mitochondrial integrity and induces the mitochondrial permeability transition pore formation and BAX activation, leading to cell death. These findings establish a direct link between 1-deoxySL chemical structure and cytotoxicity and highlight ELOVL1 inhibition as a potential therapeutic strategy for 1-deoxySL-associated diseases.
    DOI:  https://doi.org/10.1038/s41467-025-66687-8
  50. bioRxiv. 2025 Nov 01. pii: 2025.10.31.685804. [Epub ahead of print]
    ER-to-Golgi Trafficking is a Nutrient-Sensitive Checkpoint Linking Glucose Starvation to Cell Surface Remodeling.
    Joung Hyuck Joo, William Kasberg, Spencer Douglas, Uwemedimo Udoh, Alexandre Carisey, James Messing, Yong-Dong Wang, Shilpa Narina, Shondra M Pruett-Miller, Myriam Labelle, Jennifer Lippincott-Schwartz, Chi-Lun Chang, Mondira Kundu.
      Cancer cells adapt to nutrient stress by remodeling the repertoire of proteins on their surface, enabling survival and progression under starvation conditions. However, the molecular mechanisms by which nutrient cues reshape the cell surface proteome to influence cell behavior remain largely unresolved. Here, we show that acute glucose starvation, but not amino acid deprivation or mTOR inhibition, selectively impairs ER-to-Golgi export of specific cargoes, such as E-cadherin, in a SEC24C-dependent manner. Quantitative cell surface proteomics reveal that glucose deprivation remodels the cell surface proteome, notably reducing surface expression of key adhesion molecules. This nutrient-sensitive reprogramming enhances cell migration in vitro and promotes metastasis in vivo . Mechanistically, we show that AMPK and ULK1 signaling orchestrate this process independent of autophagy, with ULK1-mediated phosphorylation of SEC31A driving SEC24C-dependent COPII reorganization. These findings establish ER-to-Golgi trafficking as a nutrient-sensitive regulatory node that links metabolic stress to cell surface remodeling and metastatic potential.
    DOI:  https://doi.org/10.1101/2025.10.31.685804
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