bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2025–09–28
67 papers selected by
Christian Frezza, Universität zu Köln
  1. Ribonucleotide incorporation into mitochondrial DNA drives inflammation.
  2. Mitochondria expel tainted DNA - spurring age-related inflammation.
  3. A consensus guide to preclinical indirect calorimetry experiments.
  4. Charcot-Marie-Tooth type 2A variants of mitofusin 2 sensitize cells to apoptotic cell death.
  5. The nuclear pore complex connects energy sensing to transcriptional plasticity in longevity.
  6. Cholesterol fuels microglia in chronic stroke.
  7. TRPML1 signaling at lysosomes-mitochondria nexus drives triple-negative breast cancer mitophagy, metabolic reprogramming and chemoresistance.
  8. A single-cell and spatial genomics atlas of human skin fibroblasts reveals shared disease-related fibroblast subtypes across tissues.
  9. Mitochondrial uncoupling, energy substrate utilization, and brown adipose tissue as therapeutic targets in cancer.
  10. Purine nucleotides are competitive inhibitors of apo-GOT1.
  11. Molecular Cell Biology of Apoptosis in Health and Disease.
  12. Sperm meet the elevated energy demands to attain fertilization competence by increasing flux through aldolase.
  13. Deciphering the MYCN-driven metabolic microenvironment of neuroblastoma.
  14. Convergent pathways of reductive mitochondrial evolution characterised with hypercubic inference.
  15. Reprogramming neuroblastoma by diet-enhanced polyamine depletion.
  16. Mevalonate Biosynthesis is a Metabolic Vulnerability of Gemcitabine-resistant Pancreatic Cancer.
  17. Sensing within: Mitochondrial inside-out signal transduction.
  18. A non-apoptotic caspase-8-meteorin pathway in hepatocytes promotes MASH fibrosis.
  19. Age-related remodeling of the sialoglycans dampens murine CD8+ T cell function.
  20. Ubiquitin precursor with C-terminal extension promotes proteostasis and longevity.
  21. Tissue injury leads to the accumulation of somatic mtDNA mutations.
  22. Cholesterol metabolic reprogramming mediates microglia-induced chronic neuroinflammation and hinders neurorestoration following stroke.
  23. Mitochondrial Ca2+ in Cancer Growth and Metabolism.
  24. Aging in mice alters regionally enriched striatal astrocytes.
  25. SMAD4 induces opposite effects on metastatic growth from pancreatic tumors depending on the organ of residence.
  26. RIPK1 autophosphorylation at S161 mediates cell death and inflammation.
  27. The interplay of the cGAS-STING pathway with the lysosome.
  28. FAK modulates glioblastoma stem cell energetics via regulation of glycolysis and glutamine oxidation.
  29. CD8+ T cell stressors converge on shared metabolic-epigenetic networks.
  30. Organelle-specific signaling of cGAS-STING.
  31. Brown adipose tissue activity impacts systemic lactate clearance in male mice.
  32. CDK12 regulates cellular metabolism to promote glioblastoma growth.
  33. The Biodiversity Cell Atlas: mapping the tree of life at cellular resolution.
  34. Ageing-related decline of translation as a consequence of transcription dysregulation.
  35. Herbal terpenoids activate autophagy and mitophagy through modulation of bioenergetics and protect from metabolic stress, sarcopenia and epigenetic aging.
  36. HEBP2-governed glutamine competition between tumor and macrophages dictates immunotherapy efficacy in triple-negative breast cancer.
  37. Stearoyl-CoA Desaturases regulate stem and progenitor cell metabolism and function in response to nutrient abundance.
  38. Cryo-mtscATAC-seq for single-cell mitochondrial DNA genotyping and clonal tracing in archived human tissues.
  39. Oncogenic driver mutations underlie the spatial tumour immune landscape of non-small cell lung cancer.
  40. Dietary α-Ketoglutarate delays lung adenocarcinoma in females and modulates TBX5-associated transcriptional programs and the immune microenvironment.
  41. Shooting for the stars: caspase-8-meteorin in MASH and fibrosis.
  42. Exploiting dysregulated iron homeostasis to eradicate persistent high-grade serous ovarian cancer.
  43. Taurine transport is a critical modulator of ionic fluxes during NLRP3 inflammasome activation.
  44. Hierarchical metabolic engineering for rewiring cellular metabolism.
  45. Hypoxia exposure fine-tunes mitochondrial function in sea turtle cells.
  46. The Neurolipid Atlas: a lipidomics resource for neurodegenerative diseases.
  47. V-ATPase-dependent induction of selective autophagy.
  48. Cardiac adaptation to endurance exercise training requires suppression of GDF15 via PGC-1α.
  49. Visions of the future of molecular cell biology.
  50. Gliomas phenocopy an inborn error of metabolism to drive neuronal activity and tumor growth.
  51. CRISPR screens identify the ATPase VCP as a druggable therapeutic vulnerability in cholangiocarcinoma.
  52. Enhancing Late-Life Survival and Mobility via Mitohormesis by Reducing Mitochondrial Calcium Levels.
  53. Independent serum metabolomics approaches identify disrupted glutamic acid and serine metabolism in Parkinson's disease patients.
  54. The Supersulfide-Producing Activity of Rat Cystathionine γ-Lyase Is Irreversibly Inactivated by L-CysNO but Not by L-GSNO.
  55. Cross-Organ Mitochondrial Communication in Stress and Disease.
  56. Oxaloacetate sensing promotes innate immune antiviral defence against influenza virus infection.
  57. EML4-ALK variant-specific genetic interactions shape lung tumorigenesis.
  58. An injury-associated lobular microniche is associated with the classical tumor cell phenotype in pancreatic cancer.
  59. Slc7a7 licenses macrophage glutaminolysis for restorative functions in atherosclerosis.
  60. Lysosomes signal through the epigenome to regulate longevity across generations.
  61. Targeting hepatocyte-specific SLC2A8 blocks hepatic steatosis and dissociates TCA cycle flux inhibition from glutamine anaplerosis.
  62. Clonal tracing of blood stem cells across mouse and human lifespans.
  63. Lysosomal LRRC8 complex impacts lysosomal pH, morphology, and systemic glucose metabolism.
  64. Astrocytes functionally integrate multiple synapses via specialized leaflet domains.
  65. The DREAM complex links somatic mutation, lifespan, and disease.
  66. Microbial metabolic pathways guide response to immune checkpoint blockade therapy.
  67. Remote control of AMPK via extracellular adenosine controls tissue growth.
  1. Nature. 2025 Sep 24.
    Ribonucleotide incorporation into mitochondrial DNA drives inflammation.
    Amir Bahat, Dusanka Milenkovic, Eileen Cors, Mabel Barnett, Sadig Niftullayev, Athanasios Katsalifis, Marc Schwill, Petra Kirschner, Thomas MacVicar, Patrick Giavalisco, Louise Jenninger, Anders R Clausen, Vincent Paupe, Julien Prudent, Nils-Göran Larsson, Manuel Rogg, Christoph Schell, Isabella Muylaert, Erik Lekholm, Hendrik Nolte, Maria Falkenberg, Thomas Langer.
      Metabolic dysregulation can lead to inflammatory responses1,2. Imbalanced nucleotide synthesis triggers the release of mitochondrial DNA (mtDNA) to the cytosol and an innate immune response through cGAS-STING signalling3. However, how nucleotide deficiency drives mtDNA-dependent inflammation has not been elucidated. Here we show that nucleotide imbalance leads to an increased misincorporation of ribonucleotides into mtDNA during age-dependent renal inflammation in a mouse model lacking the mitochondrial exonuclease MGME14, in various tissues of aged mice and in cells lacking the mitochondrial i-AAA protease YME1L. Similarly, reduced deoxyribonucleotide synthesis increases the ribonucleotide content of mtDNA in cell-cycle-arrested senescent cells. This leads to mtDNA release into the cytosol, cGAS-STING activation and the mtDNA-dependent senescence-associated secretory phenotype (SASP), which can be suppressed by exogenously added deoxyribonucleosides. Our results highlight the sensitivity of mtDNA to aberrant ribonucleotide incorporation and show that imbalanced nucleotide metabolism leads to age- and mtDNA-dependent inflammatory responses and SASP in senescence.
    DOI:  https://doi.org/10.1038/s41586-025-09541-7
  2. Nature. 2025 Sep 26.
    Mitochondria expel tainted DNA - spurring age-related inflammation.
    Gemma Conroy.
      
    Keywords:  Ageing; Cell biology; Genetics; Metabolism
    DOI:  https://doi.org/10.1038/d41586-025-03064-x
  3. Nat Metab. 2025 Sep;7(9): 1765-1780
    A consensus guide to preclinical indirect calorimetry experiments.
    International Indirect Calorimetry Consensus Committee (IICCC)
      Understanding the complex factors influencing mammalian metabolism and body weight homeostasis is a long-standing challenge requiring knowledge of energy intake, absorption and expenditure. Using measurements of respiratory gas exchange, indirect calorimetry can provide non-invasive estimates of whole-body energy expenditure. However, inconsistent measurement units and flawed data normalization methods have slowed progress in this field. This guide aims to establish consensus standards to unify indirect calorimetry experiments and their analysis for more consistent, meaningful and reproducible results. By establishing community-driven standards, we hope to facilitate data comparison across research datasets. This advance will allow the creation of an in-depth, machine-readable data repository built on shared standards. This overdue initiative stands to markedly improve the accuracy and depth of efforts to interrogate mammalian metabolism. Data sharing according to established best practices will also accelerate the translation of basic findings into clinical applications for metabolic diseases afflicting global populations.
    DOI:  https://doi.org/10.1038/s42255-025-01360-4
  4. J Cell Sci. 2025 Sep 15. pii: jcs263691. [Epub ahead of print]138(18):
    Charcot-Marie-Tooth type 2A variants of mitofusin 2 sensitize cells to apoptotic cell death.
    Mariana Joaquim, Maria-Bianca Bulimaga, Marie A Mohn, Solenn Plouzennec, Leon Osinski, Selver Altin, Esther Mahabir, Arnaud Chevrollier, Mafalda Escobar-Henriques.
      The neuropathy Charcot-Marie-Tooth (CMT) is an incurable disease with a lack of genotype-phenotype correlation. Variants of the mitochondrial protein mitofusin 2 (MFN2), a large GTPase that mediates mitochondrial fusion, are responsible for the subtype CMT type 2A (CMT2A). Interestingly, beyond membrane remodelling, additional roles of MFN2 have been identified, expanding the possibilities to explore its involvement in disease. Here, we investigated how cellular functions of MFN2 are associated with variants present in individuals with CMT2A. Using human cellular models, we observed that cells expressing CMT2A variants display increased endoplasmic reticulum (ER) stress and apoptotic cell death. Increased cleavage of PARP1, caspase 9, caspase 7 and caspase 3, alongside BAX translocation to mitochondria, pointed towards effects on intrinsic apoptosis. Moreover, although disruption of fusion and fission dynamics per se did not correlate with cell death markers, expression of MFN1 or MFN2 alleviated the apoptosis markers of CMT2A variant cell lines. In sum, our results highlight excessive cell death by intrinsic apoptosis as a potential target in CMT2A disease.
    Keywords:  Apoptosis; CMT2A; Cell death; Charcot–Marie–Tooth; Fusion; MFN2; Mitochondria
    DOI:  https://doi.org/10.1242/jcs.263691
  5. Mol Cell. 2025 Sep 23. pii: S1097-2765(25)00741-5. [Epub ahead of print]
    The nuclear pore complex connects energy sensing to transcriptional plasticity in longevity.
    Yifei Zhou, Fasih M Ahsan, Sinclair W Emans, Alexander A Soukas.
      As the only gateway governing nucleocytoplasmic transport, the nuclear pore complex (NPC) maintains fundamental cellular processes and deteriorates with age. However, the study of age-related roles of single NPC components remains challenging owing to the complexity of NPC composition. Here, we demonstrate that the central energy sensor, AMP-activated protein kinase (AMPK), post-translationally regulates the abundance of the nucleoporin NPP-16/NUP50 in response to nutrient availability and energetic stress. In turn, NPP-16/NUP50 promotes transcriptional activation of lipid catabolism to extend the lifespan of Caenorhabditis elegans independently of its role in nuclear transport. Rather, the intrinsically disordered region (IDR) of NPP-16/NUP50, through direct interaction with the transcriptional machinery, transactivates the promoters of catabolic genes. Remarkably, elevated NPP-16/NUP50 levels are sufficient to promote longevity and metabolic stress defenses. AMPK-NUP50 signaling is conserved in humans, indicating that bridging energy sensing to metabolic adaptation is an ancient role of this signaling axis.
    Keywords:  aging; energy sensing; intrinsically disordered regions; lipid metabolism; longevity; metabolic rewiring; nuclear pore complex; nucleoporins; transcriptional regulation
    DOI:  https://doi.org/10.1016/j.molcel.2025.08.035
  6. Nat Metab. 2025 Sep 23.
    Cholesterol fuels microglia in chronic stroke.
    Stefano Pluchino, Cory M Willis.
      
    DOI:  https://doi.org/10.1038/s42255-025-01362-2
  7. bioRxiv. 2025 Sep 16. pii: 2025.09.11.675705. [Epub ahead of print]
    TRPML1 signaling at lysosomes-mitochondria nexus drives triple-negative breast cancer mitophagy, metabolic reprogramming and chemoresistance.
    Alia K Syeda, Shekoufeh Almasi, J Cory Benson, Barry E Kennedy, Ryan M Yoast, Scott M Emrich, Logan Slade, Shanmugasundaram Pakkiriswami, Vishnu V Vijayan, Shashi Gujar, Thomas Pulinilkunnil, Mohamed Trebak, Yassine El Hiani.
      Inter-organelle signaling mechanisms, particularly those at the lysosomes-mitochondria interface, are critical for cancer cell metabolism, mitophagy and survival. However, the incomplete understanding of these mechanisms has limited the development of effective therapies, especially for triple-negative breast cancers (TNBC). Here, we demonstrate the lysosomal Ca²⁺-release channel TRPML1 as a master regulator of mitochondrial bioenergetics in TNBC cells. TRPML1 knockdown (ML1-KD) in TNBC cells selectively compromises mitochondrial respiration, reprograms cell metabolism, and induces mitochondrial fragmentation without impacting non-cancerous cells. Mitochondria of ML1-KD TNBC cells sequester around the endoplasmic reticulum (ER), increasing mitochondria-ER contact sites at the expense of mitochondria-lysosomes contacts. Mechanistically, ML1-KD reduces lysosomal acidification, thus hindering autophagic flux and completion of autophagy. ML1-KD inhibits TFEB-mediated mitophagy and oxidative defense mechanisms while causing mitochondrial Ca 2+ overload, further impairing mitochondrial function. These alterations render ML1-KD TNBC cells highly sensitive to doxorubicin and paclitaxel at low doses that are typically ineffective on their own. Together, our findings establish TRPML1 as a critical inter-organelle regulator and highlight its potential as a therapeutic target to exploit the metabolic vulnerabilities of TNBC cells.
    DOI:  https://doi.org/10.1101/2025.09.11.675705
  8. Nat Immunol. 2025 Sep 24.
    A single-cell and spatial genomics atlas of human skin fibroblasts reveals shared disease-related fibroblast subtypes across tissues.
    Lloyd Steele, Bayanne Olabi, Kenny Roberts, Pavel V Mazin, Simon Koplev, Catherine Tudor, Benjamin Rumney, Chloe Admane, Treasa Jiang, Donovan Correa-Gallegos, Keerthi Priya Chakala, Aljes Binkevich, Nusayhah Hudaa Gopee, Alexander Predeus, Martin Prete, Elena Winheim, Karl Annusver, Agnes Forsthuber, Luc Francis, Sophie Frech, Clarisse Ganier, Thomas Layton, Yingzi Liu, Hao Yuan, Johann E Gudjonsson, Beate M Lichtenberger, Satveer Mahil, Jagdeep Nanchahal, Edel A O'Toole, Maksim V Plikus, Yuval Rinkevich, Emanuel Rognoni, Catherine H Smith, Sarah A Teichmann, Maria Kasper, April R Foster, Mohammad Lotfollahi, Muzlifah Haniffa.
      Fibroblasts sculpt the architecture and cellular microenvironments of various tissues. Here we constructed a spatially resolved atlas of human skin fibroblasts from healthy skin and 23 skin diseases, with comparison to 14 cross-tissue diseases. We define six major skin fibroblast subtypes in health and three that are disease-specific. We characterize two fibroblast subtypes further as they are conserved across tissues and are immune-related. The first, F3: fibroblastic reticular cell-like fibroblast (CCL19+CD74+HLA-DRA+), is a fibroblastic reticular cell-like subtype that is predicted to maintain the superficial perivascular immune niche. The second, F6: inflammatory myofibroblasts (IL11+MMP1+CXCL8+IL7R+), characterizes early human skin wounds, inflammatory diseases with scarring risk and cancer. F6: inflammatory myofibroblasts were predicted to recruit neutrophils, monocytes and B cells across multiple human tissues. Our study provides a harmonized nomenclature for skin fibroblasts in health and disease, contextualized with cross-tissue findings and clinical skin disease profiles.
    DOI:  https://doi.org/10.1038/s41590-025-02267-8
  9. NPJ Metab Health Dis. 2025 Sep 22. 3(1): 37
    Mitochondrial uncoupling, energy substrate utilization, and brown adipose tissue as therapeutic targets in cancer.
    Maurizio Ragni, Chiara Ruocco, Enzo Nisoli.
      Mitochondria play a central role in regulating cellular energy metabolism, redox homeostasis, and biosynthesis. Mitochondrial uncoupling, through the alteration in the permeability of the inner mitochondrial membrane (IMM) to the leak of protons without adenosine triphosphate (ATP) synthesis, regulates thermogenesis, glucose and lipid metabolism, and reactive oxygen species (ROS) generation. In brown adipose tissue (BAT), proton leak via uncoupling protein 1 (UCP1) is essential for thermogenesis and has been shown to improve systemic glucose homeostasis, and recent studies indicate that BAT activation can also suppress tumor growth by competing with cancer cells for glucose. Several small-molecule mitochondrial uncouplers have demonstrated anticancer effects in preclinical models, although endogenous UCPs-particularly UCP2-are often upregulated in tumors, where they may support tumor growth by buffering ROS and increasing metabolic flexibility. These seemingly contradictory observations highlight the context-dependent effects of mitochondrial uncoupling in cancer. Here, we review current understanding of mitochondrial uncoupling mechanisms, the roles of UCP isoforms, and the metabolic interplay between BAT, cancer cells, and the tumor microenvironment, with a focus on therapeutic implications.
    DOI:  https://doi.org/10.1038/s44324-025-00080-3
  10. bioRxiv. 2025 Sep 17. pii: 2025.09.17.676921. [Epub ahead of print]
    Purine nucleotides are competitive inhibitors of apo-GOT1.
    Narges Pourmandi, Arjun Jha, Kendall Muzzarelli, Hyunsu Lee, Zahra Assar, Gordon J Murray, Joseph H LaPointe, Thomas P Roddy, Gianna Medeiros, Shomit Sengupta, Costas A Lyssiotis.
      The malate-aspartate shuttle (MAS) plays a key role in cellular metabolism by transferring electrons from cytosolic NADH into the mitochondrial matrix, thereby supporting oxidative phosphorylation, in addition to the citric acid cycle and amino acid metabolism. Here, we sought to identify allosteric regulatory metabolites of the MAS enzymes cytosolic glutamic-oxaloacetic transaminase 1 (GOT1) and mitochondrial GOT2. Using the Atavistik Metabolite Proprietary Screening platform, we identified several structurally similar metabolite hits- most notably deoxyadenosine monophosphate (dAMP) and deoxyguanosine monophosphate (dGMP)-as candidate interactors with GOT1. Follow-up thermal shift assays revealed that dAMP and dGMP destabilize GOT1 in the absence of its cofactor, pyridoxal 5'-phosphate (PLP), but have no destabilizing effect when PLP is present. Crystallographic analysis confirmed that dAMP and dGMP bind in the PLP pocket of GOT1, suggesting competitive binding. Together, these results indicate that nucleotide metabolites can interact with GOT1, offering potential insights into MAS regulation and therapeutic intervention strategies.
    DOI:  https://doi.org/10.1101/2025.09.17.676921
  11. Adv Exp Med Biol. 2025 ;1481 1-28
    Molecular Cell Biology of Apoptosis in Health and Disease.
    Asma Ahmed, Stephen W G Tait.
      Apoptotic cell death is fundamental to the life of multicellular organisms, making central contributions to processes ranging from embryonic development to tissue homeostasis. Two distinct apoptosis pathways have been defined: extrinsic apoptosis and mitochondrial apoptosis. As we discuss, apoptosis is an evolutionary conserved process that is, unsurprisingly, tightly regulated. Inhibition of apoptosis can promote cancer, whereas inappropriate apoptosis has been associated with various neurodegenerative diseases. At its core, apoptosis is initiated and executed by proteases called caspases that, once activated, rapidly dismantle dying cells, ensuring that apoptosis is immunologically silent. In this chapter, we discuss the molecular mechanisms of apoptosis and its evolutionary conservation. Secondly, we highlight the emerging concept that apoptosis signalling can be engaged at non-lethal levels with diverse biological effects. Finally, we provide an overview of how apoptosis can impact health and disease, discussing ways in which apoptosis can be therapeutically targeted.
    Keywords:  BCL-2 protein family; Caspases; Cell death; Extrinsic apoptosis; MOMP; Mitochondrial apoptosis
    DOI:  https://doi.org/10.1007/978-3-031-92785-0_1
  12. Proc Natl Acad Sci U S A. 2025 Sep 30. 122(39): e2506417122
    Sperm meet the elevated energy demands to attain fertilization competence by increasing flux through aldolase.
    Sara Violante, Aye Kyaw, Lana Kouatli, Kaushik Paladugu, Lauren Apostolakis, Macy Jenks, Amy Johnson, Ryan D Sheldon, Douglas Whitten, Anthony L Schilmiller, Pablo E Visconti, Justin R Cross, Lonny R Levin, Jochen Buck, Melanie Balbach.
      Prior to ejaculation, mammalian sperm are stored in the epididymis in a "resting" metabolic state. Upon ejaculation, sperm must alter their metabolism to generate the energy needed to support the motility and maturation process known as capacitation to reach and fertilize the oocyte. How sperm regulate the capacitation-induced increase in carbon flux is unknown. Here, we use 13C stable isotope labeling in mouse sperm isolated from the cauda epididymis to follow glucose metabolism through central carbon metabolic network before and after sperm activation. As sperm transition from resting to highly activated states, they boost energy yield by increasing flux through glycolysis at the expense of the pentose phosphate pathway. Increased glycolytic activity seems to be achieved via capacitation-induced stimulation of flux through aldolase. In the mitochondria-containing midpiece, glycolytically generated pyruvate feeds the tricarboxylic acid (TCA) cycle to further maximize energy yield via oxidative phosphorylation. In the mitochondria-free principal piece of the flagellum, pyruvate produced from glycolysis is reduced to lactate by lactate dehydrogenase, which also serves to regenerate oxidized nicotinamide adenine dinucleotide (NAD+) ensuring a sufficient supply to support glycolysis. The resultant lactate is at least partially secreted. Finally, we find evidence that there is an as yet unknown endogenous source of energy in sperm, feeding the upregulation of TCA cycle intermediates. These studies provide the most complete picture of the metabolic shift which occurs in capacitating mouse sperm in glucose.
    Keywords:  aldolase; glycolysis; metabolic reprogramming; sperm; stable isotope labeling
    DOI:  https://doi.org/10.1073/pnas.2506417122
  13. Trends Mol Med. 2025 Sep 23. pii: S1471-4914(25)00193-5. [Epub ahead of print]
    Deciphering the MYCN-driven metabolic microenvironment of neuroblastoma.
    Amber Wolf, Davide Leardini, Lingzhi Li, Riccardo Masetti, Costas A Lyssiotis, Eveline Barbieri.
      Oncogenic MYCN drives aggressive disease in many cancers including neuroblastoma (NB). Metabolic reprogramming is essential to support cancer cell homeostasis and survival under nutrient- and oxygen-deprived conditions. MYCN directly reprograms many nodes of tumor-intrinsic metabolism, which have significant repercussions on the cells of the tumor microenvironment (TME), resulting in complex intercellular metabolic circuits that contribute to the immunosuppressive microenvironment of NB. These metabolic circuits are also regulated by the organismal and cellular circadian clock and host diet to further impact the TME and NB oncogenesis. This review discusses the mechanisms by which MYCN regulates the metabolic crosstalk between tumor, TME, and host, and provides evidence that therapeutic targeting of MYCN-reprogrammed metabolism can improve patient outcomes.
    Keywords:  MYCN; metabolism; neuroblastoma; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.molmed.2025.08.005
  14. J Evol Biol. 2025 Sep 24. pii: voaf111. [Epub ahead of print]
    Convergent pathways of reductive mitochondrial evolution characterised with hypercubic inference.
    Robert C Glastad, Iain G Johnston.
      For a striking example of mitochondrial behaviour beyond ATP generation, consider mitochondrion-related organelles (MROs). Hydrogenosomes, mitosomes, and other reduced mitochondrial forms have evolved through the loss of physical and functional features, from individual electron transport chain (ETC) complexes to oxidative phosphorylaytion and the very ability to produce ATP (and further). Reduction of mitochondria is a dramatic example of convergent evolution, occuring in every eukaryotic kingdom and many parallel times. Here, we use hypercubic inference, a class of methods from evolutionary accumulation modelling (EvAM), to explore the pathways of convergent mitochondrial reduction across eukaryotes. We find that most MRO diversity can be explained by small variations on two distinct pathways, starting with either the loss of Complex I or the loss of Complexes III/IV or TCA cycle steps, which tend to proceed over different characteristic timescales. We show that different clades, including ciliates and apicomplexans, reflect particular instances of these pathways. Using metabolic modelling, we connect the structure of these evolutionary pathways to the metabolic impact of the changes involved, suggesting a plausible explanation for the dramatically convergent nature of reductive evolution. We discuss this approach in connection with related theory on the genetic and functional reduction of mitochondria across organisms.
    Keywords:  convergent evolution; eukaryotic evolution; metabolism; mitochondria; mitochondrion-related organelles; reductive evolution
    DOI:  https://doi.org/10.1093/jeb/voaf111
  15. Nature. 2025 Sep 24.
    Reprogramming neuroblastoma by diet-enhanced polyamine depletion.
    Sarah Cherkaoui, Christina S Turn, Yuan Yuan, Wenyun Lu, Lifeng Yang, Matthew J McBride, Caroline Eigenmann, George E Allen, Olesya O Panasenko, Lu Zhang, Annette Vu, Kangning Liu, Yimei Li, Om H Gandhi, Lea F Surrey, Sandra D Kienast, Sebastian A Leidel, Michael Wierer, Eileen White, Joshua D Rabinowitz, Michael D Hogarty, Raphael J Morscher.
      Neuroblastoma is a highly lethal childhood tumour derived from differentiation-arrested neural crest cells1,2. Like all cancers, its growth is fuelled by metabolites obtained from either circulation or local biosynthesis3,4. Neuroblastomas depend on local polyamine biosynthesis, and the inhibitor difluoromethylornithine has shown clinical activity5. Here we show that such inhibition can be augmented by dietary restriction of upstream amino acid substrates, leading to disruption of oncogenic protein translation, tumour differentiation and profound survival gains in the Th-MYCN mouse model. Specifically, an arginine- and proline-free diet decreases the amount of the polyamine precursor ornithine and enhances tumour polyamine depletion by difluoromethylornithine. This polyamine depletion causes ribosome stalling, unexpectedly specifically at codons with adenosine in the third position. Such codons are selectively enriched in cell cycle genes and low in neuronal differentiation genes. Thus, impaired translation of these codons, induced by combined dietary and pharmacological intervention, favours a pro-differentiation proteome. These results suggest that the genes of specific cellular programmes have evolved hallmark codon usage preferences that enable coherent translational rewiring in response to metabolic stresses, and that this process can be targeted to activate differentiation of paediatric cancers.
    DOI:  https://doi.org/10.1038/s41586-025-09564-0
  16. bioRxiv. 2025 Sep 20. pii: 2025.09.19.675739. [Epub ahead of print]
    Mevalonate Biosynthesis is a Metabolic Vulnerability of Gemcitabine-resistant Pancreatic Cancer.
    Alica K Beutel, Sabrina Calderon, Ethan Nghiem, Kevin Gulay, Leonor P S Santana, Eleni Zimmer, Rima Singh, Cecily Anaraki, Natalie Yousefian, Chantal Allgöwer, Gregory Tong, Cameron Geller, Alina Chao, Dennis Juarez, Thomas Seufferlein, Alexander Muir, Cholsoon Jang, Aimee L Edinger, Marcus Seldin, Thomas F Martinez, Alexander Kleger, David K Chang, Herve Tiriac, Jennifer B Valerin, David A Fruman, Christopher J Halbrook.
      Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with a devastating prognosis. Gemcitabine, a pyrimidine anti-metabolite, is a cornerstone in PDAC therapy. However, resistance remains a major hurdle in clinical care. Resistance can arise from microenvironmental metabolites or through direct metabolic reprogramming of pancreatic cancer cells. Here, we generated PDAC models of acquired gemcitabine resistance to determine the relationship between these mechanisms. We observed that physiological levels of exogenous pyrimidines have a diminished ability to impact gemcitabine response in PDAC cells with acquired resistance. This occurs as the metabolic reprogramming of PDAC cells in response to gemcitabine treatment forces a suppression of the pyrimidine salvage pathway. Importantly, this metabolic rewiring renders gemcitabine-resistant PDAC cells highly susceptible to inhibition of the rate limiting enzyme of the mevalonate biosynthesis pathway, 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), using statins. Notably, statin treatment inhibits the growth of gemcitabine-resistant tumors in immunocompetent mouse models. Through metabolite rescue experiments, we identified geranylgeranyl pyrophosphate as the critical metabolite lost during statin treatment, resulting in reduced protein geranylation in PDAC cells. Finally, as downregulation of the HMGCR is gradually acquired during gemcitabine resistance, we observed that HMGCR expression predicts patient response to gemcitabine. Collectively, these data demonstrate that the mevalonate biosynthesis pathway represents a promising therapeutic target in gemcitabine resistance and may serve as a biomarker to stratify treatment selection in PDAC patients.
    DOI:  https://doi.org/10.1101/2025.09.19.675739
  17. Cell Chem Biol. 2025 Sep 25. pii: S2451-9456(25)00266-1. [Epub ahead of print]
    Sensing within: Mitochondrial inside-out signal transduction.
    Alva G Sainz, Furkan E Oflaz, Xinnan Wang.
      The prevailing theory on the origins of mitochondria proposes that they were once independent organisms. Though symbiotically integrated into eukaryotic cells, they have retained a striking degree of autonomy. This self-governance manifests as the capacity to sense internal metabolic, ionic, and redox states and transduce these into signals that modulate cellular function-a process we refer to as mitochondrial inside-out signaling. These mitochondria-initiated signaling mechanisms are crucial for bioenergetic homeostasis of all cells, including neurons. Unlike conventional outside-in signaling, these mitochondria-initiated signals stem from within the organelle and propagate outward, tuning cytosolic signaling pathways, nuclear transcriptional programs, and neuronal behavior. In this review, we provide mechanistic insights into this distinct and underappreciated signaling modality, discussing how internal mitochondrial conditions are sensed and transmitted to the cytosol and how these signaling events influence mitochondrial and cellular health with a focus on their implications for neuronal physiology and disease vulnerability.
    Keywords:  mitochondrial inside-out signaling; mitochondrial retrograde signaling; neurodegeneration; neuroscience; signal transduction
    DOI:  https://doi.org/10.1016/j.chembiol.2025.09.001
  18. Nat Metab. 2025 Sep 26.
    A non-apoptotic caspase-8-meteorin pathway in hepatocytes promotes MASH fibrosis.
    Xiaobo Wang, Mary P Moore, Hongxue Shi, Yang Xiao, Jiayu Zhang, Lanuza A P Faccioli, Zhiping Hu, Shareef Khalid, Danish Saleheen, Dwayne G Stupack, Tatiana Kisseleva, Alejandro Soto Gutierrez, Mitchell A Lazar, Ira Tabas.
      Metabolic-dysfunction-associated steatohepatitis (MASH) is the leading cause of chronic liver disease, but an incomplete understanding of MASH-induced liver fibrosis has limited therapeutic options. Here we show that hepatocyte caspase-8 drives MASH fibrosis through an apoptosis-independent mechanism. Hepatic caspase-8 expression correlates with liver fibrosis in both human and experimental MASH, and hepatocyte-specific caspase-8 deletion in male mice with MASH suppressed liver fibrosis and hepatic stellate cell (HSC) activation without affecting hepatocyte apoptosis. Mechanistic studies showed that a caspase-8-YY1 pathway in hepatocytes induces secretory meteorin (Metrn), which activates HSCs via a c-Kit-STAT3 pathway. Meteorin expression was increased in human and male mouse MASH livers and decreased by deletion of hepatocyte caspase-8 in MASH mice and human and mouse primary hepatocytes. Genetic restoration of hepatocyte meteorin in hepatocyte-caspase-8-deleted MASH mice restored HSC activation and liver fibrosis while silencing hepatocyte meteorin lowered liver fibrosis. These findings reveal a therapeutically targetable pathway promoting MASH fibrosis involving a non-apoptotic function of caspase-8 and a newly discovered HSC activator, meteorin.
    DOI:  https://doi.org/10.1038/s42255-025-01355-1
  19. Sci Adv. 2025 Sep 26. 11(39): eadw6755
    Age-related remodeling of the sialoglycans dampens murine CD8+ T cell function.
    Hanlin Zhang, C Kimberly Tsui, Jesse Garcia Castillo, Esther Jeong Yoon Kim, Audrey Evangelista, HengChen Liu, Larry K Joe, Nicholas Twells, Ellen A Robey, Lara K Mahal, Michel DuPage, Andrew Dillin.
      Glycans regulate cellular function, yet how aging affects the glycocalyx remains unclear. Here, we investigate changes in immune cell glycocalyx with age and find that α2,6-linked sialic acid, a glycan epitope associated with inhibitory signaling, is down-regulated in T cells from old animals. This reduction is tightly correlated with age-associated accumulation of effector T cells, which have little to no α2,6-linked sialic acid. To understand how α2,6-linked sialic acid affects T cell physiology, we generated a mouse model with T cell-specific deletion of sialyltransferase gene St6gal1. The lack of α2,6-linked sialic acid leads to reduced responsiveness in naïve T cells, leading to impaired T cell responses against Listeria monocytogenes infection and tumor growth. PD-1 pathway blockade partially restores St6gal1-deficient T cells' ability to control tumor growth. These findings suggest that α2,6-linked sialic acid is critical for maintaining long-term T cell responsiveness, and its loss may contribute to decreased T cell function with age.
    DOI:  https://doi.org/10.1126/sciadv.adw6755
  20. Mol Cell. 2025 Sep 23. pii: S1097-2765(25)00737-3. [Epub ahead of print]
    Ubiquitin precursor with C-terminal extension promotes proteostasis and longevity.
    Selver Altin, Tânia Simões, Christina Behrendt, Vincent Anton, Dennis Domke, Kai Mayor Völtzke, Rajesh Kumar, Hendrik Nolte, Thomas Hermanns, Nahal Brocke-Ahmadinejad, Katja Bendrin, Marcel Zimmermann, Reinhard Büttner, Natascia Ventura, Marcus Krüger, R Jürgen Dohmen, Kay Hofmann, Thorsten Hoppe, Andreas S Reichert, Mafalda Escobar-Henriques.
      Ubiquitin is a conserved modifier regulating the stability and function of numerous target proteins. In all eukaryotes, polyubiquitin precursors are generated and processed into ubiquitin monomers. The final ubiquitin unit always contains a C-terminal extension, but its physiological significance is unknown. Here, we show that C-terminally extended ubiquitin, termed CxUb, is essential for stress resistance, mitophagy, and longevity in Saccharomyces cerevisiae and Caenorhabditis elegans. CxUb forms ubiquitin chains and binds to a previously undescribed region within the ubiquitin chain-elongating E4 enzyme Ufd2, which also functions during stress and aging. Ufd2 recognizes CxUb and conjugates it to substrate proteins, triggering their degradation. By contrast, CxUb is not required for basal housekeeping functions of the ubiquitin-proteasome system. These data suggest that the CxUb encodes a functionally unique ubiquitin form, specialized for proteostasis defects, expanding the code of post-translational modification processes.
    Keywords:  CxUb; E4; Ufd2; aging; mitochondria; mitofusin; mitophagy; proteostasis; stress; ubiquitin
    DOI:  https://doi.org/10.1016/j.molcel.2025.08.032
  21. Nat Rev Mol Cell Biol. 2025 Sep 22.
    Tissue injury leads to the accumulation of somatic mtDNA mutations.
    Kim Baumann.
      
    DOI:  https://doi.org/10.1038/s41580-025-00904-6
  22. Nat Metab. 2025 Sep 23.
    Cholesterol metabolic reprogramming mediates microglia-induced chronic neuroinflammation and hinders neurorestoration following stroke.
    Qiang Zhao, Jiajian Li, Jingjing Feng, Xin Wang, Yueting Liu, Fei Wang, Liang Liu, Bingxue Jin, Ming Lin, Ya-Chao Wang, Xiuhua Guo, Jieli Chen, Junwei Hao.
      Chronic neuroinflammation is a major obstacle to post-stroke recovery, yet the underlying mechanisms, particularly the link between prolonged microglial activation and cholesterol metabolism, are not fully known. Here we show that ischaemic injury induces persistent microglial activation that perpetuates chronic inflammation, leading to microglial cholesterol accumulation and metabolic reprogramming. Using single-cell RNA sequencing, we identified distinct stroke-associated foamy microglia clusters characterized by extensive reprogramming of cholesterol metabolism. Furthermore, direct intracerebral free cholesterol or cholesterol crystal infusion recapitulated sustained microglial activation, directly linking aberrant cholesterol metabolism to prolonged neuroinflammatory responses. Therapeutically, we demonstrate that reducing microglial cholesterol overload through genetic or pharmacological activation of CYP46A1 in male mice promotes white matter repair and functional recovery. These findings highlight microglial cholesterol metabolism as a key driver of post-stroke inflammation, offering therapeutic strategies targeting cholesterol metabolism to mitigate long-term brain damage and promote neurorestoration, potentially improving stroke-related disability outcomes.
    DOI:  https://doi.org/10.1038/s42255-025-01379-7
  23. J Cell Physiol. 2025 Sep;240(9): e70093
    Mitochondrial Ca2+ in Cancer Growth and Metabolism.
    Jillian S Weissenrieder, J Kevin Foskett.
      Cancer is a leading cause of death in developed countries, despite many breakthroughs in targeted small molecule and immunotherapeutic interventions. A deeper understanding of the characteristics and processes that underlie malignancy will enable us to develop more effective therapeutic options to improve patient outcomes. One particular area of interest is in cancer cell metabolism. Even as early as the 1920s, Otto Warburg recognized dysregulated metabolism in cancerous cells. Altered metabolism may provide targetable nutrient dependencies for further clinical development, either by nutrient restriction or pathway inhibition. More recently, researchers have observed an increasingly strong linkage between altered mitochondrial Ca2+ homeostasis and tumor cell metabolism, with strong implications for therapeutic targeting. In this review, we summarize the literature surrounding mitochondrial Ca2+ homeostasis, metabolism, and cancer, as well as providing a discussion of the potential for mitochondrial Ca2+ modulation as an anticancer therapeutic modality.
    Keywords:  Ca2+ signaling; cancer; metabolism; mitochondria
    DOI:  https://doi.org/10.1002/jcp.70093
  24. Nat Commun. 2025 Sep 26. 16(1): 8496
    Aging in mice alters regionally enriched striatal astrocytes.
    Kay E Linker, Violeta Duran-Laforet, Matthias Ollivier, Xinzhu Yu, Dorothy P Schafer, Baljit S Khakh.
      Aging affects multiple organs and within the brain drives distinct molecular changes across different cell types. The striatum encodes motor behaviors that decline with age, but our understanding of how cells within the striatum change remains incomplete. Using single-cell RNA sequencing from young and aged mice we identify molecularly distinct astrocyte subtypes. We show that astrocytes change significantly with age, exhibiting downregulation of genes, reduced diversity, and a shift to more homogenous inflammatory transcriptomic profiles. By exploring where striatal astrocyte subtypes are located with single-cell resolution, we map astrocytes enriched in dorsal, medial, and ventral striatum. Age increases inflammatory marker transcripts in dorsal striatal astrocytes, which display greater age-related changes than ventral striatal astrocytes. We impute molecular interactions between astrocytes and neurons and find that age particularly reduced interactions related to Nrxn2. Our data show that aging alters regionally enriched striatal astrocytes asymmetrically, with dorsal striatal astrocytes exhibiting greater age-related molecular changes.
    DOI:  https://doi.org/10.1038/s41467-025-63429-8
  25. Nat Cancer. 2025 Sep 25.
    SMAD4 induces opposite effects on metastatic growth from pancreatic tumors depending on the organ of residence.
    Kaloyan M Tsanov, Francisco M Barriga, Yu-Jui Ho, Direna Alonso-Curbelo, Geulah Livshits, Sha Tian, Richard P Koche, Timour Baslan, Janelle Simon, Alexandra N Wuest, José Reyes, Jin Park, Wei Luan, John E Wilkinson, Umesh Bhanot, Jordana Ray-Kirton, Ignas Masilionis, Nevenka Dimitrova, Christine A Iacobuzio-Donahue, Ronan Chaligné, Dana Pe'er, Joan Massagué, Scott W Lowe.
      The role of driver gene mutations in sustaining tumor growth at metastatic sites is poorly understood. SMAD4 inactivation is a paradigm of such mutations and a hallmark of pancreatic ductal adenocarcinoma (PDAC). To determine whether metastatic tumors are dependent on SMAD4 inactivation, we developed a mouse model of PDAC that enables spatiotemporal control of Smad4 expression. While Smad4 inactivation in the premalignant pancreas facilitated the formation of primary tumors, Smad4 reactivation in metastatic disease suppressed liver metastases but promoted lung metastases. These divergent effects were underpinned by organ-biased differences in the tumor cells' chromatin state that emerged in the premalignant pancreas and were distinguished by the dominance of KLF4 versus RUNX1 transcription factors. Our results show how epigenetic states favored by the organ of residence can influence the output of driver mutations in metastatic tumors, which has implications for interpreting tumor genetics and therapeutically targeting metastatic disease.
    DOI:  https://doi.org/10.1038/s43018-025-01047-5
  26. J Exp Med. 2025 Dec 01. pii: e20250279. [Epub ahead of print]222(12):
    RIPK1 autophosphorylation at S161 mediates cell death and inflammation.
    Lioba Koerner, Xiaoming Li, Eveline Silnov, Lucie Laurien, Manolis Pasparakis.
      RIPK1 regulates cell death and inflammation and has been implicated in the pathogenesis of inflammatory diseases. RIPK1 autophosphorylation promotes cell death induction; however, the underlying mechanisms and the role of specific autophosphorylation sites remain elusive. Using knock-in mouse models, here we show that S161 autophosphorylation has a critical physiological function in RIPK1-mediated cell death and inflammation. S161N substitution partially suppressed RIPK1-mediated catalytic activity and cell death induction but was sufficient to prevent skin inflammation induced by keratinocyte necroptosis or apoptosis in relevant mouse models. Combined S161N and S166A mutations synergized to prevent RIPK1-mediated cell death more efficiently than the single site mutations, revealing functional redundancy. Moreover, phosphomimetic S161E mutation could overcome the necroptosis-inhibitory effect of S166A mutation, revealing that S161 phosphorylation is sufficient for necroptosis induction. Collectively, a functional interplay of S161 and S166 phosphorylation events regulates RIPK1-dependent cell death and inflammation.
    DOI:  https://doi.org/10.1084/jem.20250279
  27. Trends Biochem Sci. 2025 Sep 23. pii: S0968-0004(25)00218-X. [Epub ahead of print]
    The interplay of the cGAS-STING pathway with the lysosome.
    Yinfeng Xu, Wei Wan.
      The cyclic GMP-AMP (cGAMP) synthase (cGAS)-stimulator of interferon (IFN) genes (STING) pathway detects cytoplasmic DNA and elicits the innate immune response. Several recent studies show that cGAS-STING signaling not only terminates at the lysosome but also regulates lysosomal function. Here, we discuss the interplay of the cGAS-STING pathway with the lysosome.
    Keywords:  ESCRT; STING; TFEB; cGAS; innate immunity; lysosome
    DOI:  https://doi.org/10.1016/j.tibs.2025.08.010
  28. Dis Model Mech. 2025 Sep 22. pii: dmm.052634. [Epub ahead of print]
    FAK modulates glioblastoma stem cell energetics via regulation of glycolysis and glutamine oxidation.
    Roza H A Masalmeh, John C Dawson, Virginia Alvarez Garcia, Morwenna T Muir, Roderick N Carter, Giles Hardingham, Cameron Davies, Rosina Graham, Alex von Kriegsheim, Jair Marques, Chinmayi Pednekar, Steven M Pollard, Neil O Carragher, Valerie G Brunton, Margaret C Frame.
      Glycolysis and the TCA cycle are reprogrammed in cancer cells to meet bioenergetic and biosynthetic demands, including by engagement with the extracellular matrix (ECM). However, the mechanisms by which the ECM engagement reprograms core energy metabolism is still un known. We show that the canonical cell-ECM adhesion protein FAK, and specifically its kinase activity, is driving cellular energetics. Using a stem cell model of glioblastoma, we show that FAK gene deletion simultaneously inhibits glycolysis and glutamine oxidation, increases mitochondrial fragmentation, elevates phosphorylation of the mitochondrial protein MTFR1L at S235 and triggers a mesenchymal-to-epithelial transition. These metabolic and structural changes arise through altered acto-myosin contractility as shown by phospho-myosin light chain (p-MLC S19). This can be reversed by Rho-kinase (ROCK) inhibitors revealing mechanotransduction pathway control of both mitochondrial dynamics and glutamine oxidation. FAK-dependent metabolic programming is associated with regulation of cell migration, invasive capacity and tumour growth in vivo. Our work describes a previously unrecognised FAK-ROCK axis that couples mechanical cues to the rewiring of energy metabolism, linking cell shape, mitochondrial function, and malignant behaviour.
    Keywords:  Adhesion proteins; Extracellular matrix; Glutamine oxidation; Glycolysis; Mechanical forces; Mitochondria
    DOI:  https://doi.org/10.1242/dmm.052634
  29. Trends Endocrinol Metab. 2025 Sep 22. pii: S1043-2760(25)00190-0. [Epub ahead of print]
    CD8+ T cell stressors converge on shared metabolic-epigenetic networks.
    Yangtao Shangguan, Jianxiang Wang, Ping-Chih Ho, Yingxi Xu.
      CD8+ T cells are vital for antiviral and antitumor immunity, yet in hostile microenvironments, they experience metabolic stress, leading to mitochondrial damage, metabolic dysregulation, and chromatin remodeling that cause immune dysfunction. Aging further exacerbates these processes, with intrinsic metabolic collapse and extrinsic environmental factors jointly impairing T cell immunity. Metabolites orchestrate key epigenetic modifications, shaping transcriptional programs essential for T cell differentiation and memory formation. This review explores the interconnected metabolic and epigenetic mechanisms governing CD8+ T cell fate decisions, emphasizing how mitochondrial dysfunction, metabolic inflexibility, and nutrient competition drive CD8+ T cell exhaustion, senescence, and age-associated dysfunction. Understanding these metabolic-epigenetic circuits offers novel therapeutic avenues, including metabolic reprogramming and senescence-targeted strategies, to rejuvenate immune responses and enhance immunotherapy outcomes.
    Keywords:  T cell; aging; exhaustion; metabolism; senescence
    DOI:  https://doi.org/10.1016/j.tem.2025.08.009
  30. Trends Cell Biol. 2025 Sep 19. pii: S0962-8924(25)00198-9. [Epub ahead of print]
    Organelle-specific signaling of cGAS-STING.
    Shengduo Liu, Ailian Wang, Chen Chen, Pinglong Xu.
      Innate immune sensing through cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) surveils cytosolic DNA from invading pathogens or damaged organelles and initiates a spectrum of immune responses. It is well established that upon 2'3'-cyclic GMP-AMP (cGAMP) binding, STING exits the endoplasmic reticulum (ER), traverses the Golgi to trigger interferon programs, and finally reaches lysosomes for signal resolution through degradation, revealing a tightly choreographed itinerary for cytokine-driven immunity. However, emerging studies reveal additional layers of spatiotemporal complexity: ER-resident STING tunes in messenger RNA translation and Ca2+ efflux, Golgi-localized STING functions as a proton channel that initiates H+-dependent autophagy and transcription factor EB-directed programs for organelle homeostasis, and various mechanisms for metabolic remodeling and cell fate determination. This review synthesizes emerging organelle-specific mechanisms of cGAS-STING, delineates their roles in physiology and disease, and discusses how an organelle-centric perspective may inform selective, context-sensitive immunotherapies.
    Keywords:  cGAS–STING; cellular function; innate immunity; organelle; signaling mechanism; trafficking
    DOI:  https://doi.org/10.1016/j.tcb.2025.08.007
  31. J Physiol. 2025 Sep 22.
    Brown adipose tissue activity impacts systemic lactate clearance in male mice.
    Rémi Montané, Yannick Jeanson, Damien Lagarde, Spiro Khoury, Léana Porcher-Bibes, Jean Nakhle, Marie Sallese, Mélissa Parny, Isabelle Raymond-Letron, Emma Huard, Raphael Alves de Souza, Anne Galinier, Luc Pellerin, Anne-Karine Bouzier Sore, Jean-Philippe Pradère, Cédric Moro, Louis Casteilla, Armelle Yart, Cédric Dray, Jean-Charles Portais, Isabelle Ader, Audrey Carriere.
      Non-shivering thermogenesis in brown adipose tissue (BAT) is linked to metabolic health. Yet, how its activity states impact on systemic metabolism and in particular on lactate, a highly abundant metabolite increasingly recognized as a critical player in energy metabolism, remains unresolved. The goal of this study was to investigate the impact of BAT activity on lactate metabolism at the whole organism level. To activate or inactivate non-shivering thermogenesis in BAT, we housed C57Bl6/J male mice at 4, 21 and 30°C and then conducted lactate tolerance tests. In mice exposed to cold exposure (4°C), systemic lactate clearance was elevated. In contrast, clearance of systemic lactate was poor in mice housed under thermoneutral conditions (30°C) that inactivate BAT thermogenesis, as well as in mice deficient for the mitochondrial uncoupling protein-1. To better understand lactate metabolic fate during the clearance phase, in vivo stable isotope tracing experiments with labelled 13C-lactate and analyses by mass spectrometry were performed. These experiments revealed that lactate contribution to gluconeogenesis was increased under cold exposure while its contribution to the tricarboxylic acid cycle was reduced in BAT under thermoneutrality. Remarkably, we also identified that lactate entered a pyruvate cycling process that was highly active in BAT, and repressed at thermoneutrality. Our study shows that inactivation of non-shivering thermogenesis decreased systemic lactate clearance, concomitantly with changes in metabolic fate of lactate in BAT and in gluconeogenic organs, in male mice. KEY POINTS: Lactate clearance is enhanced upon cold exposure and reduced at thermoneutrality. UCP1-deficient mice exhibit impaired lactate clearance. Oxidative utilization of lactate in brown fat is decreased at thermoneutrality. Prolonged cold exposure increases lactate contribution to gluconeogenesis. Lactate enters a highly active pyruvate cycling process in brown adipose tissue.
    Keywords:  brown adipose tissue; cold exposure; isotopic tracing experiments; lactate metabolism; pyruvate cycling; thermoneutrality
    DOI:  https://doi.org/10.1113/JP288871
  32. JCI Insight. 2025 Sep 25. pii: e190780. [Epub ahead of print]
    CDK12 regulates cellular metabolism to promote glioblastoma growth.
    Jeong-Yeon Mun, Chang Shu, Qiuqiang Gao, Zhe Zhu, Hasan O Akman, Mike-Andrew Westhoff, Georg Karpel-Massler, Markus D Siegelin.
      Glioblastoma IDH-wildtype is the most common and aggressive primary brain tumor in adults, with poor prognosis despite current therapies. To identify new therapeutic vulnerabilities, we investigated the role of CDK12, a transcription-associated cyclin-dependent kinase, in glioblastoma. Genetic or pharmacologic inactivation of CDK12 impaired tumor growth in patientderived xenograft (PDX) models and enhanced the efficacy of temozolomide. Metabolic profiling using extracellular flux analysis and stable isotope tracing with U-¹³C-glucose and U-¹³Cglutamine showed that CDK12 inhibition disrupted mitochondrial respiration, resulting in energy depletion and apoptotic cell death characterized by caspase activation and Noxa induction. Mechanistically, we identified a direct interaction between CDK12 and GSK3β. CDK12 inhibition activated GSK3β, leading to downregulation of PPARD, a transcriptional regulator of oxidative metabolism. This CDK12-GSK3β-PPARD axis was required for glioblastoma cell proliferation and metabolic homeostasis. In vivo, CDK12 inhibition significantly extended survival without overt toxicity and induced complete tumor regression in a subset of animals. Strikingly, combined CDK12 inhibition and temozolomide treatment led to complete tumor eradication in all animals tested. These findings establish CDK12 as a key regulator of glioblastoma metabolism and survival, and provide strong preclinical rationale for its therapeutic targeting in combination with standard-of-care treatments.
    Keywords:  Apoptosis; Brain cancer; Metabolism; Oncogenes; Oncology
    DOI:  https://doi.org/10.1172/jci.insight.190780
  33. Nature. 2025 Sep;645(8082): 877-885
    The Biodiversity Cell Atlas: mapping the tree of life at cellular resolution.
    Biodiversity Cell Atlas meeting participants
      Cell types are fundamental functional units that can be traced across the tree of life. Rapid advances in single-cell technologies, coupled with the phylogenetic expansion in genome sequencing, present opportunities for the molecular characterization of cells across a broad range of organisms. Despite these developments, our understanding of eukaryotic cell diversity remains limited and we are far from decoding this diversity from genome sequences. Here we introduce the Biodiversity Cell Atlas initiative, which aims to create comprehensive single-cell molecular atlases across the eukaryotic tree of life. This community effort will be phylogenetically informed, rely on high-quality genomes and use shared standards to facilitate comparisons across species. The Biodiversity Cell Atlas aspires to deepen our understanding of the evolution and diversity of life at the cellular level, encompassing gene regulatory programs, differentiation trajectories, cell-type-specific molecular profiles and inter-organismal interactions.
    DOI:  https://doi.org/10.1038/s41586-025-09312-4
  34. J R Soc Interface. 2025 Sep;22(230): 20250323
    Ageing-related decline of translation as a consequence of transcription dysregulation.
    Sebastian Pechmann.
      The ageing-related decline of translational fidelity disrupts cellular protein homeostasis, thus contributing to the onset of cancer and neurodegeneration. However, it remains unclear what alters speed and accuracy of translation at advanced age. Here, I show that the shift in translation kinetics upon ageing is systematic and a direct consequence of transcription deregulation. Computational modelling of ageing yeast and worm Riboseq data demonstrates that the loss of translational fidelity is independent of codon identity, tRNA abundances or the specificities of anticodon-codon interactions at the ribosome. Instead, large-scale transcriptional changes during ageing perturb the codon usage of the transcriptome, which at the systems level induces a dramatic remodelling and increase in ribosome collisions and stalling. Ribosome collisions in turn reduce control over translation elongation and effect an assimilation of codon translation rates. The presented results thus explain the ageing-related decline of translational fidelity, and provide important insights towards a systems-level understanding of ageing-related human diseases linked to mistranslation and protein homeostasis failure that are especially prevalent in the brain.
    Keywords:  ageing; codon usage; computational biology; stochastic modelling; translational fidelity
    DOI:  https://doi.org/10.1098/rsif.2025.0323
  35. Nat Aging. 2025 Sep 24.
    Herbal terpenoids activate autophagy and mitophagy through modulation of bioenergetics and protect from metabolic stress, sarcopenia and epigenetic aging.
    Gabriele Civiletto, Dario Brunetti, Giulia Lizzo, Kamila Muller, Guillaume E Jacot, Ioanna Daskalaki, Federico Sizzano, Minji Huh, Ivano Di Meo, Maria Nicol Colombo, José L Sanchez-Garcia, Bertrand J Bétrisey, Alix Zollinger, Patricia Lino, Christopher Neal, Anne-Laure Egesipe, Joy Richard, Myriam Chimen, Aurélie Hermant, Benjamin Brinon, Lorane Texari, Sylviane Metairon, Mohammed Adnan Qureshi, Dhaval S Patel, Siva A Vanapalli, Marco Malavolta, Arwen W Gao, Amelia Lalou, Mauro Provinciali, Fiorenza Orlando, Valeria Tiranti, Robert T Brooke, Steve Horvath, Johan Auwerx, Jerome N Feige, Philipp Gut.
      Small molecular food components contribute to the health benefits of diets rich in fruits, vegetables, herbs and spices. The cellular mechanisms by which noncaloric bioactives promote healthspan are not well understood, limiting their use in disease prevention. Here, we deploy a whole-organism, high-content screen in zebrafish to profile food-derived compounds for activation of autophagy, a cellular quality control mechanism that promotes healthy aging. We identify thymol and carvacrol as activators of autophagy and mitophagy through a transient dampening of the mitochondrial membrane potential. Chemical stabilization of thymol-induced mitochondrial depolarization blocks mitophagy activation, suggesting a mechanism originating from the mitochondrial membrane. Supplementation with thymol prevents excess liver fat accumulation in a mouse model of diet-induced obesity, improves pink-1-dependent heat stress resilience in Caenorhabditis elegans, and slows the decline of skeletal muscle performance while delaying epigenetic aging in SAMP8 mice. Thus, terpenoids from common herbs promote autophagy during aging and metabolic overload, making them attractive molecules for nutrition-based healthspan promotion.
    DOI:  https://doi.org/10.1038/s43587-025-00957-4
  36. Cell Metab. 2025 Sep 23. pii: S1550-4131(25)00382-1. [Epub ahead of print]
    HEBP2-governed glutamine competition between tumor and macrophages dictates immunotherapy efficacy in triple-negative breast cancer.
    Yi Xiao, Ying Xu, Han Wang, Fan Yang, Xiao-Hong Ding, Tong Fu, Li Chen, Xi Jin, Ya-Xin Zhao, Ying Wang, Fenfang Chen, Zhi-Ming Shao, Yi-Zhou Jiang.
      Immunotherapy demonstrates limited efficacy in triple-negative breast cancer (TNBC), influenced by intricate metabolic interactions within the tumor microenvironment. Here, we developed a single-cell RNA sequencing (scRNA-seq) immunotherapy cohort (N = 27) and a spatial transcriptomics cohort (N = 88) to elucidate metabolic crosstalk associated with therapeutic efficacy in TNBC. We illustrated that heme binding protein 2 (HEBP2)high tumor cells (featured by active glutathione metabolism) and CCL3+ macrophages (characterized by oxidative metabolism) indicated immunotherapy efficacy and were quantitatively and spatially negatively correlated. HEBP2-mediated glutamine face-off between these cell types induced this phenomenon. Mechanistically, HEBP2 disrupted FOXA1 cytoplasmic phase separation, promoting its nuclear translocation to upregulate glutathione S-transferase P1 (GSTP1) expression and glutamine consumption in tumor cells. This metabolic shift induced ferroptosis of CCL3+ macrophages, impairing the antitumor immunity. The utilization of a GSTP1 inhibitor sensitized TNBC to immunotherapy. Collectively, we delineate a tumor-macrophage metabolic checkpoint governed by the HEBP2/GSTP1 axis and pioneer single-cell-level immunometabolism as a paradigm for evaluating immunotherapeutic vulnerabilities.
    Keywords:  immunometabolic crosstalk; immunotherapy; precision immunotherapy; single-cell metabolism; triple-negative breast cancer
    DOI:  https://doi.org/10.1016/j.cmet.2025.08.009
  37. bioRxiv. 2025 Sep 20. pii: 2025.09.17.676943. [Epub ahead of print]
    Stearoyl-CoA Desaturases regulate stem and progenitor cell metabolism and function in response to nutrient abundance.
    Kübra B Akkaya-Colak, Andrea R Keller, Maria H Festing, Khushboo Gupta, James Sledziona, Ayobami Adeniyi, Omar West, Patrick Stevens, Maciej Pietrzak, Sue E Knoblaugh, Helaina Walesewicz, Dominique A Baldwin, Judith A Simcox, James Ntambi, Steven K Clinton, Maria M Mihaylova.
      Dietary components and metabolites play a critical role in regulating intestinal stem and progenitor cell function and proliferation. Here we show that Stearoyl-CoA Desaturases (SCDs), which regulate intracellular saturated to monounsaturated fatty acids ratios, are induced in response to nutrient abundance, especially in the distal intestine, and regulate intestinal homeostasis. Genetic or pharmacological inhibition of SCDs altered lipid metabolism, increased ER stress, and reduced proliferative intestinal stem and progenitor cells in intestinal organoids. These effects were largely mitigated by oleic acid supplementation. Intestinal epithelium-specific deletion of Scd1 and Scd2 led to metabolic rewiring, leading to expansion of progenitor cell populations. DSS-induced epithelial damage revealed a dependence on SCD enzymes during regeneration, accelerating epithelial damage and inflammation in intestines lacking epithelial Scd1 and Scd2 . These findings underscore key metabolic pathways and dependencies that enable intestinal stem and progenitor cells to adapt to nutrient fluctuations and support epithelial tissue regeneration following injury.
    DOI:  https://doi.org/10.1101/2025.09.17.676943
  38. bioRxiv. 2025 Sep 20. pii: 2025.09.17.675534. [Epub ahead of print]
    Cryo-mtscATAC-seq for single-cell mitochondrial DNA genotyping and clonal tracing in archived human tissues.
    Maren Salla, Benedikt Obermayer, Marie Cotta, Ekaterina Friebel, Juliana Campo-Garcia, Georgia Charalambous, Roemel Jeusep Bueno, Dustin Lieu, Patryk Dabek, Ashley Helmuth, George Tellides, Roland Assi, Katrin Bankov, Marco Lodrini, Hedwig Deubzer, Dieter Beule, Hattie Chung, Helena Radbruch, David Capper, Frank Heppner, Sarah C Starossom, Caleb A Lareau, Ilon Liu, Leif S Ludwig.
      High-throughput clonal tracing of primary human samples relies on naturally occurring barcodes, such as somatic mitochondrial DNA (mtDNA) mutations detected via single-cell ATAC-seq (mtscATAC-seq). Fresh-frozen clinical specimens preserve tissue architecture but compromise cell integrity, thereby precluding their use in multi- omic approaches such as mitochondrial genotyping at single-cell resolution. Here, we introduce Cryo-mtscATAC-seq, a broadly applicable method for diverse pathophysiological contexts to isolate nuclei with their associated mitochondria ("CryoCells") from frozen samples for high-throughput clonal analysis. We applied Cryo-mtscATAC-seq to the neurodegenerated human brain, glioblastoma (GBM), pediatric neuroblastoma, and human aorta, and implemented mitobender, a computational tool to reduce ambient mtDNA in single-cell assays. Our approach revealed regional clonal gliogenesis and microglial expansions in amyotrophic lateral sclerosis (ALS), persistence of oligodendrocyte progenitor cell (OPC)-like clones in GBM recurrence, mtDNA depth heterogeneity after neuroblastoma chemotherapy, and oligoclonal proliferation of smooth muscle cells in human aorta. In conclusion, Cryo-mtscATAC-seq broadly extends mtDNA genotyping to archival frozen specimens across tissue types, opening new avenues for investigation of cell state- informed clonality in human health and disease.
    DOI:  https://doi.org/10.1101/2025.09.17.675534
  39. Nat Commun. 2025 Sep 25. 16(1): 8402
    Oncogenic driver mutations underlie the spatial tumour immune landscape of non-small cell lung cancer.
    Saskia Hartner, Hanie Abolfathi, Morteza Rezanejad, Bridget Liu, Elham Karimi, Dakota Rogers, Mark Sorin, Samuel Doré, Lysanne Desharnais, Michèle Orain, William Enlow, Andréanne Gagné, Yuhong Wei, Yohan Bossé, Daniela F Quail, Philippe Joubert, Logan A Walsh.
      Lung adenocarcinoma (LUAD) is a molecularly diverse form of lung cancer characterized by distinct oncogenic driver mutations that influence both tumour biology and clinical outcomes. Understanding the interplay between these oncogenic drivers and the tumour microenvironment (TME) is crucial for improving therapeutic strategies and patient management. Here, we investigate the impact of driver mutations on the composition and spatial architecture of the TME in LUAD. Using imaging mass cytometry (IMC), we analyse tumour samples from 157 LUAD patients, integrating genomic and clinical data to link specific mutations with tumour characteristics. Unique patterns are associated with mutated KRAS and EGFR tumours with TP53 co-mutations, suggesting these co-mutations reshape the TME and promote resistance to tyrosine kinase inhibitors (TKIs). Overall, our findings highlight the complex interplay between oncogenic driver mutations and the TME in LUAD, underscoring the importance of integrating genomic and cellular data to understand the underlying tumour behaviour and prognosis.
    DOI:  https://doi.org/10.1038/s41467-025-63465-4
  40. bioRxiv. 2025 Sep 21. pii: 2025.09.19.677388. [Epub ahead of print]
    Dietary α-Ketoglutarate delays lung adenocarcinoma in females and modulates TBX5-associated transcriptional programs and the immune microenvironment.
    Martin Alcaraz, Aparamita Pandey, Mia Santiago, Camelia Dumitras, Leilani Pradis, Estefany Gomez, Adriana Soto, Pasquale Saggese, Bin Liu, Steven M Dubinett, Claudio Scafoglio.
      Lung adenocarcinoma (LUAD) is the most common form of lung cancer and a leading cause of cancer-related mortality, underscoring the need for new chemopreventive strategies. α-Ketoglutarate (α-KG), a tricarboxylic acid cycle metabolite and dioxygenase cofactor, links cellular metabolism to chromatin regulation. Here, we show that dietary α-KG remodels LUAD in a sex-dependent manner. In female mice, α-KG reduced tumor area, decreased repressive histone marks (H3K27me3, H3K9me3), and upregulated TBX5 and myogenesis-associated genes. In male mice, α-KG-treated male mice exhibited increased tumor area, elevated H3K27me3, and immune remodeling characterized by CD8⁺ T cell expansion and transcriptomic signatures of T cell exhaustion. Analysis of human LUAD revealed that TBX5 expression is enriched in female tumors and associated with improved survival, suggesting it may serve as a marker of favorable outcome. Together, these findings support α-KG as an epigenetic modulator with potential chemopreventive activity in lung cancer and highlight the importance of incorporating sex as a biological variable in preclinical studies.
    DOI:  https://doi.org/10.1101/2025.09.19.677388
  41. Nat Metab. 2025 Sep 26.
    Shooting for the stars: caspase-8-meteorin in MASH and fibrosis.
    Suchira Gallage, Tabea Bieler, Mathias Heikenwalder.
      
    DOI:  https://doi.org/10.1038/s42255-025-01361-3
  42. Cell Death Discov. 2025 Sep 25. 11(1): 423
    Exploiting dysregulated iron homeostasis to eradicate persistent high-grade serous ovarian cancer.
    Australian Ovarian Cancer Study Group
      Treatments for high-grade serous ovarian cancer (HGSOC) are initially effective but most invariably fail. Although they can successfully suppress the bulk of the tumour cell population, residual cancer cells can enter alternative therapy-resistant cell fates highlighted by proliferative arrest. Understanding the nature of these fates and how cells may resume uncontrolled proliferation will lead to the development of new treatments for HGSOC. In this study, we examine the response of HGSOC cells to standard of care cisplatin chemotherapy and to the RNA Polymerase I transcription inhibitor CX-5461/Pidnarulex, two drugs that elicit a potent DNA damage response and growth arrest. Here, we identify that HGSOC cells exposed to these therapies show multiple hallmarks of therapy-induced senescence (TIS) and derive a core TIS gene expression signature irrespective of genetic background or senescence trigger. Given that TIS is a potentially escapable state, we have performed a focussed drug screen to identify drugs that eradicate senescent HGSOC cells. We identify that therapy-induced senescent HGSOC cells, including those with decreased sensitivity to senolytic drugs that inhibit the pro-survival protein BCL-XL, can be eliminated using drugs that induce ferroptosis, an iron-dependent form of cell death. Mechanistically, we demonstrate that senescent HGSOC cells have altered expression of regulators of iron metabolism leading to intracellular iron overload that underpins this targetable vulnerability. Together, we highlight elevated levels of iron as a TIS biomarker in HGSOC and the potential of inducing ferroptosis to eradicate residual HGSOC cells following initial therapy.
    DOI:  https://doi.org/10.1038/s41420-025-02716-1
  43. Cell Rep. 2025 Sep 18. pii: S2211-1247(25)01088-5. [Epub ahead of print]44(10): 116317
    Taurine transport is a critical modulator of ionic fluxes during NLRP3 inflammasome activation.
    Peter Rossi-Smith, Joohee Kim, Kamil Skirlo, Trevor Ferris, Jack P Green, Cari Stek, Kristin K Huse, Paige M Mortimer, Antoni Olona, Cecilia Wieder, Raymond Moseki, Mariana Silva Dos Santos, James I MacRae, Shiranee Sriskandan, Timothy M D Ebbels, Robert J Wilkinson, Alice E Denton, Nicolas J Matheson, Paras K Anand, Graeme Meintjes, David C Thomas, Rachel P J Lai.
      Metabolic regulation is a key feature of inflammasome activation and effector function. Using metabolomic approaches, we show that downregulation of taurine metabolism is crucial for NLRP3 inflammasome activation. Following NLRP3 activation stimuli, taurine rapidly egresses to the extracellular compartment. Taurine efflux is facilitated primarily by the volume-regulated anion channel (VRAC). Loss of intracellular taurine impairs sodium-potassium ATPase pump activity, promoting ionic dysregulation and disrupting ionic fluxes. Inhibiting VRAC, or supplementation of taurine, restores the ionic balance, abrogates IL-1β release, and reduces cellular cytotoxicity in macrophages. We further demonstrate that the protective effect of taurine is diminished when sodium-potassium ATPase is inhibited, highlighting the pump's role in taurine-mediated protection. Finally, taurine metabolism is significantly associated with the development of tuberculosis-associated immune reconstitution inflammatory syndrome, a systemic hyperinflammatory condition known to be mediated by inflammasome activation. Altogether, we identified a critical metabolic pathway that modulates inflammasome activation and drives disease pathogenesis.
    Keywords:  ATPase; CP: Metabolism; inflammasome; inflammation; ion channels; ionic fluxes; metabolism; metabolomics; taurine; tuberculosis
    DOI:  https://doi.org/10.1016/j.celrep.2025.116317
  44. FEMS Microbiol Rev. 2025 Sep 27. pii: fuaf047. [Epub ahead of print]
    Hierarchical metabolic engineering for rewiring cellular metabolism.
    Tiantian Chai, Yuxuan Tao, Chunlei Zhao, Xiulai Chen.
      Metabolic engineering is a key enabling technology for rewiring cellular metabolism to enhance production of chemicals, biofuels and materials from renewable resources. However, how to make cells into efficient factories is still challenging due to its robust metabolic networks. To open this door, metabolic engineering has realized great breakthroughs through three waves of technological research and innovations, especially the third wave. To understand the third wave of metabolic engineering better, we discuss its mainstream strategies and examples of its application at five hierarchies, including part, pathway, network, genome, and cell level, and provide insights as to how to rewire cellular metabolism in the context of maximizing product titer, yield, and productivity. Finally, we highlight future perspectives on metabolic engineering for the successful development of cell factories.
    Keywords:  Cell factory; Enzyme engineering; Machine learning; Metabolic engineering; Pathway rewiring; Synthetic biology
    DOI:  https://doi.org/10.1093/femsre/fuaf047
  45. J Physiol. 2025 Sep 24.
    Hypoxia exposure fine-tunes mitochondrial function in sea turtle cells.
    B Gabriela Arango, David C Ensminger, Dianna Xing, Céline A Godard-Codding, José Pablo Vázquez-Medina.
      Sea turtles experience extreme fluctuations in oxygen levels derived from extended breath-hold diving, yet the cellular adjustments underlying hypoxia tolerance in these animals remain poorly understood. Here, we employed metabolite profiling, extracellular flux assays and microscopy analyses of the mitochondrial reticulum to investigate how primary cells derived from sea turtles and lizards cope with extended hypoxia exposure. Cells from both species proliferate in primary culture, stain positive for fibroblast markers, are metabolically active and stabilize HIF1-α when exposed to chemical or environmental hypoxia. In contrast to lizard cells, sea turtle cells exhibit a faster and more robust response to 1 h or 24 h of hypoxia exposure (0.1% O2), upregulating antioxidant pathways and optimizing oxygen use rather than relying on glycolytic metabolism. Similarly, mitochondrial reticulum architecture is maintained without apparent fragmentation during hypoxia exposure in sea turtle cells. Consistent with these observations, sea turtle mitochondria maintain better function during reoxygenation following 24 h of hypoxia exposure. These findings show that sea turtle cells undergo intrinsic metabolic adjustments to cope with extreme oxygen fluctuations, aligning with the remarkable hypoxic tolerance exhibited by these animals, which can endure up to 7 h of breath-holding underwater. KEY POINTS: Hypoxic sea turtle cells bypass the Crabtree effect and boost antioxidant defences. Hypoxia exposure fine-tunes mitochondrial function in sea turtle cells. Preserving mitochondrial architecture during hypoxia may help sea turtle cells restart respiration upon reoxygenation after extended hypoxia.
    Keywords:  cellular respiration; diving; metabolomics; oxidative stress; reptiles
    DOI:  https://doi.org/10.1113/JP288755
  46. Nat Metab. 2025 Sep 22.
    The Neurolipid Atlas: a lipidomics resource for neurodegenerative diseases.
    Femke M Feringa, Sascha J Koppes-den Hertog, Lian Y Wang, Rico J E Derks, Iris Kruijff, Lena Erlebach, Jorin Heijneman, Ricardo Miramontes, Nadine Pömpner, Niek Blomberg, Damien Olivier-Jimenez, Lill Eva Johansen, Alexander J Cammack, Ashling Giblin, Christina E Toomey, Indigo V L Rose, Hebao Yuan, Michael E Ward, Adrian M Isaacs, Martin Kampmann, Deborah Kronenberg-Versteeg, Tammaryn Lashley, Leslie M Thompson, Alessandro Ori, Yassene Mohammed, Martin Giera, Rik van der Kant.
      Lipid alterations in the brain have been implicated in many neurodegenerative diseases. To facilitate comparative lipidomic research across brain diseases, we establish a data common named the Neurolipid Atlas that we prepopulated with isogenic induced pluripotent stem cell (iPS cell)-derived lipidomics data for different brain diseases. Additionally, the resource contains lipidomics data of human and mouse brain tissue. Leveraging multiple datasets, we demonstrate that iPS cell-derived neurons, microglia and astrocytes exhibit distinct lipid profiles that recapitulate in vivo lipotypes. Notably, the Alzheimer disease (AD) risk gene ApoE4 drives cholesterol ester (CE) accumulation specifically in human astrocytes and we also observe CE accumulation in whole-brain lipidomics from persons with AD. Multiomics interrogation of iPS cell-derived astrocytes revealed that altered cholesterol metabolism has a major role in astrocyte immune pathways such as the immunoproteasome and major histocompatibility complex class I antigen presentation. Our data commons, available online ( https://neurolipidatlas.com/ ), allows for data deposition by the community and provides a user-friendly tool and knowledge base for a better understanding of lipid dyshomeostasis in neurodegenerative diseases.
    DOI:  https://doi.org/10.1038/s42255-025-01365-z
  47. Nat Commun. 2025 Sep 26. 16(1): 8508
    V-ATPase-dependent induction of selective autophagy.
    Yuxiang Huang, Dimitra Dialynaki, Yuchen Lei, Zhihai Zhang, Charles R Evans, Daniel J Klionsky.
      The general consensus is that the vacuolar-type H+-translocating ATPase (V-ATPase) is critical for macroautophagy/autophagy. However, there is a fundamental conundrum because follicular lymphoma-associated mutations in the V-ATPase result in lysosomal/vacuolar deacidification but elevated autophagy activity under nutrient-replete conditions and the underlying mechanisms remain unclear. Here, working in yeast, we show that V-ATPase dysfunction activates a selective autophagy flux termed "V-ATPase-dependent autophagy ". By combining transcriptomic and proteomic profiling, along with genome-wide suppressor screening approaches, we found that V-ATPase-dependent autophagy is regulated through a unique mechanism distinct from classical nitrogen starvation-induced autophagy. Tryptophan metabolism negatively regulates V-ATPase-dependent autophagy via two parallel effectors. On the one hand, it activates ribosome biogenesis, thus repressing the translation of the transcription factor Gcn4/ATF4. On the other hand, tryptophan fuels NAD+ de novo biosynthesis to inhibit autophagy. These results provide an explanation for the mutational activation of autophagy seen in follicular lymphoma patients.
    DOI:  https://doi.org/10.1038/s41467-025-63472-5
  48. Nat Cardiovasc Res. 2025 Sep 24.
    Cardiac adaptation to endurance exercise training requires suppression of GDF15 via PGC-1α.
    Sumeet A Khetarpal, Haobo Li, Tevis Vitale, James Rhee, Saketh Challa, Claire Castro, Steffen Pabel, Yizhi Sun, Jing Liu, Dina Bogoslavski, Ariana Vargas-Castillo, Amanda L Smythers, Katherine A Blackmore, Louisa Grauvogel, Melanie J Mittenbühler, Melin J Khandekar, Casie Curtin, Jose Max Narvaez-Paliza, Chunyan Wang, Nicholas E Houstis, Hans-Georg Sprenger, Sean J Jurgens, Kiran J Biddinger, Alexandra Kuznetsov, Rebecca Freeman, Patrick T Ellinor, Matthias Nahrendorf, Joao A Paulo, Steven P Gygi, Phillip A Dumesic, Aarti Asnani, Krishna G Aragam, Pere Puigserver, Jason D Roh, Bruce M Spiegelman, Anthony Rosenzweig.
      Endurance exercise promotes adaptive growth and improved function of myocytes, which is supported by increased mitochondrial activity. In skeletal muscle, these benefits are in part transcriptionally coordinated by peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). The importance of PGC-1α to exercise-induced adaptations in the heart has been unclear. Here we show that deleting PGC-1α specifically in cardiomyocytes prevents the expected benefits from exercise training and instead leads to heart failure after just 6 weeks of training. Consistent with this, in humans, rare genetic variants in PPARGC1A, which encodes PGC-1α, are associated with increased risk of heart failure. In this model, we identify growth differentiation factor 15 (GDF15) as a key heart-secreted mediator that contributes to this dysfunction. Blocking cardiac Gdf15 expression improves cardiac performance and exercise capacity in these mice. Finally, in human heart tissue, lower cardiomyocyte PPARGC1A expression is associated with higher GDF15 expression and reduced cardiomyocyte density. These findings uncover a crucial role for cardiomyocyte PGC-1α in enabling healthy cardiac adaptation to exercise in part through suppression of GDF15.
    DOI:  https://doi.org/10.1038/s44161-025-00712-3
  49. Nat Rev Mol Cell Biol. 2025 Oct;26(10): 735-740
    Visions of the future of molecular cell biology.
    Monther Abu-Remaileh, Chii Jou Chan, Leilei Chen, Gozde S Demirer, Ana Fiszbein, Florian Jug, Ana Victoria Lechuga-Vieco, Raphaëlle Luisier, Julia Pagan, Benjamin R Sabari, Sichen Shao, Liming Sun, Jan J Żylicz.
      
    DOI:  https://doi.org/10.1038/s41580-025-00892-7
  50. bioRxiv. 2025 Sep 18. pii: 2025.09.15.676412. [Epub ahead of print]
    Gliomas phenocopy an inborn error of metabolism to drive neuronal activity and tumor growth.
    Kalil G Abdullah, Kenji Miki, Charles K Edgar, Shuangcheng Alivia Wu, Yi Xiao, Milan R Savani, Maged T Ghoche, Shawn E Kotermanski, Yuan-Tai Huang, Jeffrey I Traylor, Lei Guo, Kathryn Gunn, William H Hicks, Diana D Shi, Min Tang, Michael M Levitt, Mohamad El-Shami, Skyler Oken, Namya Manoj, Bailey C Smith, Vinesh T Puliyappadamba, Pranita Kaphle, Tracey Shipman, Raymond E West, Chaoying Liang, Toral R Patel, Kimmo J Hatanpaa, Prithvi Raj, Shang Ma, Alexander Ksendzovsky, Thomas D Nolin, Bradley C Lega, Pascal O Zinn, Bianca J Kuhn, Natalie M Clark, C Williams, D R Mani, Michael A Gillette, Marco A Calzado, Lin Xu, Lauren G Zacharias, Feng Cai, Thomas P Mathews, Julie-Aurore Losman, Timothy E Richardson, Benjamin Levi, Michelle Monje, Jay R Gibson, Osaama H Khan, Sameer Agnihotri, Kimberly M Huber, Simon Chamberland, Ralph J DeBerardinis, Samuel K McBrayer.
      The metabolic hallmarks of high-grade glioma (HGG) are not fully understood. Human brain tissue metabolomics revealed that the creatine synthesis pathway intermediate guanidinoacetate (GAA) accumulated ∼100-fold in HGGs relative to controls, which was caused by imbalanced activities of enzymes in this pathway. Glioma cells secreted GAA rather than using it to produce creatine, implicating an unexpected function. GAA accumulates in GAMT deficiency, an inborn error of metabolism, and elevates neuronal excitability. Neuronal excitability is also increased in glioma and drives tumor growth through neuron-glioma interactions. We hypothesized that glioma-generated GAA excites surrounding neurons. Indeed, GAA induced neuronal hyperactivity by activating GABA A receptors and causing depolarizing GABA currents in glioma-associated neurons with dysregulated chloride homeostasis. Depleting tumoral GAA decreased electrochemical activity, neuron-glioma interactions, and tumor aggressiveness. Our findings unveil a new mechanism linking cancer metabolism with cancer neuroscience and leverage human genetics to nominate GAA synthesis as a target in gliomas.
    DOI:  https://doi.org/10.1101/2025.09.15.676412
  51. Proc Natl Acad Sci U S A. 2025 Sep 30. 122(39): e2519568122
    CRISPR screens identify the ATPase VCP as a druggable therapeutic vulnerability in cholangiocarcinoma.
    Wu Yang, Siying Wang, Shuyi Ji, Jian Wang, Shuo Lian, Zhe Li, Robin A Jansen, Wei Wu, Kongyan Niu, Zhen Sun, Qi Jia, Jiaojiao Zheng, Huijue Zhu, Xuan Deng, Liqin Wang, Zhoulong Fan, Yaoping Shi, Cor Lieftink, Ming Guan, Roderick L Beijersbergen, Wenxin Qin, Qiang Gao, René Bernards, Haojie Jin.
      Cholangiocarcinoma (CCA) remains a lethal malignancy with limited therapeutic options. Through genome-wide CRISPR-Cas9 screening, we identified the adenosine triphosphatase (ATPase) valosin-containing protein (VCP) as a critical dependency in CCA. Compound screens revealed that the VCP inhibitor CB-5339 potently suppresses CCA proliferation in a panel of patient-derived organoids by inducing cellular senescence. It is known that senescent cells persist, and this can contribute to therapy resistance. To address this, we combined CB-5339 with senolytic agents (ABT-263 and conatumumab), which selectively eliminate senescent CCA cells, resulting in enhanced tumor suppression both in vitro and in vivo. Clinical analysis showed that VCP overexpression in CCA patients correlates with poor prognosis. Our study unveils a "one-two punch" strategy, targeting VCP-mediated senescence followed by senolytic clearance, offering a promising therapeutic approach for CCA.
    Keywords:  CRISPR-Cas9 screening; VCP; cholangiocarcinoma; senescence
    DOI:  https://doi.org/10.1073/pnas.2519568122
  52. Aging Cell. 2025 Sep 26. e70247
    Enhancing Late-Life Survival and Mobility via Mitohormesis by Reducing Mitochondrial Calcium Levels.
    Doruntina Bresilla, Ines Tawfik, Martin Hirtl, Sonja Gabrijelčič, Julian Ostaku, Fabienne Mossegger, Lia Wurzer, Susanne Lederer, Katarina Kalinova, Ernst Malle, Markus Schosserer, Kim Zarse, Michael Ristow, Corina T Madreiter-Sokolowski.
      Mitochondrial calcium (Ca2+) homeostasis plays a critical role in aging and cellular fitness. In the search for novel antiaging approaches, we explored how genetic and pharmacological inhibition of mitochondrial Ca2+ uptake influences the lifespan and health of Caenorhabditis elegans. Using live-cell imaging, we demonstrate that RNA interference-mediated knockdown of mcu-1, the nematode ortholog of the mitochondrial Ca2+ uniporter (MCU), reduces mitochondrial Ca2+ levels, thereby extending lifespan and preserving motility during aging, while compromising early-life survival. This longevity benefit requires intervention before day 14 and coincides with a transient increase in reactive oxygen species (ROS), which activates pathways involving pmk-1, daf-16, and skn-1, orthologs of human p38 mitogen-activated protein kinase (p38 MAPK), forkhead box O (FOXO), and nuclear factor erythroid 2-related factor 2 (NRF2), respectively. This pathway promotes antioxidant defense mechanisms and preserves mitochondrial structure and function during aging, maintaining larger, more interconnected mitochondria and restoring the oxidized/reduced nicotinamide adenine dinucleotide (NAD+/NADH) ratio and oxygen consumption rates to youthful levels. Pharmacological inhibition of mitochondrial Ca2+ uptake using the MCU inhibitor mitoxantrone mirrors the effects of mcu-1 knockdown, extending lifespan and improving fitness in aged nematodes. In human foreskin fibroblasts, short-term mitoxantrone treatment also transiently elevates ROS production and induces enhanced expression and activity of antioxidant defense enzymes, underscoring the translational relevance of findings from nematodes to human cells. Our findings suggest that modulation of mitochondrial Ca2+ uptake induces mitohormesis through ROS-mediated signaling, promoting improved longevity and healthspan in nematodes, with possible implications for healthy aging in humans.
    Keywords:   C. elegans ; aging; lifespan; longevity; mitochondria; reactive oxygen species
    DOI:  https://doi.org/10.1111/acel.70247
  53. NPJ Parkinsons Dis. 2025 Sep 25. 11(1): 274
    Independent serum metabolomics approaches identify disrupted glutamic acid and serine metabolism in Parkinson's disease patients.
    Jacopo Gervasoni, Carmen Marino, Alberto Imarisio, Lavinia Santucci, Enza Napolitano, Tommaso Nuzzo, Isar Yahyavi, Micol Avenali, Michela Cicchinelli, Gabriele Buongarzone, Caterina Galandra, Marta Picascia, Manuela Grimaldi, Claudio Pacchetti, Francesco Errico, Anna Maria D'Ursi, Andrea Urbani, Enza Maria Valente, Alessandro Usiello.
      Whether distinct blood metabolomic profiles can distinguish Parkinson's disease (PD) patients from healthy controls (HC) is still a matter of debate. Here, we employed ¹H-NMR and UPLC/MS analyses on serum samples from a cohort of PD patients and HC. Compared to HC, PD patients showed: (1) higher glutamine, serine, pyruvate and lower α-ketoglutarate levels (1H-NMR); (2) higher glycine and lower glutamic acid concentrations (UPLC/MS). Several pathways associated with amino acids, mitochondrial and antioxidant metabolism emerged as dysregulated in PD. Our findings highlight a prominent disruption of cellular bioenergetic pathways and amino acid homeostasis in PD.
    DOI:  https://doi.org/10.1038/s41531-025-01126-5
  54. Antioxidants (Basel). 2025 Sep 13. pii: 1113. [Epub ahead of print]14(9):
    The Supersulfide-Producing Activity of Rat Cystathionine γ-Lyase Is Irreversibly Inactivated by L-CysNO but Not by L-GSNO.
    Shoma Araki, Tsuyoshi Takata, Sunghyeon Yoon, Shingo Kasamatsu, Hideshi Ihara, Hidehiko Nakagawa, Takaaki Akaike, Yukihiro Tsuchiya, Yasuo Watanabe.
      Cystathionine γ-lyase (CSE) is a pyridoxal 5'-phosphate (PLP)-dependent enzyme that catalyzes the final step of the transsulfuration pathway, converting cystathionine into cysteine. Additionally, CSE is also essential for the formation of cysteine hydropolysulfide (Cys-S-(S)n-H), known as supersulfides, by metabolizing cystine under pathological conditions. We previously reported that, during cystine metabolism, CSE undergoes self-inactivation through polysulfidation at the Cys136 residue. Here, contrary to the anticipated role of L-S-nitrosocysteine (L-CysNO) as a nitric oxide (NO) donor, we demonstrate that it serves as a substrate for CSE and that its metabolites inhibit the activity of the enzyme during L-CysNO metabolism. The in vitro incubation of CSE-but not the Cys136/171Val mutant-with L-CysNO resulted in the dose-dependent inhibition of supersulfide production, which was not reversed by the reducing agents. Notably, CSE activity remained unchanged upon preincubation with other NO donors, such as S-nitrosoglutathione or D-CysNO, but was inhibited when coincubated with cysteine. Furthermore, when PLP was removed from the CSE/L-CysNO premix, L-CysNO no longer inhibited CSE activity, suggesting that CSE metabolizes L-CysNO and that its metabolites contribute to enzyme inactivation. Indeed, we identified thionitrous acid and pyruvate as the primary CSE/L-CysNO reaction products. Thus, we establish L-CysNO as a CSE substrate and demonstrate that its metabolites act as enzyme inhibitors through a novel irreversible modification at the Cys136/171 residues.
    Keywords:  S-nitrosocysteine (CysNO); cystathionine γ-lyase (CSE); nitric oxide (NO); redox regulation; supersulfides
    DOI:  https://doi.org/10.3390/antiox14091113
  55. Annu Rev Pharmacol Toxicol. 2025 Sep 22.
    Cross-Organ Mitochondrial Communication in Stress and Disease.
    Koning Shen, Jenni Durieux, Andrew Dillin.
      Growing evidence points to mitochondria as not just the "powerhouse of the cell" but as a major cellular hub for signaling. Mitochondria use signaling pathways to communicate with other organelles within the cell or organs within an organism to regulate stress response, metabolic, immune, and longevity pathways. These communication pathways are carried out by mitokine signaling molecules encompassing metabolites, lipids, proteins, and even whole mitochondrial organelles themselves. In this review, we focus on the communication pathways mitochondria use to communicate between different organs in invertebrates, mammalian models, and humans. We cover the molecular events that trigger communication, the signaling mechanisms themselves, and the impact this communication has on organismal health in the context of stress and disease. Further understanding of cross-organ mitochondrial communication pathways will inform the design of therapeutics that take advantage of their protective effects to treat diseases associated with mitochondrial dysfunction.
    DOI:  https://doi.org/10.1146/annurev-pharmtox-062124-024150
  56. Nat Microbiol. 2025 Sep 22.
    Oxaloacetate sensing promotes innate immune antiviral defence against influenza virus infection.
    Shouheng Jin, Xing He, Zheyu Wang, Tao Zhou, Jun Wang, Guihong Pan, Yin Zhang, Ling Ma, Shuai Yang, Liqiu Wang, Yaoxing Wu, Yilin Zou, Nan Qi, Jun Cui.
      Metabolic pathways determine cellular fate and function; however, the exact roles of metabolites in host defence against influenza virus remain undefined. Here we employed pharmacological inhibition and metabolomics analysis to show that the metabolic pathways of oxaloacetate (OAA) are integrated with antiviral responses to influenza virus. Cytosolic malate dehydrogenase 1 senses intracellular OAA to undergo dimerization and functions as a scaffold to recruit the transcription factor ETS2 for phosphorylation by the kinase TAOK1 at serine 313. The phosphorylated ETS2 translocates into the nucleus and supports optimal expression of TBK1, an indispensable activator of type I interferon responses. OAA supplementation provides a broad-spectrum antiviral ability, and OAA deficiency caused by Acly genetic ablation decreases antiviral immunity and renders mice more susceptible to lethal H1N1 virus infection. Our results uncover a signalling pathway through cellular OAA sensing that links metabolism and innate immunity to coordinate defence against viral challenge.
    DOI:  https://doi.org/10.1038/s41564-025-02107-3
  57. Cancer Discov. 2025 Sep 23.
    EML4-ALK variant-specific genetic interactions shape lung tumorigenesis.
    Alberto Diaz-Jimenez, Emily G Shuldiner, Kalman Somogyi, Karen Shih, Oscar Gonzalez-Velasco, Mulham Najajreh, Stewart Kim, Filiz Akkas, Christopher W Murray, Laura Andrejka, Min K Tsai, Benedikt Brors, Ilse Hofmann, Smruthy Sivakumar, Saumya D Sisoudiya, Ethan S Sokol, Hongchen Cai, Dmitri A Petrov, Monte M Winslow, Rocio Sotillo.
      Diverse fusions of EML4 and ALK are oncogenic drivers in lung adenocarcinomas. EML4-ALK variants have distinct breakpoints within EML4, but their functional differences remain poorly understood. Here, we use somatic genome editing to generate autochthonous mouse models of EML4-ALK-driven lung tumors and show that V3 is more oncogenic than V1. By employing multiplexed genome editing and quantifying the effects of 29 putative tumor suppressor genes on V1- and V3-driven lung cancer growth, we show that many tumor suppressor genes have variant-specific effects on tumorigenesis. Pharmacogenomic analyses further suggest that tumor genotype can influence therapeutic responses. Analysis of human EML4-ALK-positive lung cancers also identified variant-specific differences in their genomic landscapes. These findings suggest that EML4-ALK variants behave more like distinct oncogenes rather than a uniform entity and highlight the dramatic impact of oncogenic fusion partner proteins and coincident tumor suppressor gene alterations on the biology of oncogenic fusion-driven cancers.
    DOI:  https://doi.org/10.1158/2159-8290.CD-24-1417
  58. Nat Commun. 2025 Sep 26. 16(1): 8307
    An injury-associated lobular microniche is associated with the classical tumor cell phenotype in pancreatic cancer.
    Sara Söderqvist, Annika Viljamaa, Natalie Geyer, Anna-Lena Keller, Kseniya Ruksha, Carina Strell, Neda Hekmati, Alexandra Niculae, Jennie Engstrand, Ernesto Sparrelid, Caroline Salmén, Tânia D F Costa, Miao Zhao, Staffan Strömblad, Argyro Zacharouli, Poya Ghorbani, Sara Harrizi, Yousra Hamidi, Olga Khorosjutina, Stefina Milanova, Bernhard Schmierer, Béla Bozóky, Carlos Fernández Moro, Marco Gerling.
      Pancreatic cancer is an aggressive disease with a dense fibrotic stroma and is often accompanied by chronic inflammation. Peritumoral inflammation is typically viewed as a reaction to nearby tumor growth. Here, we report that the inflamed pancreatic lobules are frequently invaded by tumor cells, forming a distinct, non-fibrotic tumor niche. Using a semi-supervised machine learning approach for annotations of clinical samples and multiplex protein profiling, we show that tumor cells at the invasion front are closely associated with acinar cells undergoing damage-induced changes, and with activated fibroblasts expressing markers of injury. The invaded lobules are linked to classical tumor phenotypes, in contrast to fibrotic areas where tumor cells display a more basal profile, highlighting microenvironment-dependent tumor subtype differences. In female mice, lobular invasion similarly aligns with the classical tumor phenotype. Together, our data reveal that pancreatic tumors colonize injured lobules, creating a unique niche that shapes tumor characteristics and contributes to disease biology.
    DOI:  https://doi.org/10.1038/s41467-025-63864-7
  59. Nat Metab. 2025 Sep;7(9): 1924-1938
    Slc7a7 licenses macrophage glutaminolysis for restorative functions in atherosclerosis.
    Saloua Benhmammouch, Coraline Borowczyk, Clara Pierrot-Blanchet, Thibault Barouillet, Florent Murcy, Sébastien Dussaud, Marina Blanc, Camille Blériot, Tiit Örd, Lama Habbouche, Nathalie Vaillant, Yohan Gerber, Clément Cochain, Emmanuel L Gautier, Florent Ginhoux, Edward B Thorp, Erik A L Biessen, Judith C Sluimer, Susanna Bodoy, Manuel Palacin, Béatrice Bailly-Maitre, Minna U Kaikkonen, Laurent Yvan-Charvet.
      Atherosclerosis is a life-threatening condition characterized by chronic inflammation of the arterial wall. Atherosclerotic plaque macrophages are key players at the site of disease, where metabolic reprogramming dictates the progression of pathogenesis. Here we show that reduced macrophage glutaminase activity is related to glutaminase (GLS)-1 and not GLS2 expression. While glutamine synthetase serves as a metabolic rheostat controlling nutrient flux into cells in vitro, macrophage restorative functions in the context of atherosclerosis relies more heavily on glutamine influx. Enhanced glutamine flux is largely mediated by the SLC7A7 exchanger in macrophages: Slc7a7-silenced macrophages have reduced glutamine influx and GLS1-dependent glutaminolysis, impeding downstream signalling involved in macrophage restorative functions. In vivo, macrophage-specific deletion of Slc7a7 accelerates atherosclerosis in mice with more complex necrotic core composition. Finally, cell-intrinsic regulation of glutaminolysis drives macrophage metabolic and transcriptional rewiring in atherosclerosis by diverting exogenous Gln flux to balance remodelling and restorative functions. Thus, we uncover a role of SLC7A7-dependent glutamine uptake upstream of glutaminolysis in atherosclerotic plaque development and stability.
    DOI:  https://doi.org/10.1038/s42255-025-01354-2
  60. Science. 2025 Sep 25. 389(6767): 1353-1360
    Lysosomes signal through the epigenome to regulate longevity across generations.
    Qinghao Zhang, Weiwei Dang, Meng C Wang.
      The epigenome is sensitive to metabolic inputs and is crucial for aging. Lysosomes act as a signaling hub to sense metabolic cues and regulate longevity. We found that lysosomal metabolic pathways signal through the epigenome to regulate transgenerational longevity in Caenorhabditis elegans. Activation of lysosomal lipid signaling and lysosomal adenosine monophosphate-activated protein kinase (AMPK) or reduction of lysosomal mechanistic target of rapamycin (mTOR) signaling increased the expression of a histone H3.3 variant and increased its methylation on K79, leading to life-span extension across multiple generations. This transgenerational prolongevity effect required intestine-to-germline transportation of histone H3.3 and a germline-specific H3K79 methyltransferase and was recapitulated by overexpressing H3.3 or the H3K79 methyltransferase. Thus, signals from a lysosome affect the epigenome and link the soma and germ line to mediate transgenerational inheritance of longevity.
    DOI:  https://doi.org/10.1126/science.adn8754
  61. Hepatol Commun. 2025 Oct 01. pii: e0810. [Epub ahead of print]9(10):
    Targeting hepatocyte-specific SLC2A8 blocks hepatic steatosis and dissociates TCA cycle flux inhibition from glutamine anaplerosis.
    Joshua A Adams, Yiming Zhang, Jiameng Sun, Andrew Tilston-Lunel, Cassandra B Higgins, Monique Heitmeier, Sam Ballentine, Eric Tycksen, Roland E Dolle, Paul W Hruz, Brian J DeBosch.
       BACKGROUND: Excess TCA cycle and glutamine anaplerosis are hallmarks of metabolic dysfunction-associated steatotic liver disease and steatohepatitis. Blocking glutamine metabolism attenuates metabolic dysfunction-associated steatohepatitis. However, inhibiting TCA cycle flux by blocking plasma membrane carbohydrate transport is limited by the ubiquitous tissue distribution, function, and homology among the SLC2A family of facilitative carbohydrate transporters, and the potential for carbohydrate blockade to invoke or exacerbate glutamine anaplerosis. Here, we quantify alterations in hepatocyte carbon flux, define the broader metabolic consequences of hepatocyte-specific GLUT8/SLC2A8 inhibition, and delineate the antisteatotic efficacy of a novel small-molecule GLUT8-selective inhibitor.
    METHODS: We generated mice with floxed SLC2A8 alleles and expressed hepatocyte-specific Cre by breeding these mice with albumin-Cre transgenic mice, or by administering AAV8 encoding hepatocyte-specific iCre. We performed stable-isotope glucose, fructose, and glutamine metabolic labeling in isolated GLUT8WT and GLUT8LKO hepatocytes and performed metabolic phenotyping in lean and diet-induced obese GLUT8WT and GLUT8LKO mice. Finally, we performed high-throughput screening to identify a GLUT8-selective inhibitor, which we characterized using in vitro models of triglyceride accumulation.
    RESULTS: Hepatocyte-specific SLC2A8 deletion reduced diet-induced hepatic and peripheral fat accumulation and increased thermogenesis during ZT12-24 (eg, the dark phase). It also disrupted TCA cycle flux without inducing compensatory glutamine utilization. High-throughput screening identified a small-molecule, GLUT8-selective inhibitor, P20, which blocked hepatocyte TG accumulation and inflammation in in vitro steatotic and inflammatory models.
    CONCLUSIONS: Deleting the hepatocyte carbohydrate transporter GLUT8 suppresses TCA cycle flux without inducing compensatory glutamine anaplerosis. The net effect of this is liver protection against multiple forms of dietary insult. Given that selective pharmacological GLUT8 inhibition is feasible, GLUT8 may be a viable target to abate metabolic dysfunction-associated steatohepatitis and other complications of obesity.
    Keywords:  GLUT8; TCA cycle; caloric restriction; energy metabolism; fasting; fructose; glucose transporter; glutamine anaplerosis; metabolic dysfunction–associated steatohepatitis; metabolic dysfunction–associated steatotic liver disease
    DOI:  https://doi.org/10.1097/HC9.0000000000000810
  62. Blood. 2025 Sep 22. pii: blood.2024028195. [Epub ahead of print]
    Clonal tracing of blood stem cells across mouse and human lifespans.
    Alejo E Rodriguez-Fraticelli.
      For over sixty years, blood researchers have been counting clones with every tool at their disposal. Inspired by phage and fly geneticists, Till and McCulloch irradiated mice to induce chromosomal aberrations. Using this labeling strategy, they demonstrated that different types of blood cells shared the same mutation in every spleen colony, thereby proving the existence of hematopoietic stem cells. Since their breakthrough, technological advances have enabled researchers to quantify hematopoiesis at single-cell resolution in increasingly complex samples across both mice and humans. With these modern sophisticated lineage tracing methods, our foundational understanding of the blood system is being reshaped. For instance, we now interpret hematopoietic architecture as arising from stem and progenitor cells of diverse developmental origins, each with distinct fate biases encoded by unique regulatory states. Interacting with this regulatory layer, genetic mutations and epimutations arise, expanding clonally and becoming pervasive with age. Together, clonal heterogeneity and age-driven clonal selection may underlie the perplexing diversity of therapy responses in cancer and beyond. As these paradigm-shifting insights gain traction, clonal tracing is being adopted across dozens of biological and clinical studies. Here, we review the modern toolbox of clonal tracking technologies, with a focus on next-generation sequencing-based approaches, and provide a practical guide for matching specific research questions with optimal experimental strategies.
    DOI:  https://doi.org/10.1182/blood.2024028195
  63. Sci Adv. 2025 Sep 26. 11(39): eadt6366
    Lysosomal LRRC8 complex impacts lysosomal pH, morphology, and systemic glucose metabolism.
    Ashutosh Kumar, Yonghui Zhao, Litao Xie, Rahul Chadda, John D Tranter, Ryan T Mikami, Nihil Abraham, Juan Hong, Ethan Feng, David R Rawnsley, Haiyan Liu, Kayla M Henry, Gretchen Meyer, Meiqin Hu, Haoxing Xu, Antentor Hinton, Chad E Grueter, E Dale Abel, Andrew W Norris, Abhinav Diwan, Rajan Sah.
      The lysosome integrates anabolic signaling and nutrient sensing to regulate intracellular growth pathways. The leucine-rich repeat-containing 8 (LRRC8) channel complex forms a lysosomal anion channel and regulates PI3K-AKT-mTOR signaling, skeletal muscle differentiation, growth, and systemic glucose metabolism. Here, we define the endogenous LRRC8 subunits localized to a subset of lysosomes in differentiated myotubes. We show that LRRC8A affects leucine-stimulated mTOR; lysosome size; number; pH; expression of lysosomal proteins LAMP2, P62, and LC3B; and lysosomal function. Mutating an LRRC8A lysosomal targeting dileucine motif sequence (LRRC8A-L706A;L707A) in myotubes recapitulates the abnormal AKT signaling and altered lysosomal morphology and pH observed in LRRC8A knockout cells. In vivo, LRRC8A-L706A;L707A knock-in mice exhibit increased adiposity, impaired glucose tolerance and insulin resistance associated with reduced skeletal muscle PI3K-AKT-mTOR signaling, glucose uptake, and impaired incorporation of glucose into glycogen. These data reveal a lysosomal LRRC8-mediated metabolic signaling function regulating lysosomal function, systemic glucose homeostasis, and insulin sensitivity.
    DOI:  https://doi.org/10.1126/sciadv.adt6366
  64. Cell. 2025 Sep 24. pii: S0092-8674(25)01028-1. [Epub ahead of print]
    Astrocytes functionally integrate multiple synapses via specialized leaflet domains.
    Lucas Benoit, Ines Hristovska, Nicolas Liaudet, Pierre-Henri Jouneau, Arnold Fertin, Roberta de Ceglia, David Litvin, Maria Amalia Di Castro, Milica Jevtic, Ioannis Zalachoras, Toko Kikuchi, Ludovic Telley, Matteo Bergami, Yves Usson, Chihiro Hisatsune, Katsuhiko Mikoshiba, Karin Pernet-Gallay, Andrea Volterra.
      Astrocyte Ca2+ dynamics control synaptic circuits and behavior, yet the underlying biology remains poorly understood. By combining volumetric high-resolution electron microscopy and two-photon Ca2+ imaging, we characterize astrocyte leaflets that interface with synapses. These convoluted structures with ≤250 nm diameter originate from astrocytic shafts or cell bodies, contain minuscule endoplasmic reticulum saccules expressing IP3 receptors but not mitochondria, and are often interconnected via gap junctions forming domains with cytosolic continuity. Leaflets enwrap 90% of synapses in clusters and only 10% individually. By fast imaging of astrocyte peripheral microvolumes, we identify leaflet-specific Ca2+ events that were synaptically induced, IP3R1-mediated, and often displayed separate originations merging into large, long-lasting Ca2+ elevations. Using combined axon-leaflet Ca2+ imaging, we show that these complex events reflect integration of incoming inputs from different neurons. The astrocyte leaflet organization may thus coordinate, via Ca2+ signals, multiple synapses and circuits active at different spatiotemporal scales, executing computations distinct from neurons.
    Keywords:  3D electron microscopy; 3D two-photon Ca(2+) imaging; HPF and FIB-SEM; IP(3) receptors; astrocyte; astrocyte Ca(2+) signaling; astrocyte integration of synaptic signals; astrocyte leaflet; astrocyte-synapse communication; endoplasmic reticulum
    DOI:  https://doi.org/10.1016/j.cell.2025.08.036
  65. bioRxiv. 2025 Sep 18. pii: 2025.09.15.676396. [Epub ahead of print]
    The DREAM complex links somatic mutation, lifespan, and disease.
    Zane Koch, Shuvro P Nandi, Kate Licon, Arturo Bujarrabal-Dueso, David H Meyer, Safa Saeed, Pirunthan Perampalam, Frederick A Dick, Björn Schumacher, Ludmil B Alexandrov, Trey Ideker.
      The DREAM complex has emerged as a central repressor of DNA repair, raising questions as to whether such repression exerts long-term effects on human health. Here we establish that DREAM activity significantly impacts lifetime somatic mutation burden, and that such effects are linked to altered lifespan and age-related disease pathology. First, joint profiling of DREAM activity and somatic mutations across a single-cell atlas of 21 mouse tissues shows that cellular niches with lower DREAM activity have decreased mutation rates. Second, DREAM activity predicts the varied lifespans observed across 92 mammals, with low activity marking longer-lived species. Third, reduced DREAM activity in Alzheimer's patients predicts late disease onset and decreased risk for severe neuropathology. Finally, we show DREAM knockout protects against mutation accumulation in vivo , reducing single-base substitutions by 4.2% and insertion/deletions by 19.6% in brains of mice. These findings position DREAM as a key regulator of aging.
    DOI:  https://doi.org/10.1101/2025.09.15.676396
  66. Cancer Discov. 2025 Sep 25.
    Microbial metabolic pathways guide response to immune checkpoint blockade therapy.
    Iris L Mimpen, Thomas W Battaglia, Miguel Parra Martinez, Catherine Toner-Bartelds, Laurien J Zeverijn, Birgit S Geurts, Karlijn Verkerk, Louisa R Hoes, Allard W J van Renterghem, Michael Noe, Ingrid Hofland, Annegien Broeks, Vincent van der Noort, Edwin C A Stigter, Can M C Gulersonmez, Boudewijn M T Burgering, Merel van Gogh, Marcel R de Zoete, Hans Gelderblom, Krijn K Dijkstra, Lodewyk F A Wessels, Emile E Voest.
      Studies have identified a link between specific microbiome-derived bacteria and immune checkpoint blockade (ICB) efficacy. However, these species lack consistency across studies and their immunomodulatory mechanisms remain elusive. To understand the influence of the microbiome on ICB response we studied its functional capacity. Using pan-cancer metagenomics data of ICB-treated patients, we showed that community-level metabolic pathways are stable across individuals, making them suitable to predict ICB response. We identified several microbial metabolic processes significantly associated with response, including the methylerythritol phosphate (MEP) pathway, which was associated with response and induced Vδ2 T cell-mediated anti-tumor responses in patient-derived tumor organoids. In contrast, riboflavin synthesis was associated with ICB resistance, and its intermediates induced mucosal-associated invariant T (MAIT) cell-mediated immune suppression. Moreover, gut metabolomics revealed that high riboflavin levels were linked to worse survival in patients with abundant intratumoral MAIT cells. Collectively, our results highlight the relevance of metabolite-mediated microbiome-immune cell crosstalk.
    DOI:  https://doi.org/10.1158/2159-8290.CD-24-1669
  67. Nat Cell Biol. 2025 Sep 26.
    Remote control of AMPK via extracellular adenosine controls tissue growth.
    Yao Zhang, Katrin Strassburger, Aurelio A Teleman.
      Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is a regulator of cellular catabolism that is activated by AMP. As AMP accumulates in cells with low ATP, AMPK is considered a stress-activated kinase. While studying organ growth during Drosophila development, we find that AMPK can also be activated by a signalling metabolite not related to stress. Specifically, we find that two physiological inputs known to regulate organ growth rates (ecdysone (a steroid hormone) and dietary protein) modulate expression of adenosine deaminase in the intestine. This, in turn, alters circulating adenosine levels. Circulating adenosine acts as a signalling molecule by entering cells, becoming phosphorylated to AMP and activating AMPK to inhibit organ growth. Thus, AMPK activity is regulated developmentally, and AMPK activity in one tissue can be remote controlled by another tissue via circulating adenosine. Notably, this mechanism accounts for half the effect of dietary protein on tissue growth rates in Drosophila.
    DOI:  https://doi.org/10.1038/s41556-025-01764-0
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