bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2026–01–11
68 papers selected by
Christian Frezza, Universität zu Köln
  1. Don't forget protein synthesis! Mitochondria of cancer cells import glutamine to fuel metabolism and to charge tRNAs for translation.
  2. Nutrient requirements of organ-specific metastasis in breast cancer.
  3. Mitochondrial depolarization stabilizes the vitamin B12 chaperone MMADHC in the cytosol to increase MTR activity.
  4. p53 increases phospholipid headgroup scavenging in senescence.
  5. Structure of the lysosomal KICSTOR-GATOR1-SAMTOR nutrient-sensing supercomplex.
  6. Innate immune sensing via the cGAS-STING pathway restricts extrachromosomal DNA-driven tumorigenesis.
  7. Mitochondrial presequences harbor variable strengths to maintain organellar function.
  8. PHGDH at the crossroads: metabolic plasticity, metastatic paradoxes, and therapeutic reconnaissance in cancer.
  9. Active aldehydes accelerate CD8+ T cell exhaustion by metabolic alteration in the tumor microenvironment.
  10. Mitochondrial control of fuel switching via carnitine biosynthesis.
  11. MECP2 Duplication Uncouples Mitochondrial and Purine Metabolism During neuronal maturation.
  12. RPA exhaustion activates SLFN11 to eliminate cells with heightened replication stress.
  13. Career pathways, part 18.
  14. TGFβ induces an atypical EMT to evade immune mechanosurveillance in lung adenocarcinoma dormant metastasis.
  15. A clickable CoQ imaging probe reveals that cellular uptake and lysosomal trafficking depend on CD36 and NPC1.
  16. Revisiting molecular hydrogen signaling in mitochondria: Is the Rieske protein the entry point or a downstream sentinel?
  17. Aging kidney is associated with metabolic rewiring and epigenetic reprogramming.
  18. Targeting STING elicits GSDMD-dependent pyroptosis and boosts anti-tumor immunity in renal cell carcinoma.
  19. Chewing the fat: a novel mechanism for lipolysis.
  20. When heme is low, copper kills cancer.
  21. Loss of KDM6A-mediated genomic instability and metabolic reprogramming regulates response to therapeutic perturbations in bladder cancer.
  22. Amino Acid Metabolic Reprogramming in Clear Cell Renal Cell Carcinoma: Pathogenic Mechanisms and Therapeutic Targeting.
  23. Mitochondrial ROS-induced metabolic alterations differentially regulate ferroptosis sensitivity.
  24. Dual inhibition of ACLY and ACSS2 by EVT0185 reduces steatosis, hepatic stellate cell activation, and fibrosis in mouse models of MASH.
  25. Mitotic errors as triggers of cell death and inflammation.
  26. Methionine synthase reductase regulates heterochromatin independently of methionine synthesis through mitochondrial homeostasis.
  27. A dietary pan-amino acid dropout screen in vivo reveals a critical role for histidine in T-ALL.
  28. Protocol for stable isotopic tracing to assess cellular lipogenic activity in induced neural stem cells.
  29. Microbiota utilization of intestinal amino acids modulates cancer progression and anticancer immunity.
  30. Membrane-protein-mediated phase separation orchestrates organelle contact sites.
  31. EcDNA-borne structural variants drive oncogenic fusion transcript amplification.
  32. Senescence-inhibitory Δ133p53α counteracts accelerated ageing and mortality.
  33. Regulation of the Rheb GTPase via GATOR1 Complex.
  34. Extracellular GPX4 impairs antitumor immunity via dendritic ZP3 receptors.
  35. Mitochondrial asymmetry shifts T cell fate.
  36. Redundant or resilient? A systems view of ferroptosis surveillance mechanisms.
  37. Endocrine regulation of the hepatic fasting response: cues, cooperation and consequences.
  38. Chronic stress and the mitochondria-telomere axis: human evidence for a bioenergetic-debt model of early aging.
  39. CASTOR1 and CASTOR2 respond to different arginine levels to regulate mTORC1 activity.
  40. Local mitochondrial physiology defined by mtDNA quality guides purifying selection.
  41. Targeting DHODH Reveals a Metabolic Vulnerability in AR-positive and AR-negative Prostate Cancer Cells via Pyrimidine Synthesis and Metabolic Crosstalk with the TCA and Urea Cycles.
  42. The Liver Clock Tunes Transcriptional Rhythms in Skeletal Muscle to Regulate Mitochondrial Function.
  43. PTEN-loss confers dependence on the guanylate synthesis enzyme IMPDH in T-cell acute lymphoblastic leukemia.
  44. Superoxide signals for the mitophagy of dysfunctional mitochondria to maintain quality control.
  45. SLC2A1+ tumour-associated macrophages spatially control CD8+ T cell function and drive resistance to immunotherapy in non-small-cell lung cancer.
  46. Spatially resolved integrative analysis of transcriptomic and metabolomic changes in tissue injury studies.
  47. Targeting ceramide metabolism to restore hypoxia-induced apoptosis in p53-deficient colon cancer cells.
  48. Amino acid metabolism modulates chronic kidney disease progression by mediating the aging process: Mechanistic insights and therapeutic interventions.
  49. Active aldehydes drive metabolic exhaustion in CD8+ T cells.
  50. Hemoglobin and human longevity: integrating oxygen transport, redox biology, and aging pathways - a narrative review.
  51. SOX2 confers tumour permissiveness in a specific skin progenitor population.
  52. Optogenetic Proximity Labeling Maps Spatially Resolved Mitochondrial Surface Proteomes and a Locally Regulated Ribosome Pool.
  53. Impaired nitrogenous waste clearance promotes hepatocellular carcinoma.
  54. Intratumoural vaccination via checkpoint degradation-coupled antigen presentation.
  55. BDH1-Dependent Ketone Body Metabolism Maintains Müller Cell Homeostasis and Retinal Function.
  56. A catecholamine-independent pathway controlling adaptive adipocyte lipolysis.
  57. Spatial Regulation of Lysosomal Vesicle Acidification Along the Axon via mRAVE-Dependent v-ATPase Assembly.
  58. Immune evasion by macrophage-derived lactate.
  59. The complex role of nutrients in cancer spread.
  60. Insights from three decades of BRCA1/2 modeling in mice.
  61. Endometrial stromal cell-derived TMAO sustains decidualization to prevent recurrent spontaneous abortion.
  62. Immune Cell Mitochondrial Phenotypes Are Largely Preserved in Mitochondrial Diseases and Do Not Reflect Disease Severity.
  63. Neuro-epithelial circuits promote sensory convergence and intestinal immunity.
  64. Disentangling the effects of food processing from those of diet quality.
  65. Why cancer can come back years later - and how to stop it.
  66. Quantitative optical nanoscopy of mitochondrial-derived vesicles in neurons classifies pre-peroxisomal and clearing organelles.
  67. Endothelial Arf6 sustains capillary electrical signaling and cerebral blood flow through PIP 2 regeneration and activation of Kir2.1 channels.
  68. Thioredoxin interacting protein (TXNIP), a redox regulator, mediates the RAPGEF3/4 signaling dependency in primary melanoma.
  1. Mol Cell. 2026 Jan 08. pii: S1097-2765(25)01013-5. [Epub ahead of print]86(1): 6-8
    Don't forget protein synthesis! Mitochondria of cancer cells import glutamine to fuel metabolism and to charge tRNAs for translation.
    Yury S Bykov, Johannes M Herrmann.
      In this issue of Molecular Cell, Zhu et al.1 show that mitochondria of cancer cells rely on the import of glutamine not only to fuel metabolite synthesis via the tricarboxylic acid cycle but also to charge mt-tRNAGln to allow mitochondrial protein synthesis and respiration.
    DOI:  https://doi.org/10.1016/j.molcel.2025.12.014
  2. Nature. 2026 Jan 07.
    Nutrient requirements of organ-specific metastasis in breast cancer.
    Keene L Abbott, Sonu Subudhi, Raphael Ferreira, Yetiş Gültekin, Sophie C Steinbuch, Muhammad Bin Munim, Diya L Ramesh, Sophie E Honeder, Ashwin S Kumar, Michelle Wu, Jacob A Hansen, Anna Shevzov-Zebrun, Edrees H Rashan, Kian M Eghbalian, Sharanya Sivanand, Anna M Barbeau, Lisa M Riedmayr, Mark Duquette, Ahmed Ali, Nicole Henning, Sonia E Trojan, Millenia Waite, Tenzin Kunchok, Mayu A Nakano, Florian Gourgue, Gino B Ferraro, Brian T Do, Virginia Spanoudaki, Francisco J Sánchez-Rivera, Xin Jin, George M Church, Rakesh K Jain, Matthew G Vander Heiden.
      Cancer metastasis is a major contributor to patient morbidity and mortality1, yet the factors that determine the organs where cancers can metastasize are incompletely understood. Here we quantify the absolute levels of 124 metabolites in multiple tissues in mice and investigate how this relates to the ability of breast cancer cells to grow in different organs. We engineered breast cancer cells with broad metastatic potential to be auxotrophic for specific nutrients and assessed their ability to colonize different tissue sites. We then asked how tumour growth in different tissues relates to nutrient availability and tumour biosynthetic activity. We find that single nutrients alone do not define the sites where breast cancer cells can grow as metastases. In addition, we identify purine synthesis as a requirement for tumour growth and metastasis across many tissues and find that this phenotype is independent of tissue nucleotide availability or tumour de novo nucleotide synthesis activity. These data suggest that a complex interplay between multiple nutrients within the microenvironment dictates potential sites of metastatic cancer growth, and highlights the interdependence between extrinsic environmental factors and intrinsic cellular properties in influencing where breast cancer cells can grow as metastases.
    DOI:  https://doi.org/10.1038/s41586-025-09898-9
  3. bioRxiv. 2025 Dec 31. pii: 2025.12.31.697091. [Epub ahead of print]
    Mitochondrial depolarization stabilizes the vitamin B12 chaperone MMADHC in the cytosol to increase MTR activity.
    Sneha P Rath, Zhu Li, Arkajit Guha, Fangcong Dong, Ruma Banerjee, Vamsi K Mootha.
      Of the ∼1100 mitochondrial proteins, only a handful like PINK1 and ATFS-1 are known to stabilize and relocalize upon collapse of the proton motive force (PMF) to execute signaling roles. To systematically identify genes that increase exclusively at the protein level upon PMF collapse, we performed a joint proteomic and RNA-seq screen. The screen revealed 10 candidates (six mitochondrial), including the vitamin B12 chaperone MMADHC and cytosolic B12-dependent methionine synthase (MTR). MMADHC is short-lived across cell types and we show that its levels increase with PMF collapse. MMADHC stabilization precedes PINK1 activation in a time course of increasing mtDNA depletion, suggesting greater sensitivity to PMF collapse. MMADHC accumulates in mitochondria with LONP1 inhibition but in the cytosol upon PMF collapse, likely due to mitochondrial import failure. Cytosol-stabilized MMADHC increases MTR levels and activity. Altogether, the mitochondrial PMF regulates the cytosolic B12-dependent MTR, integral to one-carbon metabolism, by controlling the stability and compartmentalization of the B12 chaperone MMADHC.
    Significance Statement: Humans have only two vitamin B12-dependent enzymes - mitochondrial MMUT and cytosolic MTR - and both require a common B12 chaperone MMADHC. We discover that MMADHC is a low abundant, short-lived protein that is continuously imported and degraded by energized mitochondria. Upon collapse of the mitochondrial proton motive force, MMADHC accumulates in the cytosol and increases the levels and activity of MTR, critical for one-carbon metabolism. This PMF-dependent regulation of MMADHC stability and localization is important for understanding cofactor rationing and spatiotemporal compartmentalization of B12 metabolism.
    DOI:  https://doi.org/10.64898/2025.12.31.697091
  4. Nat Cell Biol. 2026 Jan 07.
    p53 increases phospholipid headgroup scavenging in senescence.
    Jossie J Yashinskie, Xianbing Zhu, Grace H McGregor, Karl A Wessendorf-Rodriguez, Katrina Paras, Julia S Brunner, Benjamin T Jackson, Abigail Xie, Richard Koche, Christian M Metallo, Lydia W S Finley.
      Changes in cell state are often accompanied by altered metabolic demands, and homeostasis depends on cells adapting to their changing needs. One major cell state change is senescence, which is associated with dramatic changes in cell metabolism, including increases in lipid metabolism, but how cells accommodate such alterations is poorly understood. Here we show that the transcription factor p53 increases recycling of the lipid headgroups required to meet the increased demand for membrane phospholipids during senescence. p53 activation increases the supply of phosphoethanolamine, an intermediate in the Kennedy pathway for de novo synthesis of phosphatidylethanolamine, in part by increasing lipid turnover and transactivating genes involved in autophagy and lysosomal catabolism that enable membrane turnover. Disruption of phosphoethanolamine conversion to phosphatidylethanolamine is well tolerated in the absence of p53 but results in dramatic organelle remodelling and perturbs growth and gene expression following p53 activation. Consistently, CRISPR-Cas9-based genetic screens reveal that p53-activated cells preferentially depend on genes involved in lipid metabolism and lysosomal function. Together, these results reveal lipid headgroup recycling to be a homeostatic function of p53 that confers a cell-state-specific metabolic vulnerability.
    DOI:  https://doi.org/10.1038/s41556-025-01853-0
  5. Cell. 2026 Jan 08. pii: S0092-8674(25)01418-7. [Epub ahead of print]
    Structure of the lysosomal KICSTOR-GATOR1-SAMTOR nutrient-sensing supercomplex.
    Christopher J Lupton, Charles Bayly-Jones, Shuqi Dong, Terrance Lam, Wentong Luo, Gareth D Jones, Chantel Mastos, Nicholas J Frescher, San S Lim, Alastair C Keen, Luke E Formosa, Hari Venugopal, Yong-Gang Chang, Michelle L Halls, Andrew M Ellisdon.
      The guanosine triphosphate (GTP)-bound state of the heterodimeric Rag GTPases functions as a molecular switch regulating mechanistic target of rapamycin complex 1 (mTORC1) activation at the lysosome downstream of amino acid fluctuations. Under low amino acid conditions, GTPase-activating protein (GAP) activity toward Rags 1 (GATOR1) promotes RagA GTP hydrolysis, preventing mTORC1 activation. KICSTOR recruits and regulates GATOR1 at the lysosome by undefined mechanisms. Here, we resolve the KICSTOR-GATOR1 structure, revealing a striking ∼60-nm crescent-shaped assembly. GATOR1 anchors to KICSTOR via an extensive interface, and mutations that disrupt this interaction impair mTORC1 regulation. The S-adenosylmethionine sensor SAMTOR binds KICSTOR in a manner incompatible with metabolite binding, providing structural insight into methionine sensing via SAMTOR-KICSTOR association. We discover that KICSTOR and GATOR1 form a dimeric supercomplex. This assembly restricts GATOR1 to an orientation that favors the low-affinity active GAP mode of Rag GTPase engagement while sterically restricting access to the high-affinity inhibitory mode, consistent with a model of an active lysosomal GATOR1 docking complex.
    Keywords:  GATOR1; KICSTOR; RAG GTPase; Rag-Ragulator; S-adenosylmethionine; SAMTOR; SZT2; cell metabolism; cryo-EM; mTORC1
    DOI:  https://doi.org/10.1016/j.cell.2025.12.005
  6. bioRxiv. 2026 Jan 01. pii: 2025.12.31.697191. [Epub ahead of print]
    Innate immune sensing via the cGAS-STING pathway restricts extrachromosomal DNA-driven tumorigenesis.
    Tuo Li, Qing-Lin Yang, Kailiang Qiao, Anli Zhang, Chenglong Sun, Huocong Huang, Paul S Mischel, Sihan Wu, Zhijian J Chen.
      Extrachromosomal DNAs (ecDNAs) are circular DNA fragments frequently found in human cancers, where they amplify oncogenes, drive tumor heterogeneity, and promote therapy resistance and poor prognosis. Despite their prevalence, how ecDNAs interact with the immune system remains poorly understood. Here, we show that the cytosolic DNA sensor cGAS detects ecDNA fragments in the cytoplasm and activates the innate immune response. cGAS and STING are frequently silenced in ecDNA + tumors through promoter hypermethylation. Restoring cGAS or STING in human and murine ecDNA + cancer cells reactivates innate immune signaling and selectively suppresses ecDNA + tumor growth in an immunocompetent mouse model. Using two ecDNA biogenesis models, we show that the cGAS-STING pathway restricts de novo ecDNA formation. Together, our findings identify innate immune sensing as a natural barrier to ecDNA-driven oncogenesis and establish cGAS-STING reactivation as a therapeutic strategy for ecDNA + cancers.
    Highlights: The cGAS-STING pathway is frequently silenced in ecDNA + tumors Restoration of cGAS in ecDNA + cells activates innate immune responses cGAS expression suppresses ecDNA + tumor growth in vivo The cGAS-STING pathway restricts de novo ecDNA biogenesis.
    DOI:  https://doi.org/10.64898/2025.12.31.697191
  7. J Cell Biol. 2026 Apr 06. pii: e202507116. [Epub ahead of print]225(4):
    Mitochondrial presequences harbor variable strengths to maintain organellar function.
    Youmian Yan, Baigalmaa Erdenepurev, Thiago N Menezes, Ian Collinson, Natalie M Niemi.
      Hundreds of mitochondrial proteins rely on N-terminal presequences for organellar targeting and import. While generally described as positively charged amphiphilic helices, presequences lack a consensus motif and thus likely promote protein import into mitochondria with variable efficiencies. Indeed, the concept of presequence strength underlies biological models such as stress sensing, yet a quantitative analysis of what dictates strong versus weak presequences is lacking. Furthermore, the extent to which presequence strength affects mitochondrial function and cellular fitness remains unclear. Here, we capitalize on the MitoLuc protein import assay to define multiple aspects of presequence strength. We find that select presequences, including those that regulate the mitochondrial unfolded protein response (UPRmt), impart differential import efficiencies during mitochondrial uncoupling. Surprisingly, we find that presequences beyond those associated with stress signaling promote highly variable import efficiency in vitro, suggesting presequence strength may influence a broader array of processes than currently appreciated. We exploit this variability to demonstrate that only presequences that promote robust in vitro import can fully rescue defects in respiratory growth in complex IV-deficient yeast, suggesting that presequence strength dictates metabolic potential. Collectively, our findings demonstrate that presequence strength can describe numerous metrics, such as total imported protein, maximal import velocity, or sensitivity to uncoupling, suggesting that the annotation of presequences as weak or strong requires more nuanced characterization than typically performed. Importantly, we find that such variability in presequence strength meaningfully affects cellular fitness beyond stress signaling, suggesting that organisms may broadly exploit presequence strength to fine-tune mitochondrial import and thus organellar homeostasis.
    DOI:  https://doi.org/10.1083/jcb.202507116
  8. J Biomed Sci. 2026 Jan 05. 33(1): 5
    PHGDH at the crossroads: metabolic plasticity, metastatic paradoxes, and therapeutic reconnaissance in cancer.
    Liang Hao, Bai-Qiang Li, Shi-Yang Lu, Zhong-Cai An, Zheng-Yuan Yin, Zhen-Xian Du, Hua-Qin Wang.
      Phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme of the serine biosynthesis pathway (SSP), is a central metabolic hub and multifunctional oncoprotein that drives tumorigenesis through both canonical and non-canonical mechanisms. This review outlines the multi-level regulation of PHGDH, covering epigenetic remodeling (DNA hypomethylation, H3K4me3/H3K36me3 dynamics), transcriptional control (ATF4, MYC, EWS-FLI1), post-transcriptional fine-tuning (m6A/m5C modifications, RNA-binding proteins), and post-translational modifications (ubiquitination, methylation, phosphorylation). Together, these regulatory layers allow cancer cells to adapt metabolically to microenvironmental stress. Beyond its fundamental role in supplying nucleotides, maintaining redox homeostasis, and supporting one-carbon metabolism, PHGDH also performs moonlighting function. For example, its translocation to the nucleus inhibits PARP1 to sustain oncogenic transcription, while its presence in mitochondria helps remodel electron transport chains to promote metastasis. Critically, PHGDH exhibits a therapeutic paradox wherein its inhibition can synergize with chemotherapy, radiotherapy, and immunotherapy across diverse malignancies, yet tumors develop resistance via metabolic plasticity, or by selection of PHGDH-low metastatic clones. The clinical translation of PHGDH inhibitors is further challenged by inherent neurotoxicity risks, as neurons rely on de novo serine synthesis. To address these challenges, we propose a precision roadmap that integrates spatial multi-omics, AI-driven allosteric inhibitor design, dynamic biosensing (e.g., 18F-metabolite PET), and biomarker-stratified clinical trials. By reconciling the dual nature of PHGDH biology, we can transform this metabolic linchpin from a confounding paradox into a clinically actionable vulnerability.
    Keywords:  Metastatic heterogeneity; Neurotoxicity paradox; PHGDH; Precision metabolic oncology; Serine biosynthesis pathway; Spatial multi-omics
    DOI:  https://doi.org/10.1186/s12929-025-01205-y
  9. Nat Immunol. 2026 Jan 07.
    Active aldehydes accelerate CD8+ T cell exhaustion by metabolic alteration in the tumor microenvironment.
    Yasuharu Haku, Koji Kitaoka, Koki Ichimaru, Tomoko Hirano, Jun Wang, Kazuhiro Sonomura, Asuka Maruo, Shuhei Hirose, Yu Wang, Katsuhiro Ito, Tomohiro Kozuki, Keiko Yurimoto, Mai Kiyono, Hidetaka Kosako, Toshi Menju, Hiroshi Date, Takashi Kobayashi, Koichi Omori, Tomonori Yaguchi, Tasuku Honjo, Kenji Chamoto.
      Glycolysis and mitochondrial fatty acid oxidation (FAO) regulate CD8+ T cell differentiation, but how this metabolic balance regulates T cell exhaustion is unclear. PD-1 signaling inhibits glycolysis and enhances FAO. Here, we show that CD8+ T cells in tumors adhere to glycolysis with attenuated FAO despite high PD-1 expression. Active aldehydes, final products of lipid peroxidation, accumulate in CD8+ T cells in proportion to their level of exhaustion, defined by mitochondrial mass and potential. Aldehydes promote glycolysis and inhibit FAO in T cells. Mice deficient in an FAO enzyme in T cells generate more acrolein, a representative aldehyde, enhancing T cell exhaustion and attenuating antitumor immunity. Acrolein is generated partly from mitochondria and damages mitochondrial architecture. Inhibitors of lipid peroxidation or aldehydes enhanced PD-1-blockade by rectifying metabolic imbalance. Therefore, active aldehydes resulting from FAO impairment can cause a vicious cycle of metabolic imbalance that leads to T cell exhaustion.
    DOI:  https://doi.org/10.1038/s41590-025-02370-w
  10. Science. 2026 Jan 08. eady5532
    Mitochondrial control of fuel switching via carnitine biosynthesis.
    Christopher Auger, Hiroshi Nishida, Bo Yuan, Guilherme Martins Silva, Masanori Fujimoto, Mark Li, Daisuke Katoh, Dandan Wang, Melia Granath-Panelo, Jihoon Shin, Rose Witte, Jin-Seon Yook, Anthony R P Verkerke, Alexander S Banks, Sheng Hui, Lijun Sun, Shingo Kajimura.
      Environmental adaptation often involves a shift in energy utilization toward mitochondrial fatty acid oxidation, which requires carnitine. Besides dietary sources of animal origin, carnitine biosynthesis from trimethyllysine (TML) is essential, particularly for those who consume plant-based diets; however, its molecular regulation and physiological role remain elusive. Here, we identify SLC25A45 as a mitochondrial TML carrier that controls carnitine biosynthesis and fuel switching. SLC25A45 deficiency decreased the carnitine pool and impaired mitochondrial fatty acid oxidation, shifting reliance to carbohydrate metabolism. Slc25a45-deficient mice were cold-intolerant and resistant to lipid mobilization by GLP1 receptor agonist (GLP-1RA), rendering them resistant to adipose tissue loss. Our study suggests that mitochondria serve as a regulatory checkpoint in fuel switching, with implications for metabolic adaptation and the efficacy of GLP-1RA-based anti-obesity therapy.
    DOI:  https://doi.org/10.1126/science.ady5532
  11. bioRxiv. 2025 Dec 26. pii: 2025.12.24.696399. [Epub ahead of print]
    MECP2 Duplication Uncouples Mitochondrial and Purine Metabolism During neuronal maturation.
    Gerarda Cappuccio, Guantong Qi, Xuan Qin, Saleh Mahmud Khalil, John Hunyara, Yang Li, Joel Mathews, Armand Soriano, Sivan Osenberg, Senghong Sing, Toni Claire Tacorda, Luke Parkitny, Jennifer Sheppard, George Timpone, Sergio Attanasio, Sara Bitar, Ashley Grace Anderson, Demian Rocha Ifa, Christine Coquery, Bernard Suter, Davut Pehlivan, Hu Chen, Zhandong Liu, Feng Li, Huda Y Zoghbi, Paymaan Jafar-Nejad, Mirjana Maletic-Savatic.
      Mitochondria and nucleotide metabolism are critical for cellular and developmental homeostasis, yet their potential interdependence and role in neurodevelopmental disease remain unclear. In MECP2 Duplication Syndrome (MDS), we identify a conserved correlation between mitochondrial function and purine metabolism that is disrupted across human, organoid, and mouse models. Multiomics integration reveals Complex III as the focal point of mitochondrial collapse, leading to redox stress, DNA damage, and hyperactivation of the de novo purine biosynthesis via purinosome assembly. The breakdown of mitochondria-purinosome coupling compromises genome stability, impairs radial glia proliferation, and delays neuronal maturation. By linking a defined genetic dosage imbalance to metabolic network failure, our study positions the mitochondria-purinosome coordination as a fundamental control axis for neurodevelopment and a therapeutic entry point across metabolic and neurodevelopmental disorders.
    Keywords:  MeCP2; brain organoids; metabolome; mitochondria; multiomics; neuroprogenitors; purine
    DOI:  https://doi.org/10.64898/2025.12.24.696399
  12. Nat Cell Biol. 2026 Jan 09.
    RPA exhaustion activates SLFN11 to eliminate cells with heightened replication stress.
    Tyler H Stanage, Shudong Li, Sandra Segura-Bayona, Aurora I Idilli, Rhona Millar, Graeme Hewitt, Simon J Boulton.
      SLFN11 is epigenetically silenced and confers chemoresistance in half of all cancers. In response to replication stress, SLFN11 triggers translation shutdown and p53-independent apoptosis, but how DNA damage activates SLFN11 remains unclear. Here through CRISPR-based screens we implicate SLFN11 as the critical determinant of cisplatin sensitivity in cells lacking primase-polymerase (PrimPol)-mediated repriming. SLFN11 and the downstream integrated stress response uniquely promote cisplatin-driven apoptosis in PrimPol-deficient cells. We demonstrate that replication protein A (RPA) exhaustion and single-stranded DNA exposure trigger SLFN11 activation and cell death when PrimPol is inactivated. We further identify the USP1-WDR48 deubiquitinase complex as a positive modulator of SLFN11 activation in PrimPol-deficient cells, revealing an addiction to the Fanconi anaemia pathway to resolve cisplatin lesions. Finally, we demonstrate that rapid RPA exhaustion on chemical inhibition of DNA polymerase α activates SLFN11-dependent cell death. Together, our results implicate RPA exhaustion as a general mechanism to activate SLFN11 in response to heightened replication stress.
    DOI:  https://doi.org/10.1038/s41556-025-01852-1
  13. Nat Metab. 2026 Jan 08.
    Career pathways, part 18.
    Jiyeon Kim, Angelika Harbauer.
      
    DOI:  https://doi.org/10.1038/s42255-025-01432-5
  14. Nat Cancer. 2026 Jan 05.
    TGFβ induces an atypical EMT to evade immune mechanosurveillance in lung adenocarcinoma dormant metastasis.
    Zhenghan Wang, Yassmin Elbanna, Inês Godet, Siting Gan, Lila Peters, George Lampe, Yanyan Chen, Joao Xavier, Morgan Huse, Joan Massagué.
      Different forms of epithelial-to-mesenchymal transition (EMT) manifest during tumor progression. Little is known about the mechanistic basis and functional role of these distinct EMTs. We explored this question in lung adenocarcinoma (LUAD) primitive progenitors, which are competent to enter dormancy in response to transforming growth factor-β (TGFβ) upon metastatic dissemination. The TGFβ response in these cells includes growth arrest and a full EMT that subsequently transitions into an atypical mesenchymal state of round morphology and lacking actin stress fibers. TGFβ drives this transition by inducing expression of the actin depolymerizing protein gelsolin, which converts a migratory, stress-fiber-rich phenotype into a cortical actin-rich, spheroidal state. This transition lowers the biomechanical stiffness of metastatic progenitors and protects them from killing by cytotoxic lymphocytes. Gelsolin-deficient LUAD progenitors can enter dormancy but succumb to immune surveillance. Thus, quiescent LUAD metastatic progenitors undergo an atypical EMT to avert immune surveillance during TGFβ-driven metastatic dormancy.
    DOI:  https://doi.org/10.1038/s43018-025-01094-y
  15. Redox Biol. 2025 Nov 26. pii: S2213-2317(25)00449-5. [Epub ahead of print]89 103936
    A clickable CoQ imaging probe reveals that cellular uptake and lysosomal trafficking depend on CD36 and NPC1.
    Irene Liparulo, Arkadiy Bazhin, Grace Katherine Van Wyhe, Amanda Lestari Gunawan, Neville Dadina, Justin Hyunwoo Kwon, Alanna Schepartz, Elena Goun, Andreas Stahl.
      Coenzyme Q (CoQ) is a crucial lipid-soluble antioxidant and electron transporter vital for mitochondrial respiration and cellular redox balance. Despite the role of CoQ in oxidative phosphorylation being well established, the mechanisms by which CoQ is internalized, distributed among subcellular compartments, and trafficked to mitochondria remain poorly defined. Here, we present the development of a minimally modified, azide-tagged CoQ analogue that enables high-resolution visualization of CoQ localization using fluorescence-based imaging. Using this probe, we focus our investigation on brown adipose tissue (BAT), a mitochondria-rich, highly metabolically active tissue with elevated CoQ demand. On a cellular level, we demonstrate that CoQ is internalized via receptor-mediated endocytosis, predominantly localizing to lysosomes. Genetic knockdown and pharmacological studies identify CD36 and NPC1 as essential transporters in this process. Our work provides both a technical advance for the redox biology field, with the development and characterization of a CoQ probe, and the essential new biological insight that NPC1 is linked to CoQ homeostasis and thus provides a foundation for further dissection of CoQ biology in health and disease.
    DOI:  https://doi.org/10.1016/j.redox.2025.103936
  16. Redox Biol. 2026 Jan 05. pii: S2213-2317(26)00001-7. [Epub ahead of print]89 104003
    Revisiting molecular hydrogen signaling in mitochondria: Is the Rieske protein the entry point or a downstream sentinel?
    Sergej M Ostojic.
      A recent study published in Redox Biology (Volume 88, December 2025, 103952) demonstrates that molecular hydrogen (H2) rapidly suppresses mitochondrial Complex III activity through a mechanism involving the Rieske iron-sulfur protein (RISP) and subsequent LONP1-dependent proteolysis, challenging the long-standing view of H2 as merely a selective radical scavenger. While these findings compellingly identify RISP as a key mediator of mitochondrial responses to H2, its designation as the primary molecular target warrants broader consideration. From an evolutionary and structural standpoint, RISP belongs to a wider family of hydrogenase-like mitochondrial redox proteins that retain ancient iron-sulfur architectures. Proteins such as succinate dehydrogenase subunit B (SDHB), iron-sulfur subunits of Complex I, and CISD family [2Fe-2S] proteins share comparable redox logic and strategic positioning within mitochondrial bioenergetic networks. Here, these candidates are prioritized and placed into a hierarchical, testable framework, and specific comparative structural, biochemical, and proteostatic approaches are proposed to define the true molecular entry point of H2 signaling in human mitochondria.
    Keywords:  Bioenergetics; Electron transport chain; LONP1-Mediated proteostasis; Mitochondrial redox signaling; Molecular hydrogen; Rieske iron-sulfur protein
    DOI:  https://doi.org/10.1016/j.redox.2026.104003
  17. Geroscience. 2026 Jan 07.
    Aging kidney is associated with metabolic rewiring and epigenetic reprogramming.
    Pragney Deme, Rhea Bhargava, Heddwen L Brooks, Norman J Haughey, Prerna Kumar.
      Understanding the direct connections between metabolism and chromatin dynamics may uncover potential mechanisms involved in the aging process of renal physiology. Despite known differences in incidence and aging renal disease, how biological aging intersects with renal metabolism and epigenetics in a sex-specific context remains poorly understood. Here, we determined the effect of age on renal metabolic pathways and metabolite cofactors of epigenetic modifiers in a sex-specific manner. We measured metabolites in kidney homogenates from young and aged mice by HPLC-TripleTOF (LC-MS). The major metabolic adaptations observed with aging include increased glycolysis, decreased fatty acid oxidation, mitochondrial dysfunction, oxidative stress, and impaired metabolic waste clearance in 24-month-old (aged) mice compared to 4-month-old (young) sex-matched mice. Additionally, we found elevated levels of methylation and acetylation of intermediate metabolites also known as 'epimetabolites' in aged mice. Furthermore, age-related alterations were detected in metabolites (acetyl-coenzyme A, flavin adenine dinucleotide, and α-ketoglutarate) that are essential cofactors for the activities of epigenetic enzymes. Sex-specific changes were observed with age such as, significantly enhanced amino acid catabolism and tryptophan metabolism and reduced lysophospholipase activity and ammonia clearance in aged female vs aged male mice. Our results reveal age- and sex-associated alterations in renal metabolic pathways, characterized by an increase in epigenetically modified intermediate metabolites with aging. These findings suggest a complex interplay between renal metabolomics and epigenetics and offer new insights into the mechanisms underlying sex-specific renal physiology of aging kidneys.
    Keywords:  Epimetabolites; Metabolite cofactors for epigenetic enzymes; Metabolomics; Renal aging; Sex differences
    DOI:  https://doi.org/10.1007/s11357-025-02071-0
  18. Oncogene. 2026 Jan 04.
    Targeting STING elicits GSDMD-dependent pyroptosis and boosts anti-tumor immunity in renal cell carcinoma.
    Shengpan Wu, Baojun Wang, Hongzhao Li, Hanfeng Wang, Songliang Du, Xing Huang, Yang Fan, Yu Gao, Liangyou Gu, Qingbo Huang, Jianjun Chen, Xu Zhang, Yan Huang, Xin Ma.
      While Stimulator-of-interferon genes (STING) is an innate immune adapter crucial for sensing cytosolic DNA and modulating immune microenvironment, its tumor-promoting role in tumor survival and immune evasion remains largely unknown. Here we reported that renal cancer cells are exceptionally dependent on STING for survival and evading immunosurveillance via suppressing ER stress-mediated pyroptosis. We found that STING is significantly amplified and upregulated in clear cell renal cell carcinoma (ccRCC), and its elevated expression is associated with worse clinical outcomes. Mechanically, STING depletion in RCC cells specifically triggers activation of the PERK/eIF2α/ATF4/CHOP pathway and activates cleavage of Caspase-8, thereby inducing GSDMD-mediated pyroptosis, which is independent of the innate immune pathway of STING. Moreover, animal study results revealed that STING depletion promoted infiltration of CD4+ and CD8+ T cells, consequently boosting robust antitumor immunity via pyroptosis-induced inflammation. From the perspective of targeted therapy, we found that Compound SP23, a PROTAC STING degrader, demonstrated comparable efficacy to STING depletion both in vitro and in vivo for treatment of ccRCC. These findings collectively unveiled an unforeseen function of STING in regulating GSDMD-dependent pyroptosis, thus regulating immune response in RCC. Consequently, pharmacological degradation of STING by SP23 may become an attractive strategy for treatment of advanced RCC.
    DOI:  https://doi.org/10.1038/s41388-025-03671-y
  19. Nat Metab. 2026 Jan 08.
    Chewing the fat: a novel mechanism for lipolysis.
    Alison H Affinati, Michael W Schwartz.
      
    DOI:  https://doi.org/10.1038/s42255-025-01426-3
  20. Cell. 2026 Jan 08. pii: S0092-8674(25)01423-0. [Epub ahead of print]189(1): 3-5
    When heme is low, copper kills cancer.
    Andreas Linkermann.
      Heme carries oxygen and is critical for the control of redox reactions. In this issue of Cell, Lewis and Gruber et al. demonstrate how low concentrations of heme destabilize complex IV of the respiratory chain to release copper and kill acute myeloid leukemia cells by cuproptosis.
    DOI:  https://doi.org/10.1016/j.cell.2025.12.010
  21. Nat Commun. 2026 Jan 07.
    Loss of KDM6A-mediated genomic instability and metabolic reprogramming regulates response to therapeutic perturbations in bladder cancer.
    Pratishtha Singh, Ranit D'Rozario, Bidisha Chakraborty, Swadhin Meher, Deblina Raychaudhuri, Aminah J Tannir, Yang Li, Anurag Majumdar, Jessalyn Hawkins, Yun Xiong, Philip Lorenzi, Padmanee Sharma, Kadir Akdemir, Patrick Pilie, Abhinav K Jain, Byron Hing Lung Lee, Sangeeta Goswami.
      Mutations in epigenetic regulators are common in bladder cancer, yet their impact on therapeutic responses remains unclear. Here, we identify that loss-of-function mutations in KDM6A, a histone demethylase altered in about 26% of advanced bladder cancers, are associated with poor survival after cisplatin chemotherapy, whereas they correlate with improved outcomes with anti-PD-1 therapy. Using CRISPR-Cas9-engineered murine and human bladder cancer models, we show that KDM6A deficiency increases formation of extrachromosomal circular DNA carrying chemoresistance loci, promoting cisplatin resistance. In parallel, KDM6A loss impairs DNA repair and rewires tumor metabolism, reducing glycolysis and lactate output. This metabolic shift diminishes histone lactylation in regulatory T cells, suppressing immunoregulatory genes and limiting expansion of PD-1hi regulatory T cells. Collectively, our findings establish KDM6A mutation as a key regulator of therapeutic responses, providing a foundation for its use in guiding precision therapy in advanced bladder cancer.
    DOI:  https://doi.org/10.1038/s41467-025-68132-2
  22. Cancer Lett. 2026 Jan 04. pii: S0304-3835(26)00007-8. [Epub ahead of print] 218244
    Amino Acid Metabolic Reprogramming in Clear Cell Renal Cell Carcinoma: Pathogenic Mechanisms and Therapeutic Targeting.
    Junzhe Xie, Fangjing Ni, Jialiang Shao, Dongliang Zhang, Tuanjie Guo, Xiang Wang.
      Kidney cancer is a major global health burden, with clear cell renal cell carcinoma (ccRCC) as the most common and aggressive subtype. Beyond the typical alterations of high glucose uptake and lipid accumulation, amino acid metabolism dysregulation in ccRCC is also gradually being uncovered. Pathways involving glutamine, cystine, serine, glycine, branched-chain amino acids, methionine, aspartate, arginine, proline and tryptophan are extensively rewired. These alterations enable cancer cells to sustain proliferation and biosynthesis, maintain redox balance, remodel the immune microenvironment, and develop resistance to therapy. At the same time, such reprogramming creates metabolic dependencies and vulnerabilities, including glutamine and cystine addiction as well as arginine auxotrophy. Dysregulation of key enzymes such as GLS1, ASS1 and IDO1 further highlights potential therapeutic targets. Exploiting these vulnerabilities through metabolic inhibitors or rational combinations with targeted and immunotherapy holds promise for overcoming resistance and improving outcomes in ccRCC.
    Keywords:  amino acid metabolism; clear cell renal cell carcinoma; metabolic reprogramming; therapeutic vulnerability
    DOI:  https://doi.org/10.1016/j.canlet.2026.218244
  23. bioRxiv. 2025 Dec 23. pii: 2025.12.21.695848. [Epub ahead of print]
    Mitochondrial ROS-induced metabolic alterations differentially regulate ferroptosis sensitivity.
    Somesh Banerjee, Matthew Ryan Smith, Yining Irene Wang, Michael Wang, Derrik Gratz, Gregory K Tharp, Sumin Kang, Peijian He.
      Ferroptosis is an iron-catalyzed lipid peroxidation (LP)-dependent cell death. Induction of mitochondrial ROS (mtROS) is crucial in the execution of ferroptosis, but the underlying mechanism remains unclear. Through utilizing the hepatocyte model and RNA-seq analysis, we determined mtROS-dependent metabolic changes that modulate ferroptosis sensitivity. Elevated mtROS production and LP suppressed glycolysis, fatty acid oxidation, and citric acid cycle activity, representing adaptive responses that protect cells from ferroptosis. On the other hand, mtROS-driven signaling impaired glutathione biosynthesis and downregulated genes involved in coenzyme Q10 (CoQ) biosynthesis, including those in the mevalonate pathway and CoQ8A, a key stabilizer of the CoQ biosynthetic complex. Importantly, silencing CoQ8A expression enhanced, whereas overexpression of CoQ8A reduced, ferroptosis susceptibility of hepatocytes and various cancer cell types. The mtROS-mediated downregulation of CoQ8A was dependent on farnesoid X receptor (FXR) and retinoid X receptors (RXRs). Collectively, our findings highlight that mtROS promotes ferroptosis, at least in part, by suppressing glutathione and CoQ biosynthesis.
    DOI:  https://doi.org/10.64898/2025.12.21.695848
  24. Cell Metab. 2026 Jan 06. pii: S1550-4131(25)00529-7. [Epub ahead of print]38(1): 33-49.e10
    Dual inhibition of ACLY and ACSS2 by EVT0185 reduces steatosis, hepatic stellate cell activation, and fibrosis in mouse models of MASH.
    Fiorella Di Pastena, Jaya Gautam, James S V Lally, Russta Fayyazi, Estelle Grasset, Dipankar Bhattacharya, Gio Fidelito, Elham Ahmadi, Logan K Townsend, Battsetseg Batchuluun, Daniela Carmen Oniciu, Spencer Heaton, Roger S Newton, Theodoros Tsakiridis, Evangelia E Tsakiridis, Suhrid Banskota, Parneet Deo, François Briand, Kat Hall, Eunice Lee, Vijayaragavan Muralidharan, Matthew J Watt, Scott L Friedman, Dongdong Wang, Gregory R Steinberg.
      Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by steatosis, inflammation, and fibrosis driven by hepatic stellate cell (HSC) activation. Acetyl-CoA is central to de novo lipogenesis (DNL) and cholesterol synthesis and is generated from citrate via ATP citrate lyase (ACLY) or from acetate via acetyl-CoA synthetase (ACSS2). Here, we demonstrate that a dual inhibitor of ACLY and ACSS2, EVT0185, reduces serum and liver triglycerides, insulin resistance, and fibrosis. EVT0185 directly suppresses HSC activation in vivo and in vitro, with spatial transcriptomics and single-cell RNA sequencing revealing inhibition of acetate metabolism via ACSS2 and cholesterol synthesis as key drivers of the phenotype. EVT0185 also inhibits de novo lipogenesis in human liver slices and blocks TGFβ1-induced activation of primary human HSCs. These findings suggest that targeting cholesterol and acetate metabolism through dual ACLY and ACSS2 inhibition represents a promising therapeutic approach for MASH and liver fibrosis.
    Keywords:  EVT0185; HSCs; MASH; acetate; acetyl-CoA metabolism; cholesterol; fibrosis; hepatic stellate cells; metabolic dysfunction-associated steatohepatitis
    DOI:  https://doi.org/10.1016/j.cmet.2025.11.015
  25. Nat Cell Biol. 2026 Jan 06.
    Mitotic errors as triggers of cell death and inflammation.
    Dario Rizzotto, Christian Zierhut, Andreas Villunger.
      Bursts of cell proliferation after infection, injury or transformation can coincide with DNA damage and spindle assembly defects. These increase the risk of cell cycle arrest in mitosis, during which many cellular processes are uniquely regulated. Ultimately, cells arrested during mitosis may die, but adaptive mechanisms also allow their escape into the next interphase. This step can have variable consequences, including chromosome missegregation, polyploidization and centrosome amplification. Escaping cells can also initiate innate immune signalling, enter senescence or engage cell death, which in turn alert the microenvironment through nucleic acid sensing mechanisms and/or the release of danger-associated molecular patterns. Here we discuss the causes and consequences of deregulated mitosis and postmitotic cell fate, highlighting the impact of DNA damage repair, the spindle assembly checkpoint and extra centrosomes on genome integrity, as well as inflammatory signalling. Finally, we attempt to reconcile conflicting observations and propose variable modes that activate innate immune responses after mitotic perturbations.
    DOI:  https://doi.org/10.1038/s41556-025-01785-9
  26. bioRxiv. 2025 Dec 23. pii: 2025.12.19.695597. [Epub ahead of print]
    Methionine synthase reductase regulates heterochromatin independently of methionine synthesis through mitochondrial homeostasis.
    Fernanda Rezende Pabst, Andrey Tvardovskiy, Iratxe Estibariz, Veronica Finazzi, Pauline Couacault, Anna Artati, Michael Witting, Antonio Scialdone, Till Bartke, Daphne Selvaggia Cabianca.
      Metabolic enzymes can influence chromatin organization by modulating the availability of key metabolites, yet how specific metabolic reactions affect chromatin function remains poorly understood. Here, we show that in Caenorhabditis elegans, the methionine-cycle enzyme methionine synthase reductase (MTRR-1/MSR) regulates heterochromatin independently of methionine synthesis. Loss of MTRR-1, but not of the methionine synthase METR-1/MS, specifically reduces heterochromatic histone methylation, derepresses repetitive elements, and causes developmental delay. Multi-omics profiling revealed that mtrr-1 mutants activate transcriptional programs associated with mitochondrial stress and accumulate long-chain acylcarnitines, indicating disrupted mitochondrial homeostasis. Functional assays confirmed altered mitochondrial respiration in mtrr-1 mutants, while direct perturbation of mitochondrial function was sufficient to induce heterochromatin defects. Together, our results reveal a previously unrecognized mitochondria-to-chromatin axis controlled by the methionine-cycle enzyme MTRR-1/MSR.
    DOI:  https://doi.org/10.64898/2025.12.19.695597
  27. bioRxiv. 2025 Dec 23. pii: 2025.12.21.694897. [Epub ahead of print]
    A dietary pan-amino acid dropout screen in vivo reveals a critical role for histidine in T-ALL.
    Komal Mandleywala, Simona Ulrich, Victoria da Silva-Diz, Puneet Sharma, Christopher Thai, Oekyung Kim, Maya Aleksandrova, Gwendolyn Chung, Cristian Eggers, Dieter Lütjohann, Tanaya Kulkarni, Amartya Singh, M Elena Díaz-Rubio, Michael Wierer, Sebastian A Leidel, Xiaoyang Su, Eileen P White, Joshua D Rabinowitz, Raphael J Morscher, Daniel Herranz.
      Dietary interventions show therapeutic potential in cancer, but systematic comparisons are lacking. We performed a dietary pan-amino acid dropout screen in an orthotopic model of NOTCH1-driven T-cell acute lymphoblastic leukemia and identified histidine depletion as uniquely antileukemic. Histidine-restricted diets extended survival of leukemic mice in a dose-dependent manner, while remaining well-tolerated. Mechanistically, multiomic profiling revealed that histidine deprivation-induced ribosome stalling activates GCN2 to suppress cholesterol biosynthesis pathways critical for leukemic proliferation. Dietary cholesterol supplementation partially reverted the antileukemic effects of histidine restriction in vivo . These findings couple histidine levels and translational control to cholesterol metabolism, which can be therapeutically exploited for cancer treatment. Our results suggest that defined dietary amino acid restrictions may expose broader therapeutic opportunities in diseases beyond cancer.
    DOI:  https://doi.org/10.64898/2025.12.21.694897
  28. STAR Protoc. 2026 Jan 03. pii: S2666-1667(25)00715-4. [Epub ahead of print]7(1): 104309
    Protocol for stable isotopic tracing to assess cellular lipogenic activity in induced neural stem cells.
    Rosana-Bristena Ionescu, Julie A Reisz, Monika Dzieciatkowska, Daniel Stephenson, Alexandra M Nicaise, Pranathi Prasad, Cory M Willis, Marta Suarez Cubero, Luca Peruzzotti-Jametti, Frank Edenhofer, Christian Frezza, Stefano Pluchino, Angelo D'Alessandro.
      Here, we present a protocol to assess the lipogenic phenotype of induced neural stem cells (iNSCs) using stable isotopic tracing. We describe steps for the culture and preparation of iNSCs, labeling with [13C6]-glucose and [13C5, 15N2]-glutamine, and the subsequent extraction of metabolites, lipids, and proteins from the same sample. This protocol supports single-specimen, mass spectrometry-based multi-omics workflows and is applicable to steady-state analyses, stable isotope tracing, and characterization of protein post-translational modifications. For complete details on the use and execution of this protocol, please refer to Ionescu et al.1.
    Keywords:  metabolism; neuroscience; proteomics; protocols in metabolomics and lipidomics; stem cells
    DOI:  https://doi.org/10.1016/j.xpro.2025.104309
  29. Cell Host Microbe. 2026 Jan 02. pii: S1931-3128(25)00522-0. [Epub ahead of print]
    Microbiota utilization of intestinal amino acids modulates cancer progression and anticancer immunity.
    JRI Live Cell Bank Consortium
      The human microbiota modulates cancer progression through largely unexplored mechanisms. Defining causal pathways is essential for monitoring and fine-tuning the microbiota to improve cancer treatment. Given that amino acid (aa) metabolism is often dysregulated in cancer, we assessed the role of microbiota pathways that modulate intestinal aa levels on colorectal tumor progression in mice. We found that the Bacteroides gene bo-ansB affects tumor responses to dietary asparagine (Asn) by reducing intestinal Asn levels. In mice receiving dietary Asn, bo-ansB promotes tumor progression by altering tumor-infiltrating CD8+ T cells. Mechanistically, bo-ansB depletes Asn in the tumor microenvironment (TME), suppressing the expression of an Asn transporter (SLC1A5) in CD8+ T cells and impairing their stem-like properties and effector functions. In humans, microbiota-encoded genes contributing to aa depletion are associated with colorectal cancer progression. Collectively, these findings reveal nutrient-dependent modulation of anticancer immunity by the gut microbiota and identify diet-microbiota-cancer crosstalk as a potential therapeutic target.
    Keywords:  Bacteroides asparaginase; CD8 T cell; amino acid transporter SLC1A5; antitumor immunity; asparagine; diet-microbiota-cancer crosstalk; gut microbiota; host-microbe interactions; microbial amino acid metabolism
    DOI:  https://doi.org/10.1016/j.chom.2025.12.003
  30. Mol Cell. 2026 Jan 08. pii: S1097-2765(25)00980-3. [Epub ahead of print]86(1): 135-149.e9
    Membrane-protein-mediated phase separation orchestrates organelle contact sites.
    Christian Hoffmann, Takahiro Nagao, Taka A Tsunoyama, Johannes Vincent Tromm, Chinyere Logan, Koki Nakamura, Han Wang, Frans Bianchi, Geert van den Bogaart, Akihiro Kusumi, Yusuke Hirabayashi, Dragomir Milovanovic.
      Mitochondria and the endoplasmic reticulum (ER) contain large areas that are in close proximity. Yet the mechanism of how these inter-organellar adhesions are formed remains elusive. Tight functional connections, termed "membrane contact sites," assemble at these areas and are essential for exchanging metabolites and lipids between the organelles. Recently, the ER-resident protein PDZ domain-containing protein 8 (PDZD8) was identified as a tether between the ER and mitochondria or late endosomes/lysosomes. Here, we show that PDZD8 can undergo phase separation via its intrinsically disordered region (IDR). Endogenously labeled PDZD8 forms condensates on membranes both in vitro and in mammalian cells. Electron microscopy analyses indicate that the expression of full-length PDZD8 rescues the decrease in inter-organelle contacts in PDZD8 knockout cells but not PDZD8 lacking its IDR. Together, this study identifies that PDZD8 condensates at the lipid interfaces act as an adhesive framework that stitches together the neighboring organelles and supports the structural and functional integrity of inter-organelle communication.
    Keywords:  PDZD8; biomolecular condensates; endoplasmic reticulum; liquid-liquid phase separation; membrane contact sites; mitochondria
    DOI:  https://doi.org/10.1016/j.molcel.2025.12.006
  31. Cell. 2026 Jan 07. pii: S0092-8674(25)01422-9. [Epub ahead of print]
    EcDNA-borne structural variants drive oncogenic fusion transcript amplification.
    Hyerim Yi, Shu Zhang, Jason Swinderman, Yanbo Wang, Vishnupriya Kanakaveti, King L Hung, Ivy Tsz-Lo Wong, Suhas Srinivasan, Ellis J Curtis, Aarohi Bhargava-Shah, Rui Li, Matthew G Jones, Jens Luebeck, Chris Bailey, Yanding Zhao, Julia A Belk, Katerina Kraft, Quanming Shi, Xiaowei Yan, Simon K Pritchard, Kabir S Mahajan, Frances Liang, Mariam Jamal-Hanjani, Dean W Felsher, Luke A Gilbert, Vineet Bafna, Paul S Mischel, Howard Y Chang.
      Extrachromosomal DNA (ecDNA) amplifications are key drivers of human cancers. Here, we show that ecDNAs are major platforms for generating and amplifying oncogene fusion transcripts across diverse cancer types. By integrating analysis of whole-genome and transcriptome sequences from tumor samples and cancer cell lines of a wide variety of tissue types, we reveal that ecDNAs have the highest rate of oncogene fusion events of any copy-number alteration. Focusing on the most common ecDNA fusion hotspot, we find that fusion of the 5' end of the long noncoding RNA gene, PVT1-with exon 1 joined to diverse 3' partners-confers increased RNA stability, potentially via an SRSF1-dependent mechanism, and enhances MYC-dependent transcription and cancer cell survival. These results demonstrate that ecDNA fosters genome instability and frequent oncogene fusion formation in cancer.
    Keywords:  PVT1; RNA fusion; RNA stability; SRSF1; cancer; ecDNA; extrachromosomal DNA; oncogene
    DOI:  https://doi.org/10.1016/j.cell.2025.12.009
  32. bioRxiv. 2026 Jan 04. pii: 2025.12.31.697195. [Epub ahead of print]
    Senescence-inhibitory Δ133p53α counteracts accelerated ageing and mortality.
    Leo Yamada, Huaitian Liu, Natalia von Muhlinen, Curtis C Harris, Izumi Horikawa.
      Research on progeria not only contributes to treatments for the disease but also enhances our understanding of physiological ageing 1 . Mouse models of progeria recapitulate pathological ageing phenotypes seen in patients, including cardiovascular defects, increased cellular senescence, systemic inflammation, DNA damage accumulation, and shortened lifespan 2 . In cultured cells from Hutchinson-Gilford progeria syndrome (HGPS) patients, the human p53 isoform Δ133p53α was previously shown to inhibit p53-mediated cellular senescence, proinflammatory IL-6 production, and DNA damage accumulation, and to extend cellular replicative lifespan 3 . Here we show that, in a heterozygous HGPS mouse model 4 , transgenic expression of Δ133p53α reproduces these in vitro -observed effects across multiple organs in vivo and extends median lifespan by 11% (387 versus 349 days, P = 0.0379). In the aorta and skin, Δ133p53α abrogates progeria-characteristic pathological changes and preserves tissue integrity. Our data further suggest that Δ133p53α may promote a broad spectrum of ageing-counteracting mechanisms, including bone homeostasis, metabolic fitness, antioxidant defense, youthful epigenome, and tissue stemness. Together with the anti-inflammatory and tissue-preserving effects of Δ133p53α in naturally aged mice and its age-associated downregulation in human tissues, this study suggests that Δ133p53α-based therapeutic strategies may be applicable not only to HGPS but also as broader interventions for preventing or delaying ageing.
    DOI:  https://doi.org/10.64898/2025.12.31.697195
  33. bioRxiv. 2025 Dec 23. pii: 2025.12.20.695697. [Epub ahead of print]
    Regulation of the Rheb GTPase via GATOR1 Complex.
    Aditi Prabhakar, William B Mair.
      mTORC1 coordinates cellular growth and metabolism by integrating inputs from both amino acids and growth factors, and its activation requires two upstream branches involving the Rag GTPases and the Rheb GTPase. These branches are regulated by distinct GAP complexes: GATOR1 (Depdc5-Nprl2-Nprl3) inhibits RagA/B, and TSC (TSC1-TSC2-TBC1D7) inhibits Rheb. Despite the prevailing view that these pathways converge only at mTORC1 itself, several observations suggest upstream crosstalk. This gap is especially striking in organisms like C. elegans and S. cerevisiae that lack the TSC complex yet maintain fully responsive mTORC1 signaling. How these inputs are dynamically coordinated under complex physiological conditions and in organisms lacking the key components remain unknown. We performed unbiased quantitative proteomics in C. elegans and identified the GATOR1 complex as a previously unrecognized RHEB-1 ( C. elegans ortholog of Rheb) interactor. Through biochemical validation in human cells, we show that nucleotide-free Rheb associates with the Nprl2-Nprl3 subunits of GATOR1, whereas GTP-bound or membrane-detached Rheb mutants fail to bind. Nutrient stress, but not direct pharmacologic inhibition of mTORC1, robustly induced this interaction. In TSC2-null cells, where Rheb is constitutively GTP-loaded, Rheb-Nprl2/3 binding was strongly diminished and was restored by expressing the nucleotide-free Rheb S20N mutant, demonstrating that Rheb's nucleotide state governs this interaction. Pulldown assays confirmed that the Nprl2/3 heterodimer is sufficient for binding nucleotide-free Rheb. Structural modeling using AlphaFold3 consistently positioned Rheb at a conserved site on Nprl3 distinct from the RagA/B GAP-active surface of Nprl2, supporting a non-catalytic mode of association. Together, these findings identify a conserved, nutrient-regulated physical interaction between Rheb and the Nprl2/3 subunits of GATOR1, revealing a previously unrecognized point of convergence between the growth factor and amino acid branches of the mTORC1 pathway. This model provides a direct molecular link between the Rag and Rheb branches, furthering our understanding of how nutrient stress fine-tunes mTORC1 signaling.
    DOI:  https://doi.org/10.64898/2025.12.20.695697
  34. Cell. 2026 Jan 05. pii: S0092-8674(25)01378-9. [Epub ahead of print]
    Extracellular GPX4 impairs antitumor immunity via dendritic ZP3 receptors.
    Jiao Liu, Xiutao Cai, Junhao Lin, Zhenhui Zhang, Qile Zhou, Xiao Zhang, Lifang Ma, Yayou Miao, Ruoxi Zhang, Chunhua Yu, Yingyi Yang, Yangchun Xie, Rui Kang, Daniel J Klionsky, Peng Liu, Guido Kroemer, Daolin Tang, Jiayi Wang.
      Understanding the immunogenic properties of different forms of cell death is critical for rationalized antineoplastic therapeutic development. Here, we identify a regulatory axis that suppresses the immunogenicity of ferroptosis. During ferroptosis, but not apoptosis, cuproptosis, or necroptosis, cancer cells release glutathione peroxidase 4 (GPX4), which binds to zona pellucida glycoprotein 3 (ZP3) on the surface of dendritic cells (DCs), activates the 3',5'-cyclic adenosine monophosphate (cAMP)-protein kinase AMP-activated (PRKA) signaling cascade, inhibits glycolysis, and impairs maturation and activation of DCs, leading to a T cell priming defect. Disrupting the interaction between GPX4 and ZP3 restores DC metabolic activity and enhances antitumor immunity. In preclinical models, blockade of this pathway improves cancer immunosurveillance and potentiates cytotoxic T cell responses when combined with chemotherapy, immunochemotherapy, or radiotherapy. Clinically, high ZP3 expression predicts poor prognosis across multiple solid tumor types, while increased circulating GPX4 levels and ZP3 expression in DCs correlate with resistance to first-line therapies. These findings reveal an immunosuppressive danger signal that limits tumor immunity.
    Keywords:  cancer therapy; cell death; immunogenicity; oxidative stress; zona pellucida family
    DOI:  https://doi.org/10.1016/j.cell.2025.12.002
  35. Nat Cell Biol. 2026 Jan 05.
    Mitochondrial asymmetry shifts T cell fate.
    Sarah May Russell, Mirren Charnley.
      
    DOI:  https://doi.org/10.1038/s41556-025-01841-4
  36. Cell Chem Biol. 2026 Jan 06. pii: S2451-9456(25)00393-9. [Epub ahead of print]
    Redundant or resilient? A systems view of ferroptosis surveillance mechanisms.
    Deguang Liang, Xuejun Jiang.
      Ferroptosis is an iron-dependent form of regulated necrosis driven by phospholipid peroxidation. Its suppression relies on a multilayered surveillance system-including neutralizing phospholipid peroxides, terminating the propagation of lipid peroxidation, and limiting the substrates for phospholipid peroxidation-that operates across subcellular compartments and adapts to tissue-specific demands. Rather than functioning redundantly, these defense mechanisms are deployed in a resilient, context-specific manner, shaped by the metabolic profiles, redox states, and regenerative capacities of distinct cell types. Intact ferroptosis surveillance may be especially crucial for post-mitotic cells such as neurons, as its failure can lead to oxidative damage and irreversible degeneration. In contrast, cancer cells actively acquire ferroptosis resistance by upregulating antioxidant networks and reprogramming lipid metabolism, thereby creating a therapeutic vulnerability. Understanding how ferroptosis surveillance is spatially organized and dynamically regulated provides a framework for precision interventions-restoring redox resilience in degenerative disease or selectively inducing ferroptosis in tumors.
    Keywords:  ferroptosis; ferroptosis surveillance; free radical trapping; lipid peroxidation; phospholipid remodeling
    DOI:  https://doi.org/10.1016/j.chembiol.2025.11.013
  37. Nat Rev Endocrinol. 2026 Jan 09.
    Endocrine regulation of the hepatic fasting response: cues, cooperation and consequences.
    Dana Goldberg, Ido Goldstein.
      Upon fasting, mammals undergo a fasting response in which the liver's main role is producing fuel (glucose and ketone bodies) to supply extra-hepatic tissues. Glucose is produced by glycogenolysis and gluconeogenesis, and ketone bodies are produced by ketogenesis, which is preceded by lipolysis and fatty acid oxidation. Hepatic fuel production during fasting is controlled by hormonal and metabolic cues, collectively termed here 'fasting cues'. In this Review, we discuss fasting cues that directly signal hepatocytes and whose plasma levels increase upon fasting, namely, glucagon, glucocorticoids, growth hormone, adrenaline, free fatty acids, asprosin and GP73. We outline the fasting-dependent increases in blood levels of these cues, how they regulate transcription and the metabolic consequences of these cues in hepatocytes. We put particular emphasis on their role in directing fuel production. The perception of endocrine control of fuel production is shifting from the classic 'counter-regulatory' notion that fasting cues are simply opposing insulin action, to the realization that fasting cues cooperate with each other to elicit a synergistic response and also complement each other's actions indirectly. We discuss these modes of crosstalk and cooperation between fasting cues and describe the effects of signal integration on the transcriptional and metabolic response to fasting.
    DOI:  https://doi.org/10.1038/s41574-025-01228-3
  38. Biogerontology. 2026 Jan 06. 27(1): 33
    Chronic stress and the mitochondria-telomere axis: human evidence for a bioenergetic-debt model of early aging.
    Torsak Tippairote, Pruettithada Hoonkaew, Aunchisa Suksawang, Prayfan Tippairote.
      Chronic stress has been linked to mitochondrial dysfunction and impaired telomere maintenance, yet the mechanistic relationships connecting these pathways in humans remain poorly resolved. Using longitudinal findings from the Guillén-Parra cohort as a motivating human example, this Perspective offers a reinterpreted framework that proposes a unifying energetic interpretation in which bioenergetic insufficiency-defined as a mismatch between stress-induced energetic demand and mitochondrial throughout-rather than accumulated molecular damage, forms the upstream constraint linking stress physiology, mitochondrial performance, and telomerase regulation. In this cohort, lower baseline mitochondrial energetic capacity predicted greater longitudinal declines in telomerase activity, while telomere length remained stable across the short observation window, supporting the view that telomerase activity represents an early, energy-sensitive marker of unresolved stress adaptation, whereas telomere shortening is a delayed structural consequence. Interpreted within the Exposure-Related Malnutrition (ERM) framework, these patterns suggest that repeated activation of stress-response pathways without adequate metabolic recovery limits mitochondrial throughput and progressively compromises genome maintenance. In contrast, repeated exposure to mild stressors followed by sufficient recovery promotes adaptive strengthening of mitochondrial function and telomeric maintenance, consistent with physiological hormesis. We outline a roadmap integrating telomerase activity with dynamic indices of mitochondrial and redox function, including NAD⁺ availability, and emerging biomarkers of systemic energetic strain, such as circulating cell-free mitochondrial DNA and GDF15. By reframing aging phenotypes as early-stage failures of energetic resolution, this model highlights modifiable windows of vulnerability and hormesis-informed strategies-including exercise-induced adaptive stress, circadian alignment, and nutritional sufficiency-as actionable pathways for preserving mitochondrial resilience and telomere maintenance.
    Keywords:  Bioenergetic stress; Cellular senescence; Mitochondrial energetics; Psychological stress; Telomerase activity
    DOI:  https://doi.org/10.1007/s10522-025-10377-x
  39. Mol Cell. 2026 Jan 07. pii: S1097-2765(25)01015-9. [Epub ahead of print]
    CASTOR1 and CASTOR2 respond to different arginine levels to regulate mTORC1 activity.
    Chan Liu, Yifan Zhang, Yilun Wang, Min Wu, Yunchao Li, Jiashuai Wei, Jiawen Shi, Rong Wang, Li Su, Tingting Yang, Jin Li, Junjie Xiao, Jianping Ding, Tianlong Zhang.
      Mechanistic target of rapamycin complex 1 (mTORC1) is a central regulator of cell growth, responding to amino acid availability. While mTORC1 is modulated by amino acid sensors like CASTOR1, the mechanisms driving its dynamic response to fluctuating amino acid levels remain unclear. Here, we investigate the role of CASTOR2, an understudied CASTOR1 homolog, in regulating mTORC1 activity. We show that CASTOR1 and CASTOR2 bind to arginine similarly but differ in their sensitivity: CASTOR1 responds to low arginine levels, whereas CASTOR2 responds to high arginine concentrations. Both proteins interact with the GATOR2 component Mios, inhibiting its binding to GATOR1. Arginine binding to CASTOR1/2 induces conformational changes at the aspartate kinase, chorismate mutase, and TyrA (ACT) domain (ACT2-ACT4) interface, leading to its dissociation from Mios. Functionally, we demonstrate that CASTOR proteins are highly expressed in muscle tissue and, in C2C12 cells, they regulate mTORC1 and myogenesis in response to different arginine availability. These findings highlight how CASTOR proteins function as dual arginine sensors to fine-tune mTORC1 activity.
    Keywords:  CASTOR1; CASTOR2; GATOR1; GATOR2; amino acid sensor; arginine; mTORC1 signaling; myogenesis
    DOI:  https://doi.org/10.1016/j.molcel.2025.12.016
  40. PLoS Genet. 2026 Jan 09. 22(1): e1011836
    Local mitochondrial physiology defined by mtDNA quality guides purifying selection.
    Felix Thoma, Johannes Hagen, Romina Rathberger, Francesco Padovani, David Hörl, Kurt M Schmoller, Christof Osman.
      The mitochondrial genome (mtDNA) encodes essential subunits of the electron transport chain and ATP synthase. Mutations in these genes impair oxidative phosphorylation, compromise mitochondrial ATP production and cellular energy supply, and can cause mitochondrial diseases. These consequences highlight the importance of mtDNA quality control (mtDNA-QC), the process by which cells selectively maintain intact mtDNA to preserve respiratory function. Here, we developed a high-throughput flow cytometry assay for Saccharomyces cerevisiae to track mtDNA segregation in cell populations derived from heteroplasmic zygotes, in which wild-type (WT) mtDNA is fluorescently labeled and mutant mtDNA remains unlabeled. Using this approach, we observe purifying selection against mtDNA lacking subunits of complex III (COB), complex IV (COX2) or the ATP synthase (ATP6), under fermentative conditions that do not require respiratory activity. By integrating cytometric data with growth assays, qPCR-based mtDNA copy-number measurements, and simulations, we find that the decline of mtDNAΔatp6 in populations derived from heteroplasmic zygotes is largely explained by the combination of its reduced mtDNA copy number-biasing zygotes toward higher contributions of intact mtDNA-and the proliferative disadvantage of cells carrying this variant. In contrast, the loss of mtDNAΔcob and mtDNAΔcox2 cannot be explained by growth defects and copy-number asymmetries alone, indicating an additional intracellular selection against these mutant genomes when intact mtDNA is present. In heteroplasmic cells containing both intact and mutant mtDNA, fluorescent reporters revealed local reductions in ATP levels and membrane potential ([Formula: see text]) near mutant genomes, indicating spatial heterogeneity in mitochondrial physiology that reflects local mtDNA quality. Disruption of the respiratory chain by deletion of nuclear-encoded subunits (RIP1, COX4) abolished these physiological gradients and impaired mtDNA-QC, suggesting that local bioenergetic differences are required for selective recognition. Together, our findings support a model in which yeast cells assess local respiratory function as a proxy for mtDNA integrity, enabling intracellular selection for functional mitochondrial genomes.
    DOI:  https://doi.org/10.1371/journal.pgen.1011836
  41. Mol Metab. 2026 Jan 06. pii: S2212-8778(25)00223-6. [Epub ahead of print] 102316
    Targeting DHODH Reveals a Metabolic Vulnerability in AR-positive and AR-negative Prostate Cancer Cells via Pyrimidine Synthesis and Metabolic Crosstalk with the TCA and Urea Cycles.
    Maxime Labroy, Marc-Oliver Paré, Line Berthiaume, Mélissa Thomas, Cynthia Jobin, Alain Veilleux, Martin Pelletier, Frédéric Pouliot, Jean-Yves Masson, Étienne Audet-Walsh.
      Following recurrence, the cornerstone clinical therapy to treat prostate cancer (PCa) is to inhibit the androgen receptor (AR) signaling. While AR inhibition is initially successful, tumors will eventually develop treatment resistance and evolve into lethal castration-resistant PCa. To discover new anti-metabolic treatments for PCa, a high-throughput anti-metabolic drug screening was performed in PC3 cells, an AR-negative PCa cell line. This screening identified the dihydroorotate dehydrogenase (DHODH) enzyme as a metabolic vulnerability, using both AR-positive and AR-negative models, including the neuroendocrine cell line LASCPC-01 and patient-derived organoids. DHODH is required for de novo pyrimidine synthesis and is the sole mitochondrial enzyme of this pathway. Using extracellular flux assays and targeted metabolomics, DHODH inhibition was shown to impair the pyrimidine synthesis pathway, as expected, along with a significant reprogramming of mitochondrial metabolism, with a massive increase in fumarate (>10-fold). Using 13C6-glucose, it was shown that following DHODH inhibition, PCa cells redirect carbons from glucose toward biosynthetic pathways rather than the TCA cycle. In parallel, using 13C5-glutamine, it was shown that PCa cells use this amino acid to fuel a reverse TCA cycle. Finally, 13C1-aspartate and 15N1-glutamine highlighted the connection between pyrimidine synthesis and the urea cycle, redirecting pyrimidine synthesis intermediates toward the urea cycle as a stress response mechanism upon DHODH inhibition. Consequently, combination therapies targeting DHODH and glutamine metabolism were synergistic in impairing PCa cell proliferation. Altogether, these results highlight DHODH as a metabolic vulnerability of AR-positive and AR-negative PCa cells by regulating central carbon and nitrogen metabolism.
    Keywords:  BAY-2402234; DHODH; NEPC; androgen receptor; aspartate; cancer metabolism; castration-resistant prostate cancer; glucose; glutamine; mitochondria; neuroendocrine differentiation; neuroendocrine prostate cancer; nucleotide synthesis; prostate cancer
    DOI:  https://doi.org/10.1016/j.molmet.2025.102316
  42. J Biol Rhythms. 2026 Jan 04. 7487304251386926
    The Liver Clock Tunes Transcriptional Rhythms in Skeletal Muscle to Regulate Mitochondrial Function.
    Valentina Sica, Tomoki Sato, Ioannis Tsialtas, Sophia Hernandez, Siwei Chen, Pierre Baldi, Pura Muñoz-Cánoves, Paolo Sassone-Corsi, Kevin B Koronowski, Jacob G Smith.
      Circadian clocks present throughout the brain and body coordinate diverse physiological processes to support daily homeostasis, yet the specific interorgan signaling axes involved are not well defined. We previously demonstrated that the skeletal muscle clock controls transcript oscillations of genes involved in fatty acid metabolism in the liver, yet the impact of the liver clock on the muscle remained unknown. Here, we use male hepatocyte-specific Bmal1 KO mice (Bmal1hep-/-) to reveal that approximately one-third of transcript rhythms in skeletal muscle are influenced by the liver clock in vivo. Treatment of myotubes with serum harvested from Bmal1hep-/- mice inhibits expression of genes involved in metabolic pathways, including oxidative phosphorylation. Only small transcriptional changes were induced by liver clock-driven endocrine communication in vitro, leading us to surmise that the liver clock acts to fine-tune metabolic gene expression in muscle. Consistent with functional tuning, treatment of myotubes with serum collected from Bmal1hep-/- mice during the dark phase lowers mitochondrial ATP production compared with serum from wild-type mice. Overall, our results reveal communication between the liver clock and skeletal muscle, uncovering a bidirectional endocrine communication pathway that may contribute to the metabolic phenotypes of circadian disruption.
    Keywords:  Bmal1; circadian clocks; circadian rhythms; clock communication; interorgan crosstalk; liver metabolism; mitochondria; muscle-liver axis; peripheral clocks; skeletal muscle
    DOI:  https://doi.org/10.1177/07487304251386926
  43. bioRxiv. 2025 Dec 24. pii: 2025.12.22.696045. [Epub ahead of print]
    PTEN-loss confers dependence on the guanylate synthesis enzyme IMPDH in T-cell acute lymphoblastic leukemia.
    Rayees A Padder, Thu Le Le, Emily Hyde, Maria E D Rubio, Eric Chiles, Namratha Sheshadri, Kelly Mulraney, Wei-Xing Zong, Xiaoyang Su, Daniel Herranz, Alexander J Valvezan.
      Loss of the tumor suppressor PTEN is common in T-cell acute lymphoblastic leukemia (T-ALL), and is associated with poor prognosis. PTEN-loss drives robust activation of AKT/mTORC1 signaling to promote leukemic cell growth. We find that PTEN-loss in T-ALL confers dependence on the guanylate nucleotide synthesis enzyme inosine 5'-monophosphate dehydrogenase (IMPDH) for cell growth and viability. This metabolic vulnerability is dependent on sustained mTORC1 signaling and can be exploited using clinically approved IMPDH inhibitors to selectively kill PTEN-deficient T-ALL cells, and extend survival in genetic and xenograft T-ALL models in mice. Mechanistically, IMPDH inhibitors cause early DNA replication stress, followed by DNA damage. In contrast to treatment with mTORC1 inhibitors, these events culminate in robust and selective cell death in PTEN-deficient T-ALL cells. These findings reveal a targetable metabolic vulnerability in T-ALL, which could provide rationale for repurposing clinically approved IMPDH inhibitors.
    DOI:  https://doi.org/10.64898/2025.12.22.696045
  44. Redox Biol. 2025 Dec 24. pii: S2213-2317(25)00492-6. [Epub ahead of print]89 103979
    Superoxide signals for the mitophagy of dysfunctional mitochondria to maintain quality control.
    William M Curtis, Patrick C Bradshaw.
      The mechanism of selecting dysfunctional mitochondria for mitophagy is only partially understood. Evidence suggests the mechanism involves reactions of superoxide (O2-•), hydrogen peroxide (H2O2), nitric oxide (NO•), peroxynitrite (ONOO-), carbonate radicals (•CO3-), nitrogen dioxide radicals (•NO2), hydroxyl radicals (•OH), oxygen (•O2• or O2), and carbon dioxide (CO2). However, the larger picture of how these reactions are organized to induce mitophagy is unclear. Extensive evidence suggests that increased mitochondrial matrix O2-• is associated with the mitophagy of dysfunctional organelles. In most cells, mitochondrial O2-• is mainly produced by the reaction of O2 with free radical intermediate forms of coenzyme Q (CoQ) and flavins, which are generated in substantial amounts in the inner membrane and matrix space of dysfunctional mitochondria. Mitochondrial O2-• plays two key roles in orchestrating mitophagy. First, it is dismutated by mitochondrial matrix superoxide dismutase 2 (SOD2) to H2O2. This diffusible messenger directs the nuclear and cytoplasmic compartments to prepare for mitophagy, including the generation of cytoplasmic NADPH and glutathione and the increased synthesis of membrane-diffusible NO•. Second, mitochondrial matrix space O2-• readily reacts with NO• to form ONOO-, which initiates a cascade of free radical reactions culminating in mitochondrial membrane depolarization and PINK1 and Parkin-driven mitophagy. Compelling observations that support the proposed mechanism are given. This mechanism could be targeted for the treatment of diseases characterized by dysfunctional mitophagy, such as Parkinson's disease. Because of the central role of mitochondrial O2-• as a sentinel for selective mitophagy, we have named this hypothesis the superoxide sentinel hypothesis of mitochondrial quality control.
    Keywords:  DJ-1; Mitophagy; NADPH; Nitric oxide synthase; Parkinson's disease; Superoxide sentinel hypothesis
    DOI:  https://doi.org/10.1016/j.redox.2025.103979
  45. Nat Cell Biol. 2026 Jan 07.
    SLC2A1+ tumour-associated macrophages spatially control CD8+ T cell function and drive resistance to immunotherapy in non-small-cell lung cancer.
    Lei Wang, Han Chu, Degao Chen, Yuxuan Wei, Jia Jia, Liqi Li, Linfeng He, Lina Peng, Fangfang Liu, Shanshan Huang, Zheng Jin, Dong Zhou, WenFeng Fang, Tao Jiang, Shouxia Xu, Xiaofang Ding, Haoyang Cai, Xindong Liu, Qingzhu Jia, Bo Zhu, Qian Chu.
      Tumour-associated macrophages (TAMs) contribute to immune checkpoint blockade resistance, but their impact on intratumoural CD8⁺ T cell distribution remains unclear. Here we show that the expression of the glucose transporter SLC2A1 is spatially negatively correlated with CD8⁺ T cell distribution in both non-small-cell lung cancer (NSCLC) biopsies and murine tumour models. Tumour cell-specific Slc2a1 knockdown fails to reproduce the therapeutic benefit of SLC2A1 inhibition, whereas TAM-specific deletion of Slc2a1 suppresses tumour growth by enhancing the spatial homogeneity and effector function of intratumoural CD8⁺ T cells, thereby improving αPD-L1 efficacy. Spatial profiling of NSCLC specimens further revealed that SLC2A1⁺ TAM-enriched regions exhibit reduced CD8⁺ T cell density, and spatial proximity between these populations predicts resistance to αPD-(L)1 therapy. These findings identify SLC2A1⁺ TAMs as drivers of spatial CD8⁺ T cell exclusion and highlight TAM-specific SLC2A1 as a therapeutic target to overcome immune checkpoint blockade resistance in NSCLC.
    DOI:  https://doi.org/10.1038/s41556-025-01840-5
  46. Nat Commun. 2026 Jan 07. 17(1): 205
    Spatially resolved integrative analysis of transcriptomic and metabolomic changes in tissue injury studies.
    Eleanor C Williams, Lovisa Franzén, Martina Olsson Lindvall, Gregory Hamm, Steven Oag, Muntasir Mamun Majumder, James Denholm, Azam Hamidinekoo, Javier Escudero Morlanes, Marco Vicari, Joakim Lundeberg, Laura Setyo, Trevor M Godfrey, Livia S Eberlin, Aleksandr Zakirov, Jorrit J Hornberg, Marianna Stamou, Patrik L Ståhl, Anna Ollerstam, Jennifer Y Tan, Irina Mohorianu.
      Recent developments in spatially resolved -omics have enabled the joint study of gene expression, metabolite levels and tissue morphology, offering greater insights into biological pathways. Integrating these modalities from matched tissue sections to probe spatially-coordinated processes, however, remains challenging. Here we introduce MAGPIE, a framework for co-registering spatially resolved transcriptomics, metabolomics, and tissue morphology from the same or consecutive sections. We show MAGPIE's generalisability and scalability on spatial multi-omics data from multiple tissues, combining Visium with MALDI and DESI mass spectrometry imaging. MAGPIE was also applied to new multi-modal datasets generated with a specialised sampling strategy to characterise the metabolic and transcriptomic landscape in an in vivo model of drug-induced pulmonary fibrosis and to link small-molecule co-detection with endogenous lung responses. MAGPIE demonstrates the refined resolution and enhanced interpretability that spatial multi-modal analyses provide for studying tissue injury especially in pharmacological contexts, and delivers a modular, accessible workflow for data integration.
    DOI:  https://doi.org/10.1038/s41467-025-68003-w
  47. PLoS One. 2026 ;21(1): e0340295
    Targeting ceramide metabolism to restore hypoxia-induced apoptosis in p53-deficient colon cancer cells.
    Karen Mechleb, Nancy Hourani, Maya Fakhry, Osama A Alyamani, Rouba Hage-Sleiman, Hicham Younes, Antoine Abou Fayad, Nadia Soudani, Amer Sakr, Nadine Darwiche, Georges Nemer, Raya Saab, Marguerite Mrad, Ghassan Dbaibo.
      Hypoxic stress in solid tumors triggers growth arrest and apoptosis through p53 activation and stabilization. This environment inactivates p53 and drives the expansion of p53-mutant clones, which accentuate tumor aggressiveness. Ceramide, a signaling sphingolipid, was previously identified as a downstream collaborator with p53 in the stress-induced apoptosis and cell cycle arrest. Among sphingolipids, the balance between pro- and anti-apoptotic products, dictated by the expression and activity of appropriate enzymes, helps determine cell fate in response to hypoxia. The current study aimed to understand the role of ceramide in HCT116 human colon cancer cells response to hypoxia in the presence or absence of p53, and to determine whether the modulation of ceramide metabolism could sensitize the resistant p53-deficient cells to hypoxia-induced cell death. We observed that HCT116 p53-deficient cells were resistant to hypoxic cell death. We explored the role of ceramide in this response by screening for different sphingolipid metabolites through liquid-chromatography-mass spectrometry, and by measuring the expression of key enzymes involved in ceramide biosynthesis and breakdown. We also evaluated the changes in the cellular response to hypoxia associated with introduction of sphingolipid metabolites or with modulating the activity of related sphingolipid-metabolizing enzymes. In hypoxic p53-deficient cells, ceramide was synthesized via the de novo pathway through the action of ceramide synthases and dihydroceramide desaturase (DEGS1) driving the evasion of hypoxia-induced apoptosis. Among the accumulating ceramide species in p53 deficient cells, C24-ceramide was the most abundant and possibly contributing to their resistance. Tipping the sphingolipid balance in favor of pro-apoptotic sphingolipids, through the addition of C6 ceramide or sphingosine, or through the combined pharmacologic inhibition of DEGS1 and sphingosine kinase 1, helped circumvent the cellular resistance to hypoxia-induced apoptosis in cells lacking p53. Therefore, modulating sphingolipid metabolism may be a viable approach in the treatment of solid tumors with hypoxic regions.
    DOI:  https://doi.org/10.1371/journal.pone.0340295
  48. Diabetes Obes Metab. 2026 Jan 07.
    Amino acid metabolism modulates chronic kidney disease progression by mediating the aging process: Mechanistic insights and therapeutic interventions.
    Yi Song, Hang Zhou, Linxin Ye, Yifan Liu, Feng Guo, Guijun Qin.
      The kidneys play a vital role in maintaining systemic homeostasis by eliminating waste products, modulating metabolic homeostasis, and performing endocrine functions. Aging, characterized by hallmarks including oxidative stress, chronic inflammation, and metabolic dysregulation, constitutes a major predisposing factor for the pathogenesis of renal diseases. Amino acids serve as critical regulators of cellular metabolism, stress responses, and immune regulation, rendering amino acid metabolism intimately linked to the aging process. This review focuses on the multifaceted interplay between amino acid metabolism and renal aging, with particular emphasis on its implications in chronic kidney disease and related disorders: In senescent cells, accumulated branched-chain amino acids activate the mammalian target of rapamycin complex 1 (mTORC1), while tryptophan metabolites activate the aryl hydrocarbon receptor (AhR). Taurine deficiency impairs mitochondrial function and antioxidant defenses. Glutamine metabolism regulates the clearance of senescent cells through mechanisms including modulation of lysosomal pH and apoptosis. Glycine enhances glutathione synthesis and mitigates oxidative and inflammatory damage. In addition to modulating the aging process, urea cycle amino acids exhibit altered levels in kidney diseases and frequently serve as indicators of disease severity. Furthermore, we propose several promising therapeutic strategies, including nutritional interventions directed at specific amino acids and pharmacological therapies that target the modulation of amino acid metabolism. The relationship between amino acid availability and aging in kidney disease is not merely linear but involves a complex and dynamic interplay. Elucidating these mechanisms with advanced methods is key to developing novel clinical interventions and building a theoretical foundation for translational research.
    Keywords:  aging; amino acid metabolism; chronic kidney disease; therapeutic interventions
    DOI:  https://doi.org/10.1111/dom.70463
  49. Nat Immunol. 2026 Jan 08.
    Active aldehydes drive metabolic exhaustion in CD8+ T cells.
      
    DOI:  https://doi.org/10.1038/s41590-025-02413-2
  50. Ann Med Surg (Lond). 2026 Jan;88(1): 580-586
    Hemoglobin and human longevity: integrating oxygen transport, redox biology, and aging pathways - a narrative review.
    Emmanuel Ifeanyi Obeagu.
      Hemoglobin, the vital protein responsible for oxygen transport in the bloodstream, plays an indispensable role in sustaining life and cellular function. Traditionally viewed through the lens of hematology and respiratory physiology, hemoglobin is now being explored as a key determinant of healthy aging and human longevity. As the primary regulator of tissue oxygenation, its efficiency influences mitochondrial activity, energy metabolism, and organ vitality - all of which are central to lifespan regulation. Emerging evidence suggests that both low and excessively high hemoglobin levels are linked to increased morbidity and mortality in aging populations, underscoring the need for homeostatic balance. The dynamic interplay between hemoglobin concentration, erythropoiesis, hypoxia-inducible pathways, and oxidative stress reveals a complex biochemical network influencing aging at the molecular level. Hemoglobin's oxidative byproducts, if unchecked, can induce cellular senescence, compromise immune responses, and contribute to degenerative conditions commonly associated with advanced age.
    Keywords:  cellular senescence; erythropoiesis; hemoglobin; longevity; oxygen transport
    DOI:  https://doi.org/10.1097/MS9.0000000000004508
  51. Nat Commun. 2026 Jan 08. 17(1): 304
    SOX2 confers tumour permissiveness in a specific skin progenitor population.
    Patricia P Centeno, Christopher Chester, Georgios Kanellos, Catriona A Ford, Patrizia Cammareri, Gareth J Inman, Thomas Jamieson, Rachel A Ridgway, Richard Marais, Andrew D Campbell, Owen J Sansom.
      The continuous renewal of the skin relies on stem and progenitor cells, yet their differential susceptibility to oncogenic mutations in cutaneous squamous cell carcinoma (cSCC) remains unclear. Rapid cSCC develops in melanoma patients on BRAF inhibitors due to paradoxical MAPK activation. To model this in mice, we use two complementary approaches: HRASG12V with a BRAF inhibitor to mimic paradoxical MAPK activation, and BRAFV600E, which drives MAPK hyperactivation without further treatment. We target these mutations to the interfollicular stem and differentiation-committed progenitors of the basal epidermis. While stem cells rapidly form tumours, progenitors exhibit long-latency resistance despite retaining mutations and repopulating the basal layer. Ultimately, both populations produce similar tumours, showing a shared transformation process. However, SOX2 is uniquely upregulated in progenitor-derived tumours and is expressed in 20% of human cSCC, indicating it might mark tumours arising from committed progenitors. Here, we show that SOX2 overexpression, along with MAPK activation, in progenitors induces a stem-like state and renders this otherwise resistant population permissive to rapid transformation.
    DOI:  https://doi.org/10.1038/s41467-025-66251-4
  52. bioRxiv. 2025 Dec 23. pii: 2025.12.21.693523. [Epub ahead of print]
    Optogenetic Proximity Labeling Maps Spatially Resolved Mitochondrial Surface Proteomes and a Locally Regulated Ribosome Pool.
    Chulhwan S Kwak, Zehui Du, Joseph S Creery, Emily M Wilkerson, Michael B Major, Joshua E Elias, Xinnan Wang.
      Outer mitochondrial membranes (OMM) function as dynamic hubs for inter-organelle communication, integrating bidirectional signals, and coordinating organelle behavior in a context-dependent manner. However, tools for mapping mitochondrial surface proteomes with high spatial and temporal resolution remain limited. Here, we introduce an optogenetic proximity labeling strategy using LOV-Turbo, a light-activated biotin ligase, to profile mitochondrial surface proteomes with improved precision, temporal control, and reduced background. By fusing LOV-Turbo to a panel of variants of an OMM-anchored protein, Miro1, we generate spatially distinct baits that resolve modular architectures and regulatory states of the OMM proteomes across diverse conditions, a database we name MitoSurf. Building on this proteomic map, we present RiboLOOM, a platform that defines LOV-Turbo labeled ribosomes and their bound mRNAs at the mitochondrial surface. MitoSurf and RiboLOOM uncover a spatially distinct ribosome pool at the OMM that is maintained by Miro1, enabling local mRNA engagement and translation of mitochondria-related proteins. These findings establish Miro1 as a key organizer of mitochondrial protein biogenesis through spatial confinement of surface-associated ribosomes. Our platform reveals an uncharted layer of mitochondrial surface biology and provides a generalizable strategy to dissect dynamic RNA-protein-organelle interfaces in living cells.
    DOI:  https://doi.org/10.64898/2025.12.21.693523
  53. Sci Adv. 2026 Jan 09. 12(2): eaec0766
    Impaired nitrogenous waste clearance promotes hepatocellular carcinoma.
    Xinlu Han, Jianliang Shen, Junrong Yan, Rahul Tacke, Weiwei Dai, Qingqing Mao, Heineken Queen Daguplo, Shuyang Liu, Ariful Islam, Tong Liu, Mark C Koch, Richard Z Lin, Hong Li, Tracy Anthony, Ping Xie, Lanjing Zhang, Shenglan Gao, M Celeste Simon, Xin Chen, Jiekun Yang, Xiaoyang Su, Wei-Xing Zong.
      In mammals, hepatic urea cycle enzymes (UCEs) convert ammonia, the toxic nitrogenous waste, into urea for excretion. In hepatocellular carcinoma (HCC), UCE expression is often heterogeneously repressed, but its role in tumorigenesis is unclear. We show that, as in patients, UCE expression is markedly reduced in multiple HCC mouse models, including those driven by oncogenic c-MET/β-catenin, leading to impaired ammonia clearance, altered amino acid metabolism, and increased pyrimidine synthesis. In contrast, UCE expression is largely preserved in c-MET/sgAxin1 tumors, allowing assessment of the consequences of UCE loss. Silencing individual UCEs increases ammonia burden and accelerates HCC with reprogrammed amino acid and pyrimidine metabolism, supporting a causal role for defective ammonia detoxification in oncogenesis. Notably, dietary protein restriction lowers hepatic ammonia and slows tumor growth. These findings establish a mechanistic link between nitrogen overload and hepatocarcinogenesis and highlight protein restriction as a feasible therapeutic strategy for patients with impaired nitrogenous waste handling.
    DOI:  https://doi.org/10.1126/sciadv.aec0766
  54. Nature. 2026 Jan 07.
    Intratumoural vaccination via checkpoint degradation-coupled antigen presentation.
    Yu Han, Yicong Ma, Miao Pei, Shenyi Yin, Jiahao Wang, Liyu Guo, Yike Fang, Weiming Guo, Chunjiang Deng, Su Zhao, Xueyin Lu, Jianzhong Jeff Xi, Heng Zhang, Peng R Chen.
      Decreased cross-presentation by antigen-presenting cells induces the scarcity of tumour-reactive T cells within the tumour bed, rendering in situ T cell rejuvenation through immunogenicity reprogramming highly desirable yet challenging1-3. Here we developed an intratumoural vaccination chimera (iVAC) to reprogram tumour cells into an antigen-presenting state (APC-like tumour cells) with restored anti-tumour immunity. The iVAC chimeras consist of a covalently engineered PD-L1 degrader conjugated to immunogenic antigens, which could relieve immune checkpoint inhibition while enforcing the cross-presentation of exogenous antigens. Functionally, the iVAC-induced antigen processing and presentation elicited potent tumour killing through reactivation of resident antigen-specific CD8+ T cells, which simultaneously remodelled the tumour microenvironment to promote durable tumour-specific immunity. Extending this strategy, we used iVAC with a cytomegalovirus (CMV)-derived antigen to activate CMV-specific T cells against breast cancer in vitro, in a humanized mouse model as well as in a patient-derived tumour model. This study establishes a foundation for chemically reprogramming cancer cells within tumour beds to endow APC-like functions, providing an avenue for stimulating anti-tumour immunity.
    DOI:  https://doi.org/10.1038/s41586-025-09903-1
  55. bioRxiv. 2025 Dec 27. pii: 2025.12.27.696636. [Epub ahead of print]
    BDH1-Dependent Ketone Body Metabolism Maintains Müller Cell Homeostasis and Retinal Function.
    Richa Garg, Eshani Karmakar, David DeBruin, Shauna Prasad, Ethan Naquin, Michelle Brennan, Niloofar Piri, Oleg Kisselev, Jaya P Gnana-Prakasam.
      Ketone body metabolism serves as an auxiliary regulator of cellular energetics and redox balance, particularly during prolonged fasting and carbohydrate restriction, yet its role in retinal homeostasis under physiological conditions remains poorly defined. β-hydroxybutyrate dehydrogenase 1 (BDH1) is a mitochondrial enzyme that interconverts acetoacetate and β-hydroxybutyrate, and is required for efficient ketone utilization. Here, we investigated the impact of impaired endogenous ketone metabolism on retinal function using global and retinal pigment epithelium (RPE)-specific BDH1 knockout (KO) mice. Global BDH1 KO mice showed reduced circulating β-hydroxybutyrate and blunted fasting-induced ketone elevations, accompanied by ganglion cell loss, structural abnormalities on fundus and OCT imaging, and diminished scotopic and photopic electroretinogram (ERG) a- and b-wave amplitudes, consistent with impaired photoreceptor responses and downstream bipolar and Müller cell signaling. In contrast, RPE-specific BDH1 KO mice exhibited no changes in ERG responses or retinal morphology. Transcriptomic and molecular analyses in global KO retinas revealed disrupted Müller cell homeostasis, including reduced CAMKII-CREB activation, which is required for EAAT1 glutamate transporter expression. Administration of exogenous β-hydroxybutyrate, in vitro and in vivo, restored CAMKII-CREB-EAAT1 signaling, glutamate uptake, and antioxidant gene expression in BDH1 KO mice, demonstrating a central role for ketone bodies in Müller cell metabolic support, glutamate homeostasis, and redox balance. Together with reduced BDH1 expression in human AMD retinas, these findings identify the BDH1-β-hydroxybutyrate axis as a critical metabolic pathway for Müller cell function and retinal integrity, and highlight ketone metabolism as a potential therapeutic target in degenerative retinal diseases.
    Keywords:  AMD; CAMKII-CREB; Müller cells; glutamate transporter; neurodegeneration; retinal dysfunction; β-hydroxybutyrate
    DOI:  https://doi.org/10.64898/2025.12.27.696636
  56. Nat Metab. 2026 Jan 08.
    A catecholamine-independent pathway controlling adaptive adipocyte lipolysis.
    Xiao Zhang, Sreejith S Panicker, Jordan M Bollinger, Anurag Majumdar, Rami Kheireddine, Lila F Dabill, Clara Kim, Brian Kleiboeker, Fengrui Zhang, Yongbin Chen, Kristann L Magee, Brian S Learman, Adam Kepecs, Gretchen A Meyer, Jun Liu, Steven A Thomas, Irfan J Lodhi, Ormond A MacDougald, Erica L Scheller.
      Several adipose depots, including constitutive bone marrow adipose tissue, resist conventional lipolytic cues. However, under starvation, wasting or cachexia, the body eventually catabolizes stable adipocytes through unknown mechanisms. Here we developed a mouse model of brain-evoked depletion of all fat, including stable constitutive bone marrow adipose tissue, independent of food intake, to study this phenomenon. Genetic, surgical and chemical approaches demonstrated that catabolism of stable adipocytes required adipose triglyceride lipase-dependent lipolysis but was independent of local nerves, the sympathetic nervous system and catecholamines. Instead, concurrent hypoglycaemia and hypoinsulinaemia activated a potent catabolic state by suppressing lipid storage and increasing catecholamine-independent lipolysis via downregulation of cell-autonomous lipolytic inhibitors including G0s2. This was also sufficient to delipidate classical adipose depots and was recapitulated in tumour-associated cachexic mice. Overall, this defines unique adaptations of stable adipocytes to resist lipolysis in healthy states while isolating a potent catecholamine-independent neurosystemic pathway by which the body can rapidly catabolize all adipose tissues.
    DOI:  https://doi.org/10.1038/s42255-025-01424-5
  57. bioRxiv. 2025 Dec 23. pii: 2025.12.22.696043. [Epub ahead of print]
    Spatial Regulation of Lysosomal Vesicle Acidification Along the Axon via mRAVE-Dependent v-ATPase Assembly.
    Surbhi Verma, Nireekshit Addanki Tirumala, Xiaolin Zhu, Raffaella De Pace, Juan S Bonifacino.
      Lysosomal acidification is essential for neuronal homeostasis, supporting degradative clearance and metabolic signaling in all neuronal domains. Yet, how lysosomal acidification is spatially regulated within neurons remains unclear. Here, we show that assembly of the membrane-embedded V 0 and cytosolic V 1 domains of the vacuolar H⁺-ATPase (v-ATPase) - the proton pump that drives lysosomal acidification - governs spatial and functional lysosome diversity. In non-neuronal cells, V 1 -V 0 association is higher in perinuclear lysosomes, correlating with increased acidity of this population. In neurons, axonal V 0 -positive vesicles move bidirectionally, whereas V 1 -V 0 -positive vesicles move almost exclusively in the retrograde direction, consistent with the higher acidity of retrograde lysosomal vesicles. Depletion of DMXL2, a subunit of the mRAVE complex that promotes V 1 -V 0 assembly, reduces V 1 association, acidification, transport, and proteolytic activity of retrograde lysosomal vesicles in the axon. Together, these findings reveal a spatially regulated mechanism for the acidification of axonal lysosomal vesicles and identify mRAVE-dependent v-ATPase assembly as a key determinant of this process. Subjects: Organelles, Trafficking, Disease.
    DOI:  https://doi.org/10.64898/2025.12.22.696043
  58. Nat Cell Biol. 2026 Jan 08.
    Immune evasion by macrophage-derived lactate.
    He Ren, Leina Ma, Xiaoming Jiang, Zhimin Lu.
      
    DOI:  https://doi.org/10.1038/s41556-025-01842-3
  59. Nature. 2026 Jan 07.
    The complex role of nutrients in cancer spread.
    Sandhya Yadav, Tara TeSlaa.
      
    Keywords:  Cancer; Medical research
    DOI:  https://doi.org/10.1038/d41586-025-03988-4
  60. Nat Genet. 2026 Jan 06.
    Insights from three decades of BRCA1/2 modeling in mice.
    Julia-Star Darnold, Jos Jonkers.
      Since the discovery of the BRCA1 and BRCA2 (hereafter referred to as BRCA1/2) hereditary breast and ovarian cancer genes three decades ago, genetically engineered and patient-derived mouse models have been instrumental in advancing our understanding of BRCA1/2 biology, particularly their roles in normal development, tumor suppression and therapy response. Brca1/2-mutant mouse models and derivative cell lines have facilitated in vivo dissection of BRCA1/2 functions and identification of the cellular origin and (epi)genetic drivers of BRCA1/2-associated cancer. Genetically engineered and patient-derived mouse tumor models have also been instrumental in developing new (combination) therapies for patients with BRCA1/2-mutated cancers and to study mechanisms of therapy resistance. In this Perspective, we highlight the crucial insights into the complex biology of BRCA1/2 these models have afforded and emphasize those aspects that remain to be elucidated. We also propose next-generation mouse models to further advance our understanding of BRCA1/2 and improve the quality of life of mutation carriers.
    DOI:  https://doi.org/10.1038/s41588-025-02448-z
  61. Cell Metab. 2026 Jan 08. pii: S1550-4131(25)00528-5. [Epub ahead of print]
    Endometrial stromal cell-derived TMAO sustains decidualization to prevent recurrent spontaneous abortion.
    Yu-Ling Chen, Lin-Chen Tang, Wei Zhou, Xin Sun, Zhen-Zhen Lai, Sha Xu, Ke Cai, Yan Shi, Rui Zhao, Xiang-Yu Zhou, Jun Jim Zhang, Fei Li, Bo Li, Ming-Qing Li, Li-Ping Jin, Jian-Yuan Zhao.
      Recurrent spontaneous abortion (RSA), often linked to defective endometrial stromal cell (ESC) decidualization, lacks effective metabolism-targeted therapies. Here, we identify the in situ synthesis of trimethylamine N-oxide (TMAO) in human decidua as a critical safeguard. Metabolomics revealed significantly lower TMAO levels in decidual tissues of individuals experiencing RSA. Mechanistically, cyclic AMP (cAMP)-protein kinase A (PKA)-cAMP-responsive element-binding protein 1 (CREB1) signaling upregulated flavin-containing monooxygenase 3 (FMO3) in ESCs, driving local TMAO accumulation. TMAO directly bound the C terminus of 14-3-3η, enhancing its interaction with phosphoinositide-dependent protein kinase 1 (PDK1) to relieve PDK1-mediated suppression of forkhead box protein O1 (FOXO1). This promoted FOXO1 nuclear translocation and the activation of decidualization markers. Through mouse models employing dietary choline restriction, and FMO3 inhibition via pharmacological or genetic knockout, we demonstrated that endometrial TMAO deficiency impairs decidualization and increases pregnancy loss. Strikingly, TMAO restored decidualization capacity in 15% of patient-derived ESCs with inherent dysfunction. Our findings unveil endometrial TMAO synthesis as a metabolic checkpoint for decidualization and propose it as a therapeutic candidate for RSA.
    Keywords:  14-3-3η; endometrial stromal cell; forkhead box protein O1; recurrent spontaneous abortion; trimethylamine N-oxide
    DOI:  https://doi.org/10.1016/j.cmet.2025.11.014
  62. Neurol Genet. 2026 Feb;12(1): e200343
    Immune Cell Mitochondrial Phenotypes Are Largely Preserved in Mitochondrial Diseases and Do Not Reflect Disease Severity.
    Cynthia C Liu, Mangesh Kurade, Anna S Monzel, Catherine Kelly, Robert-Paul Juster, Caroline Trumpff, Michio Hirano, Martin Picard.
       Background and Objectives: The aim of this study was to profile immune cell mitochondrial phenotypes in mitochondrial diseases (MitoD) and evaluate how these phenotypes relate to disease manifestations or biomarkers.
    Methods: We profiled mitochondrial content and oxidative phosphorylation (OxPhos) enzymatic activities in isolated monocytes, lymphocytes, neutrophils, platelets, and mixed peripheral blood mononuclear cells (PBMCs) from 37 individuals with MitoD (m.3243A > G, n = 23; single, large-scale mitochondrial DNA (mtDNA) deletions, n = 14) and 68 healthy women and men from the Mitochondrial Stress, Brain Imaging, and Epigenetics study.
    Results: We first confirmed and quantified robust cell type differences in mitochondrial content; activities of OxPhos complexes I, II, and IV; and the mitochondrial respiratory capacity (MRC) index. In relation to MitoD, neither mitochondrial content nor OxPhos capacity was consistently affected, other than a mild monocyte-specific reduction in complex I (partially mtDNA encoded) relative to complex II (entirely nDNA encoded), consistent with the mtDNA defects examined. Relative to the large differences in cell type-specific mitochondrial phenotypes, differences in MitoD relative to controls were generally small (<25%) across mitochondrial measures. MitoD biomarkers growth differentiation factor 15 and fibroblast growth factor 21, as well as clinical disease severity measures, were most strongly related to mitochondrial abnormalities in platelets, and most weakly related to mitochondrial OxPhos capacity in lymphocytes, which are known to eliminate mtDNA defects. Finally, comparing PBMCs collected in the morning/fasted state with those in the afternoon/fed state after a stressful experience, we report significant time-dependent changes in mitochondrial biology over hours.
    Conclusions: Overall, these results demonstrate that the dynamic and cell type-specific mitochondrial phenotypes are preserved in MitoD and are generally unrelated to symptom severity.
    DOI:  https://doi.org/10.1212/NXG.0000000000200343
  63. Nature. 2026 Jan 07.
    Neuro-epithelial circuits promote sensory convergence and intestinal immunity.
    Wen Zhang, Elizabeth R Emanuel, Hiroshi Yano, Jazib Uddin, Stephen Gaudino, Zili Xie, Hiroshi Ichise, Zhen Wang, Maureen N Cowan, Mengze Lyu, Xiaoxiao Hou, Peng Zeng, Elin Hu, Victoria Ribeiro de Godoy, Alex Grier, Nina Estep, Julien R Ishibashi, Stephanie Anover-Sombke, Peter J Skene, Toufic Mayassi, Ramnik J Xavier, Ronald N Germain, Anna-Maria Globig, Maximilian Heeg, Ananda W Goldrath, Brian S Kim, Hongzhen Hu, David Artis.
      Type 2 inflammation at barrier surfaces is an evolutionarily conserved response that promotes immunity to helminth parasites, allergic inflammation and tissue repair1-4. Direct sensing of environmental triggers by epithelial cells initiates type 2 inflammation, and signals derived from neurons can modulate immune responses5-8. However, how diverse sensory inputs from epithelial, neuronal and immune cells are coordinated and integrated remains unclear. Here we identify that TRPV1+ pain-sensing nociceptors co-opt chemosensory epithelial tuft cells to initiate a cascade of tissue responses that drive type 2 inflammation. Chemogenetic silencing or chemical ablation of TRPV1+ nociceptors results in a significant reduction in intestinal tuft cells and defective anti-helminth type 2 immunity. By contrast, chemogenetic activation of TRPV1+ nociceptors leads to remodelling of CGRP+ nerve fibres, significantly increased CGRP expression, enhanced tuft cell accumulation and protective anti-helminth type 2 immunity. Using spatial transcriptomic and single-cell RNA sequencing analyses, we reveal that nociceptor activation promotes rapid epithelial progenitor cell proliferation and differentiation. Mechanistically, intestinal epithelial cell-intrinsic and tuft cell-intrinsic expression of CGRP receptor subunits are required for tuft cell responses and type 2 immunity to helminth infection. Together, these results identify sensory convergence of a neuronal-epithelial tuft cell circuit as a critical upstream determinant of type 2 immunity and tissue adaptation.
    DOI:  https://doi.org/10.1038/s41586-025-09921-z
  64. Cell Metab. 2026 Jan 06. pii: S1550-4131(25)00538-8. [Epub ahead of print]38(1): 3-4
    Disentangling the effects of food processing from those of diet quality.
    Lea Ellen Matthiessen, Beatriz Philippi Rosane, Laurin Mosig, Lilia Ahrné, Faidon Magkos, Susanne Gjedsted Bügel.
      
    DOI:  https://doi.org/10.1016/j.cmet.2025.12.007
  65. Nature. 2026 Jan;649(8096): 282-284
    Why cancer can come back years later - and how to stop it.
    Amanda Heidt.
      
    Keywords:  Cancer; Cell biology; Diseases; Drug discovery
    DOI:  https://doi.org/10.1038/d41586-025-04149-3
  66. Nat Commun. 2026 Jan 08.
    Quantitative optical nanoscopy of mitochondrial-derived vesicles in neurons classifies pre-peroxisomal and clearing organelles.
    Giovanna Coceano, Jonatan Alvelid, Martina Damenti, Gabriella Ferretti, Johannes Mueller, Joanna Rorbach, Ilaria Testa.
      Healthy mitochondria are crucial for maintaining neuronal homeostasis. Their activity depends on a dynamic lipid and protein exchange through fusion, fission, and vesicular trafficking. Studying vesicles in neurons is challenging with conventional microscopy due to their small size, heterogeneity, and dynamics. We use multicolour stimulated emission depletion nanoscopy to uncover the ultrastructure of mitochondrial-derived vesicles (MDVs) in live neurons, biosensors to define their functional state, and a pulse-chase strategy to identify their turnover in situ. We identified three populations of vesicular structures: one transporting degradation products originating from oxidative stress, one shuttling cargo and newly translated proteins for local organelle biogenesis and one consisting of small, functional mitochondria. Furthermore, we provide evidence supporting that de novo peroxisomes biogenesis occurs via the fusion of endoplasmic reticulum and MDVs at mitochondrial sites. Our data provide mechanistic insight into organelle biogenesis driven by significant diversity in MDV morphology, functional state, and molecular composition.
    DOI:  https://doi.org/10.1038/s41467-025-68160-y
  67. bioRxiv. 2025 Dec 25. pii: 2025.12.23.696233. [Epub ahead of print]
    Endothelial Arf6 sustains capillary electrical signaling and cerebral blood flow through PIP 2 regeneration and activation of Kir2.1 channels.
    Maria F Noterman-Soulinthavong, María Sancho, Saúl Huerta de la Cruz, Michael Yarboro, Maurizio Mandala, Masayo Koide, Nathalie Beaufort, Katalin Todorov-Völgyi, Emma Moreland, David Hill-Eubanks, Martin Dichgans, Mark T Nelson.
      Brain capillaries sense neural activity and direct blood flow to active regions-a process termed neurovascular coupling that underlies activity-dependent increases in local perfusion (functional hyperemia). A key contributor to functional hyperemic responses is the capillary endothelial cell (cEC) inward rectifier K + (Kir2.1) channel, which is activated by neuronal activity-derived extracellular K + and initiates vasodilatory electrical signals that propagate through the vascular network. Kir2.1 channel function requires continual production of its lipid cofactor, phosphatidylinositol-4,5-bisphosphate (PIP 2 ), and is compromised in mouse models of cerebral small vessel (cSVD). Although decreased PIP 2 availability is a common feature of cSVD, mechanisms underlying PIP 2 synthesis remain poorly understood. We hypothesized that Arf6, a small GTPase expressed in cECs that stimulates PIP 2 production, is critical for this process. Using patch-clamp electrophysiology, we demonstrate that inhibiting Arf6 activity progressively decreased cEC Kir2.1 channel activity. This deficit corresponded to loss of capillary-to-arteriole electrical signaling in isolated vessels and diminished functional hyperemia in vivo . Exogenously provided PIP 2 restored Kir2.1 currents and functional hyperemia after Arf6 inhibition or genetic knockdown. Collectively, our data indicate that cEC Arf6 sustains Kir2.1 activity by maintaining PIP 2 levels and demonstrate that diminished PIP 2 synthesis is sufficient to impair functional hyperemia. Furthermore, we identify Arf6 as a mechanistic link between PIP 2 production and endothelial electrical signaling, highlighting Arf6 as a potential therapeutic target for restoring functional hyperemia.
    Significance Statement: Active brain regions send electrical signals through capillaries to dilate upstream arterioles and increase blood flow. The resulting activity-dependent increase in local blood flow (functional hyperemia) is mediated through inward-rectifier potassium (Kir2.1) channels. These channels- and hence functional hyperemia-require continuous regeneration of the lipid cofactor PIP 2 (phosphatidylinositol-4,5-bisphosphate). If PIP 2 is deficient, electrical signaling fails-a defect characteristic of models of cerebral small vessel disease and Alzheimer's disease. We identify the small GTPase Arf6 as a key to maintaining PIP 2 and thus preserving capillary Kir2.1 activity and functional hyperemia. Our findings reveal an important pathway for PIP 2 homeostasis and position Arf6 as a cornerstone upholding functional hyperemic responses, highlighting Arf6 as a target for restoring cerebral blood flow in disease.
    DOI:  https://doi.org/10.64898/2025.12.23.696233
  68. bioRxiv. 2025 Dec 29. pii: 2025.12.29.696903. [Epub ahead of print]
    Thioredoxin interacting protein (TXNIP), a redox regulator, mediates the RAPGEF3/4 signaling dependency in primary melanoma.
    Sireesh Kumar Teertam, Mithalesh K Singh, Sarah Altameemi, Sonia Gude, Sushmita Roy, Ryan Rossman, Michael A Newton, Daniel D Bennett, Nihal Ahmad, Xiaodong Cheng, Vijayasaradhi Setaluri.
      RAP guanine exchange factors (RAPGEF3/4) also known as EPAC1/2 (Exchange Protein Activated by cyclic AMP) are important signaling proteins. In cutaneous melanoma, we reported that loss of dependency on RAPGEF3/4 is associated with metastatic progression. Here, we investigated the molecular mechanisms underlying EPAC1/2 signaling in melanoma. Using transformed human melanocytes, chemical inhibition and genetic deletion of EPAC in Braf/Pten mice, we show that EPAC activation is an early event in melanomagenesis and is required for the growth of transformed melanocytes in vitro and melanomagenesis in vivo . Query of the Cancer Genome Atlas (TCGA) and immunohistochemical analysis of melanoma tumors showed that low EPAC mRNA and RAP1-GTP protein correlate with better diseases free survival of patients with primary melanoma. RNAseq analysis of patient-matched primary and metastatic melanoma cells treated with EPAC inhibitor ESI-09 revealed that TXNIP, an important regulator of redox homeostasis, is a downstream effector of EPAC-RAP1 signaling. Our data also show that EPACs promote melanoma growth by regulation of redox homeostasis and mitochondrial reactive oxygen species through activation of mechanistic target of rapamycin complex 1 (mTORC1) that stabilizes hypoxia-inducible factor 1-alpha (HIF-1α), a transcriptional activator of TXNIP and glycolytic enzymes. Our data suggest that targeting mechanisms that metastatic melanoma cells employ to bypass EPAC dependency as a potential therapeutic approach for melanoma.
    DOI:  https://doi.org/10.64898/2025.12.29.696903
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