bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2025–12–28
fifty papers selected by
Christian Frezza, Universität zu Köln
  1. Dynamic and differential renal cortical cell-specific mitochondrial metabolism in response to fasting.
  2. Mitochondrial glutamine import sustains electron transport chain integrity independently of glutaminolysis in cancer.
  3. Mitochondrial VHL rewires cell metabolism in hypoxia.
  4. Mitochondrial contact site and cristae organizing system promotes modular assembly of cytochrome c oxidase.
  5. A reversible feedback mechanism regulating mitochondrial heme synthesis.
  6. Deciphering the antitumor immune effects of succinate.
  7. Pharmacological inhibition of MCL-1 disrupts mitochondrial cristae and depletes the human neural progenitor cell pool.
  8. Chromatin stability safeguards mitochondrial homeostasis and prevents mTORC1 hyperactivation.
  9. Mitochondrial control of fuel switching via carnitine biosynthesis.
  10. Targeting Ogt in ADPKD mitigates metabolic reprogramming and renal cystogenesis, extending survival.
  11. Basic Science and Pathogenesis.
  12. Prostate cancer cells converge to an inflammatory-like state upon metastatic dissemination.
  13. A gut-to-brain pathway that limits protein intake.
  14. Hepatic adaptation to chronic metabolic stress primes tumorigenesis.
  15. HIF-1α-mediated feedback prevents TOR signalling from depleting oxygen supply and triggering stress during normal development.
  16. Genome-scale spatial mapping of the Hodgkin lymphoma microenvironment identifies tumor cell survival factors.
  17. Loss of heterozygosity exposes germline mutations in complex I and drives Warburg metabolism in oncocytic carcinoma of the thyroid.
  18. Synergistic Roles of FAHD-1 and PYC-1 in Mitochondrial Function, Behavior, and Longevity in C. elegans.
  19. Bioinformatic analysis of metastasis-associated metabolic landscape reveals an oncogenic role for the transsulfuration pathway.
  20. A Polymeric Nanocarrier Platform for Rapid and Precise Fatty Acid Tracing in Cells.
  21. Turnover and Quality Control of Mitochondrial DNA.
  22. Reconstructing the three-dimensional architecture of extrachromosomal DNA with ec3D.
  23. Transsulfuration metabolism is essential for ferroptosis resistance in quiescent endothelial cells.
  24. Preliminary Evidence for Increased Histone Succinylation as a Potential Epigenetic Marker for Longevity.
  25. Deep Mutational Scanning of FDX1 Identifies Key Structural Determinants of Lipoylation and Cuproptosis.
  26. Systematic screening of tryptophan metabolism identifies site- and microbial-specific signatures of tryptophan utilization in experimental colitis.
  27. ATP in Mitochondria: Quantitative Measurement, Regulation, and Physiological Role.
  28. Clonal evolution and transcriptional plasticity shape metastatic dissemination routes in prostate cancer.
  29. Targeting STING to generate therapeutic anti-tumor immunity.
  30. Lysosomal swelling triggers LRRK2 activity.
  31. Single cell profiling framework reveals metabolic subpopulations as drivers of bioproduction heterogeneity.
  32. Glutamate indicators with increased sensitivity and tailored deactivation rates.
  33. Activated T cells degrade extracellular proteins to enhance effector functions.
  34. Mitochondrial membrane junction-mediated ATP channeling drives activity-dependent glucose metabolism.
  35. T CELLS promote the growth of small-cell lung carcinoma via an IL-6/CD74 axis.
  36. Lymph node microenvironment rewires ferroptosis redox defenses.
  37. Oncometabolite fumarate impairs ATR-CHK1 signaling by succinating RPA1 in Fumarate Hydratase-deficient renal cell carcinoma cells.
  38. Mismatch repair deficiency drives malignant progression and alters the tumor immune microenvironment in glioblastoma models.
  39. Mitochondria-derived PEP licenses glycerolipid synthesis via SLC25A35.
  40. Positioning and reversible suppression of CCR7+ dendritic cells in perivascular tumor niches shape cancer immunity.
  41. Epitranscriptomic control of cancer hallmarks: Functions, mechanisms, and therapeutics of RNA modifications.
  42. RamanOmics Decodes Spatial Vibrational-Molecular Architecture and Rewiring in Aging and Repair.
  43. Macropinocytosis facilitates amino acid acquisition from extracellular fluid to support cell proliferation in macrophages.
  44. Latent brain subtypes of chronotype reveal unique behavioral and health profiles across population cohorts.
  45. Using Mathematical Modeling of Tumor Metabolism to Predict the Magnitude, Composition, and Hypoxic Interactions of Microenvironment Acidosis.
  46. Inheriting chromosome conformation.
  47. Enhanced non-enzymatic H2S generation extends lifespan and healthspan in male mice.
  48. Interphase chromosome conformation is specified by distinct folding programmes inherited through mitotic chromosomes or the cytoplasm.
  49. Tumor-produced ammonia is metabolized by regulatory T cells to further impede anti-tumor immunity.
  50. The circadian clock regulates scavenging of fluid-borne substrates by brain border-associated macrophages.
  1. Am J Physiol Renal Physiol. 2025 Dec 22.
    Dynamic and differential renal cortical cell-specific mitochondrial metabolism in response to fasting.
    Kyle Feola, Andrea Henning Venable, Mina Rasouli, Julie Do, Tatyana Broomfield, Claire Llamas, Dana Straus, Joshua C Russell, Prashant Mishra, Behzad Najafian, Sarah C Huen.
      The metabolic health of the kidney is directly correlated to the risk of progressive kidney disease. Our understanding of the metabolic processes that fuel the diverse functions of the kidney is limited by the kidney's structural and functional heterogeneity, especially in key metabolic organelles like the mitochondria. As the kidney contains many different cell types, we sought to determine the intra-renal mitochondrial heterogeneity that contributes to cell-specific metabolism. To interrogate this, we utilized a recently developed mitochondrial tagging technique, MITO-Tag, to isolate kidney cell-type specific mitochondria. Here, we investigated mitochondrial functional capacities and the metabolomes of the early and late proximal tubule (PT) and the distal convoluted tubule (DCT). The conditional MITO-Tag transgene was combined with Slc34a1-CreERT2, Ggt1-Cre, or Pvalb-Cre transgenes to generate mouse models capable of cell-specific isolation of hemagglutinin (HA)-tagged mitochondria from the early PT, late PT, or the DCT, respectively. Functional assays measuring mitochondrial respiratory and fatty acid oxidation (FAO) capacities and metabolomics were performed on anti-HA immunoprecipitated mitochondria from kidneys of ad libitum fed and 24-hour fasted male mice. The renal MITO-Tag models targeting the early PT, late PT, and DCT revealed differential mitochondrial respiratory and FAO capacities which dynamically changed during fasting conditions. The renal MITO-Tag model captured differential mitochondrial metabolism and functional capacities across the early PT, late PT, and DCT at baseline and in response to fasting.
    Keywords:  cellular metabolic heterogeneity; kidney; metabolism; mitochondria; tubular epithelium
    DOI:  https://doi.org/10.1152/ajprenal.00235.2025
  2. Mol Cell. 2025 Dec 22. pii: S1097-2765(25)00975-X. [Epub ahead of print]
    Mitochondrial glutamine import sustains electron transport chain integrity independently of glutaminolysis in cancer.
    Lingzhi Zhu, Kuishen Wu, Jianwei You, Wen Mi, Jie Xu, Liucheng Li, Fang Yang, Xinyi Xia, Haohang Yan, Fei Li, Li Chen, Pingyu Liu, Fuming Li.
      Oxidative phosphorylation (OXPHOS) fulfills energy metabolism and biosynthesis through the tricarboxylic acid (TCA) cycle and an intact electron transport chain (ETC). Mitochondrial glutamine import (MGI) replenishes the TCA cycle through glutaminolysis, but its broader roles in cancer remain unclear. Here, we show that MGI sustains OXPHOS independently of glutaminolysis by maintaining ETC integrity. Exogenous glutamate availability abrogates cellular dependence on glutaminolysis but not SLC1A5var-mediated MGI. Blocking MGI elicits severe mitochondrial defects, reducing mitochondrial glucose oxidation and increasing glutamine reductive carboxylation. MGI, but not glutaminolysis, is essential for mitochondrial translation by enabling biogenesis of Gln-mt-tRNAGln, the most limiting mitochondrial aminoacyl-tRNA in cancer cells. Finally, deleting SLC1A5 in mice and targeting SLC1A5var in xenograft tumors inhibit Gln-mt-tRNAGln biogenesis and mitochondrial translation and blunt tumor growth. Our findings uncover a previously unrecognized role of MGI in safeguarding ETC integrity independently of glutaminolysis and inform a therapeutic option by targeting MGI to abrogate OXPHOS for cancer treatment.
    Keywords:  SLC1A5var; glutamine; glutaminolysis; mitochondrial glutamine import; mitochondrial translation
    DOI:  https://doi.org/10.1016/j.molcel.2025.12.001
  3. Cell Metab. 2025 Dec 22. pii: S1550-4131(25)00527-3. [Epub ahead of print]
    Mitochondrial VHL rewires cell metabolism in hypoxia.
    Guobang Li, Wenfeng Pan, Long Wu, Zhiliang Cai, Haoming Chen, Xingui Wu, Tiantian Yu, Kun Liao, Hui Zhang, Xingqiao Wen, Bo Li.
      Under normoxia, von Hippel-Lindau (VHL) protein targets the oxygen-induced, hydroxylated α subunits of hypoxia-inducible factors (HIFs) for degradation to orchestrate mammalian oxygen sensing. However, whether VHL plays non-canonical roles in hypoxia, when protein hydroxylation is attenuated, remains elusive. Here, we show that most cytosolic VHL is degraded under chronic hypoxia, with the remaining VHL pool primarily translocating to the mitochondria. Mitochondrial VHL binds and inhibits 3-methylcrotonyl-coenzyme A carboxylase subunit 2 (MCCC2), an essential subunit of the leucine catabolic machinery. Accumulated leucine allosterically activates glutamate dehydrogenase to promote glutaminolysis, generating sufficient lipids and nucleotides to support hypoxic cell growth. Furthermore, SRC-mediated VHL phosphorylation and protein arginine methyltransferase 5 (PRMT5)-mediated MCCC2 methylation synergistically regulate the VHL-MCCC2 interaction and concomitant metabolic changes, which are recapitulated in animal models of ischemic injury and functionally associated with VHL mutations in cancer. Our study highlights VHL as a bona fide regulator of hypoxic metabolism within mitochondria, rather than a solely "standby adaptor" for HIFs under hypoxia.
    Keywords:  VHL; hypoxia; leucine; metabolism; mitochondria
    DOI:  https://doi.org/10.1016/j.cmet.2025.11.013
  4. Cell Rep. 2025 Dec 18. pii: S2211-1247(25)01499-8. [Epub ahead of print]45(1): 116727
    Mitochondrial contact site and cristae organizing system promotes modular assembly of cytochrome c oxidase.
    Lilia Colina-Tenorio, Patrick Horten, Enzo Scifo, Susanne E Horvath, Rhena F U Klar, Chantal Priesnitz, Fabian den Brave, Martin van der Laan, Thomas Becker, Kuo Song, Heike Rampelt.
      Mitochondrial cytochrome c oxidase, complex IV (CIV) of the respiratory chain, is assembled in a modular fashion from mitochondrial as well as nuclear-encoded subunits, guided by numerous assembly factors. This intricate process is further complicated by the characteristic architecture of the inner mitochondrial membrane. The mitochondrial contact site and cristae organizing system (MICOS) maintains the stability of crista junctions that connect the cristae, the site of mitochondrial respiration, with the inner boundary membrane, where newly imported respiratory subunits first arrive. Here, we report that MICOS facilitates specific assembly steps of CIV and associates with intermediates of the Cox1 and Cox3 modules. Moreover, MICOS recruits a variety of assembly factors even in the absence of ongoing CIV biogenesis, directly or via the mitochondrial multifunctional assembly (MIMAS). Our results establish MICOS as an important agent in efficient respiratory chain assembly that promotes CIV biogenesis within the compartmentalized inner membrane architecture.
    Keywords:  CP: Cell biology; CP: Metabolism; MICOS; MIMAS; Mic60; cristae; cytochrome c oxidase; mitochondria; protein assembly; respiratory chain
    DOI:  https://doi.org/10.1016/j.celrep.2025.116727
  5. J Biol Chem. 2025 Dec 22. pii: S0021-9258(25)02941-2. [Epub ahead of print] 111089
    A reversible feedback mechanism regulating mitochondrial heme synthesis.
    Iva Chitrakar, Alexis B Roberson, Pedro H Ayres-Galhardo, Breann L Brown.
      Proper heme biosynthesis is essential for numerous cellular functions across nearly all life forms. In humans, dysregulated heme metabolism is linked to multiple blood diseases, neurodegeneration, cardiovascular disease, and metabolic disorders. Erythroid heme production begins with the rate-limiting enzyme Aminolevulinic Acid Synthase (ALAS2) in the mitochondrion. Although prior studies discuss the regulation of ALAS2 in the nucleus and cytoplasm, its modulation as a mature mitochondrial matrix enzyme remains poorly understood. We report that heme binds mature human ALAS2 with high affinity, acting as a reversible mixed inhibitor that reduces enzymatic activity. Structural modeling supports the hypothesis that two flexible regions of ALAS2 interact with heme, locking the enzyme in an inactive conformation and occluding the active site. Our work reveals a negative feedback mechanism for heme synthesis, offering insights into the spatial regulation of ALAS2 and the maturation of the essential heme cofactor.
    Keywords:  Heme; aminolevulinic acid; enzyme inhibition; enzymology; erythropoiesis; heme regulatory motif; protein structure and function; pyridoxal 5-phosphate
    DOI:  https://doi.org/10.1016/j.jbc.2025.111089
  6. Trends Endocrinol Metab. 2025 Dec 22. pii: S1043-2760(25)00265-6. [Epub ahead of print]
    Deciphering the antitumor immune effects of succinate.
    Ziyan Xia, Zhaoyi Li, Peng Jiang.
      Through metabolic remodeling, tumor cells can modulate neighboring CD8+ T cell function via metabolites. A recent study by Ma et al., published in Immunity, reveals that tumor-cell-derived succinate exhibits an antitumor immune effect, promoting the survival and stemness of CD8+ T cells by enhancing mitochondrial fitness and inducing epigenetic reprogramming.
    Keywords:  CD8(+) T cell stemness; ICB therapy; epigenetic regulation; mitochondrial homeostasis; succinate
    DOI:  https://doi.org/10.1016/j.tem.2025.12.001
  7. bioRxiv. 2025 Dec 22. pii: 2025.12.12.694056. [Epub ahead of print]
    Pharmacological inhibition of MCL-1 disrupts mitochondrial cristae and depletes the human neural progenitor cell pool.
    Marina R Hanna, Madison Yarbrough, Melanie Gil, James Costanzo, Vivian Gama.
      Myeloid Cell Leukemia-1 (MCL-1) is canonically an anti-apoptotic protein that is crucial for early neurodevelopment. Loss of MCL-1 results in embryonic-lethal neurodevelopmental defects that cannot be rescued by other anti-apoptotic proteins of the B-cell lymphoma 2 (BCL-2) family. Here, we pharmacologically inhibit MCL-1 in human neural stem cells and find non-apoptotic roles for MCL-1 in sustaining mitochondrial cristae integrity, fatty acid oxidation, and neural progenitor identity. MCL-1 inhibition disrupts mitochondrial ultrastructure, leading to swollen mitochondria with disorganized cristae and destabilization of the OPA1-MICOS machinery that maintains inner membrane architecture. These structural defects are accompanied by impaired lipid droplet accumulation and altered expression of β-oxidation enzymes, revealing a tight link between cristae architecture and metabolic competence. Functionally, in the absence of caspase-mediated cell death, MCL-1 inhibition selectively depletes intermediate progenitor cells without affecting proliferation, indicating a direct role in lineage progression. Together, our findings identify MCL-1 as a modulator of cristae organization, linking lipid metabolism to neural progenitor fate. This work establishes mitochondrial inner membrane architecture as an instructive determinant of human neurogenesis and highlights the non-canonical MCL-1 functions as critical regulators of human brain development.
    DOI:  https://doi.org/10.64898/2025.12.12.694056
  8. bioRxiv. 2025 Dec 12. pii: 2025.12.09.693285. [Epub ahead of print]
    Chromatin stability safeguards mitochondrial homeostasis and prevents mTORC1 hyperactivation.
    Vinoth Sigamani, Mohd Yousuf, Daniel L Johnson, Brian D Strahl, R Nicholas Laribee.
      Cells dynamically regulate chromatin in response to nutrient flux which promotes the transcriptional changes necessary for adaptation. The mechanistic target of rapamycin complex 1 (mTORC1) kinase integrates nutrient signaling with chromatin regulation, yet whether chromatin stability feeds back to mTORC1 activation and stress adaption remains unknown. We previously identified histone H3 at lysine 37 (H3K37) as essential for the response to mTORC1 stress such that mutation of H3K37 to alanine (H3K37A) causes cell death upon mTORC1 inhibition. Herein, we show that H3K37-dependent chromatin stability prevents proteasome-mediated histone degradation, restricts mTORC1 signaling, and safeguards mitochondrial homeostasis during mTORC1 stress. Genetic interaction analyses reveal that H3K37A combined with mutants that destabilize chromatin, including loss of the Set2 H3K36 methyltransferase, Rpd3S histone deacetylase, or multiple histone deposition pathways, causes synthetic lethality when mTORC1 is inhibited. Transcriptome analysis indicates that H3K37A misregulates the mitochondrial transcriptome during mTORC1 stress, which increases mitochondrial reactive oxygen species (ROS) and triggers lethal mitochondrial retrograde signaling. Inactivation of retrograde signaling, or ROS neutralization, rescues viability of H3K37A and chromatin stability mutants during mTORC1 stress. These findings establish chromatin stability as a key safeguard that restrains mTORC1 activity and prevents toxic mitochondrial stress during metabolic adaptation.
    DOI:  https://doi.org/10.64898/2025.12.09.693285
  9. bioRxiv. 2025 Dec 20. pii: 2025.12.16.694762. [Epub ahead of print]
    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, Anthony Verkerke, Alexander Banks, Sheng Tony Hui, Lijun Sun, Jin-Seon Yook, Rose Witte, Shingo Kajimura.
      Metabolic adaptation to environmental changes, such as fasting and cold exposure, involves a dynamic shift in fuel utilization from glucose to fatty acid oxidation, a process that relies on carnitine-mediated fatty acid oxidation in mitochondria. While dietary sources of animal origin (e.g., red meat) contribute to the carnitine pool, de novo carnitine synthesis from trimethyllysine (TML) is essential, particularly for those whose dietary sources are vegetables and fruits that contain negligible amounts of carnitine. However, the molecular pathway of de novo carnitine synthesis and its physiological significance remain poorly understood. Here, we showed that SLC25A45 is a mitochondrial TML carrier that controls de novo carnitine biosynthesis in vivo. Genetic loss of SLC25A45 results in systemic carnitine and acylcarnitine deficiency, leading to impaired fatty acid oxidation and thermogenesis during cold adaptation, while promoting glucose catabolism. Notably, Slc25a45-deficient mice maintained a high respiratory exchange ratio and impaired lipid mobilization following treatment with a GLP1 receptor agonist (GLP-1RA), rendering them resistant to GLP-1RA-induced adipose tissue loss. Together, the present study identifies SLC25A45 as a regulatory checkpoint in fuel switching during adaptation, with implications for systemic energy balance and response to GLP-1RA-mediated anti-obesity therapy.
    DOI:  https://doi.org/10.64898/2025.12.16.694762
  10. bioRxiv. 2025 Dec 16. pii: 2025.12.14.693989. [Epub ahead of print]
    Targeting Ogt in ADPKD mitigates metabolic reprogramming and renal cystogenesis, extending survival.
    Matthew A Kavanaugh, Saleem Ahmad, Dona Greta Isai, Heather A L Riddell, Amanda P Assis, Chadhve Ranganathan, Aakriti Chaturvedi, Vincent Lam, Nikhitha Muthineni, Rayyan Abid, Jenna E Jurgensmeyer, Casey Blades, Michele T Pritchard, Madhulika Sharma, Darren P Wallace, Stephen C Parnell, Chad Slawson, Pamela V Tran.
      Aberrant cell metabolism drives autosomal dominant polycystic kidney disease (ADPKD). O-GlcNAcylation, a metabolically regulated post-translational modification, is elevated in ADPKD kidneys. Using rapidly and slowly progressive ADPKD mouse models, we demonstrate that deleting O-GlcNAc transferase ( Ogt ) reduces renal cystogenesis and extends survival in a rapidly progressive model from postnatal day 21 to over a year. Pharmacological OGT inhibition similarly reduced cyst formation of patient-derived renal epithelial cells in vitro . In Pkd1 conditional knockout kidneys, Ogt deletion maintained phosphorylated AMPK and mitochondrial respiratory chain complex levels, preserving cellular energy sensing and production. Further, metabolomic analysis revealed normalization of glycolysis and of the hexosamine and hyaluronic acid biosynthesis pathways. In contrast, dysregulation of these pathways in Pkd1 conditional knockout kidneys culminated in increased tricarboxylic acid cycle entry, increased O-GlcNAc, and increased hyaluronic acid in the extracellular matrix, respectively. These findings identify Ogt as a central metabolic regulator and therapeutic target, linking metabolism to intracellular and extracellular mechanisms of cyst formation.
    DOI:  https://doi.org/10.64898/2025.12.14.693989
  11. Alzheimers Dement. 2025 Dec;21 Suppl 1 e102364
    Basic Science and Pathogenesis.
    Sara Yunta-Sánchez, Regina Mengual-Fenollar, Juan Pedro Bolaños, Rubén Quintana-Cabrera.
       BACKGROUND: In the nervous system, mitochondria can be transferred between neural cells through intercellular tunneling nanotubes (TNTs), microvesicles, or as free organelles. This transfer not only alters the mitochondrial content and respiration of recipient neural cells but also triggers a profound rewiring of their physiology, with glial cells and immune responses playing key roles in this reconfiguration.
    METHOD: Primary co-cultures of neurons and glial cells, along with in vivo analysis of mitochondrial transfer in mouse brains, were monitored using kinetic microscopy, flow cytometry, and metabolic flux analyses to explore the physiological changes in neural cells. Mitochondrial DNA (mtDNA) transmission was tracked through RT-PCR and ARMS-PCR to examine hierarchical transfer and acquisition.
    RESULT: Communication between neural cells, particularly through TNTs, shows dynamic mitochondrial transfer, regulated by mitochondrial transport, fusion, and fission events. These events respond to structural and signaling changes in intercellular communication, mainly via TNTs. As a result, transmitted mitochondria reconfigure the content, metabolism, and mtDNA composition in recipient neurons and astrocytes. Notably, we observe a significant role of microglia and astrocytes upon mitochondrial acquisition in mouse brains, suggesting inflammatory events that may coordinate mitochondrial transfer as key regulators of metabolic rewiring and cognitive effects in the nervous system.
    CONCLUSION: Our findings provide evidence that a multilayered mitochondrial transfer is a critical mechanism for reconfiguring neural metabolism, immune responses, and overall neural physiology.
    DOI:  https://doi.org/10.1002/alz70855_102364
  12. Nat Commun. 2025 Dec 23. 16(1): 11339
    Prostate cancer cells converge to an inflammatory-like state upon metastatic dissemination.
    Tina Keshavarzian, Kira Furlano, Giacomo Grillo, Lisanne Mout, Christopher Arlidge, Faizan Hasan, Ankita Nand, Migle Mikutenaite, Evdoxia Karadoulama, Ashish Goyal, Elisabeth L Pezzuto, Jessica Heilmann, Jakub Sykora, Sarah Minner, Thorsten Schlomm, Guido Sauter, Ronald Simon, Housheng Hansen He, Joachim Weischenfeldt, Christoph Plass, Clarissa Gerhäuser, Mathieu Lupien.
      Identifying drivers of cancer progression to guide treatment selection is hindered by our limited understanding of tumor heterogeneity and its impact on tumor evolution. Here, we delineate the phenotypic variability across ~300,000 cells collected from multiple tumor loci in primary prostate and matched locoregional metastases using single-cell chromatin accessibility and gene expression sequencing. We find inter-patient heterogeneity to be confined to malignant populations. Within individual tumor loci, we see phenotypic heterogeneity among malignant cell populations despite a shared clonal genotypic architecture. We also observe that malignant cell populations disseminating to locoregional lymph nodes mirror the clonal architecture and phenotypic heterogeneity across primary tumor loci, while shifting from canonical prostate-cancer states to non-canonical inflammatory-like states. Our findings suggest a bottleneck imposed during the dissemination process, funneling prostate cancer cells toward an inflammatory-like cell state. These insights into the interplay between phenotypic identity and clonal architecture refine our understanding of prostate cancer progression and suggest that convergence of cancer cells towards an inflammatory-like state underlies dissemination to lymph nodes, offering a critical framework for future studies into prostate cancer metastatic potential.
    DOI:  https://doi.org/10.1038/s41467-025-67856-5
  13. Cell. 2025 Dec 24. pii: S0092-8674(25)01363-7. [Epub ahead of print]188(26): 7333-7334
    A gut-to-brain pathway that limits protein intake.
    Marito Hayashi.
      In this issue of Cell, Jaschke and Luchsinger et al. uncover a gut-to-brain signaling mechanism that dynamically shapes protein intake. During recovery from extreme fasting, ammonia derived from the metabolism of specific dietary amino acids is detected by Trpa1-expressing intestinal epithelial cells, leading to the activation of a protein aversion pathway.
    DOI:  https://doi.org/10.1016/j.cell.2025.11.028
  14. Cell. 2025 Dec 22. pii: S0092-8674(25)01366-2. [Epub ahead of print]
    Hepatic adaptation to chronic metabolic stress primes tumorigenesis.
    Constantine N Tzouanas, Jessica E S Shay, Marc S Sherman, Adam J Rubin, Benjamin E Mead, Tyler T Dao, Junyan Tao, Brandon M Lehrich, George Eng, Jeffrey Patterson-Fortin, Titus Butzlaff, Miyeko D Mana, Kellie E Kolb, Chad Walesky, Brian J Pepe-Mooney, Colton J Smith, Sanjay M Prakadan, Michelle L Ramseier, Yuzhou Evelyn Tong, Julia Joung, Fangtao Chi, Thomas McMahon-Skates, Carolyn L Winston, Woo-Jeong Jeong, Katherine J Aney, Ethan Chen, Sahar Nissim, Feng Zhang, Vikram Deshpande, Satdarshan P Monga, Georg M Lauer, Wolfram Goessling, Ömer H Yilmaz, Alex K Shalek.
      During chronic stress, cells must support both tissue function and their own survival. Hepatocytes perform metabolic, synthetic, and detoxification roles, but chronic nutrient imbalances can induce hepatocyte death and precipitate metabolic dysfunction-associated steatohepatitis (MASH, formerly NASH). Despite prior work identifying stress-induced drivers of hepatocyte death, chronic stress' functional impact on surviving cells remains unclear. Through cross-species longitudinal single-cell multi-omics, we show that ongoing stress drives prognostic developmental and cancer-associated programs in non-transformed hepatocytes while reducing their mature functional identity. Creating integrative computational methods, we identify and then experimentally validate master regulators perturbing hepatocyte functional balance, increasing proliferation under stress, and directly priming future tumorigenesis. Through geographic regression on human tissue microarray spatial transcriptomics, we uncover spatially structured multicellular communities and signaling interactions shaping stress responses. Our work reveals how cells' early solutions to chronic stress can prime future tumorigenesis and outcomes, unifying diverse modes of cellular dysfunction around core actionable mechanisms.
    Keywords:  chronic stress response; computational methods development; epigenetic priming; genetic perturbation; liver; metabolism; single-cell genomics; tissue memory
    DOI:  https://doi.org/10.1016/j.cell.2025.11.031
  15. Nat Commun. 2025 Dec 21.
    HIF-1α-mediated feedback prevents TOR signalling from depleting oxygen supply and triggering stress during normal development.
    Yifan Zhao, Cyrille Alexandre, Gavin Kelly, Jean-Paul Vincent, Gantas Perez-Mockus.
      Growth deceleration before growth termination is a universal feature of growth during development. Transcriptomics analysis reveals that during their two-day period of growth deceleration, wing imaginal discs of Drosophila undergo a progressive metabolic shift from oxidative phosphorylation towards glycolysis. Ultra-sensitive reporters of HIF-1α stability and activity show that imaginal discs become increasingly hypoxic during development in normoxic conditions, suggesting that limiting oxygen supply could underlie growth deceleration. We confirm the expectation that rising levels of HIF-1α dampen TOR signalling activity through transcriptional activation of REDD1. Conversely, excess TOR leads, in a tissue-size-dependent manner, to hypoxia, which boosts HIF-1α levels and activity. Thus, HIF-1α mediates a negative feedback loop whereby TOR signalling triggers hypoxia, which in turn reduces TOR signalling. Abrogation of this feedback by Sima/HIF-1α knockdown leads to cellular stress, which is alleviated by reduced TOR signalling or a modest increase in environmental oxygen. We conclude that Sima/HIF-1α prevents TOR-mediated growth from depleting local oxygen supplies during normal development.
    DOI:  https://doi.org/10.1038/s41467-025-67089-6
  16. Nat Commun. 2025 Dec 20.
    Genome-scale spatial mapping of the Hodgkin lymphoma microenvironment identifies tumor cell survival factors.
    Vignesh Shanmugam, Neriman Tokcan, Daniel Chafamo, Sean Sullivan, Mehdi Borji, Haley Martin, Gail Newton, Naeem Nadaf, Saoirse Hanbury, Irving Barrera, Dylan Cable, Jackson Weir, Orr Ashenberg, Geraldine Pinkus, Scott Rodig, Caroline Uhler, Evan Macosko, Margaret Shipp, Abner Louissaint, Fei Chen, Todd R Golub.
      A central challenge in cancer research is to identify the secreted factors that sustain tumor cell survival. This is best exemplified in Hodgkin lymphoma, where malignant cells constitute a minor fraction of the tumor and rely on signals from the microenvironment for survival. Using genome-wide transcriptional profiling with spatial and single-cell resolution, we show that the neighborhood around malignant cells forms a distinct niche of 31 non-malignant cell types, enriched in helper T cells and myeloid cells, but depleted of plasma cells. Moreover, our spatial analysis nominates IL13 as a candidate survival factor. Recombinant IL13 augments malignant cell growth in vitro, and genome-wide loss-of-function screens across >1000 human cancer cell lines identify IL4R and IL13RA1, heterodimeric components of the IL13 receptor, as uniquely essential in Hodgkin lymphoma. Importantly, blocking antibodies phenocopy genetic inactivation. Our findings provide a biological rationale for testing IL13-directed therapies, which are already FDA-approved, in Hodgkin lymphoma.
    DOI:  https://doi.org/10.1038/s41467-025-67539-1
  17. bioRxiv. 2025 Dec 09. pii: 2025.12.06.692631. [Epub ahead of print]
    Loss of heterozygosity exposes germline mutations in complex I and drives Warburg metabolism in oncocytic carcinoma of the thyroid.
    Celia de la Calle Arregui, Anderson R Frank, Kelvin Mun, Jiwoong Kim, Kuntal Majmudar, Justin A Bishop, Cheryl Lewis, Yang Xie, David G McFadden.
      Oncocytic (Hürthle cell) carcinoma of the thyroid (OCT) is characterized by widespread loss of heterozygosity (LOH), mitochondrial accumulation and recurrent mitochondrial DNA mutations leading to impairment of complex I. Here, we establish and characterize a novel OCT cell line, UT946, which displays severe mitochondrial electron transport chain dysfunction and a Warburg metabolic phenotype. Using a series of cytoplasmic hybrids, we establish that the complex I defect in UT946 stems from a nuclear-encoded loss of function mutation in the complex I subunit NDUFS1. To our surprise, the mutation in NDUFS1 was inherited as a recessive germline allele that underwent LOH in the tumor to expose functional loss of complex I. A re-analysis of 91 OCT tumor genomes revealed that LOH-driven exposure of recessive germline mutations in complex I subunits was a recurrent mechanism underlying complex I inactivation in OCT. These findings unveil a new germline-driven mechanism of complex I loss and metabolic reprogramming in cancer, and provide further evidence of the strong selective pressure for complex I impairment in OCT.
    Teaser: Germline mutations in complex I induce aerobic glycolysis in oncocytic carcinoma of the thyroid through somatic loss of heterozygosity.
    DOI:  https://doi.org/10.64898/2025.12.06.692631
  18. Adv Biol (Weinh). 2025 Dec 22. e00410
    Synergistic Roles of FAHD-1 and PYC-1 in Mitochondrial Function, Behavior, and Longevity in C. elegans.
    Riccardo Giaquinta, Andreas Andric, Matthias Scheppach, Alexander K H Weiss.
      Mitochondrial metabolism plays a central role in organismal physiology and aging. In Caenorhabditis elegans, FAHD-1 (oxaloacetate decarboxylase) and PYC-1 (pyruvate carboxylase) catalyze opposing reactions that influence oxaloacetate homeostasis within the tricarboxylic acid cycle. To dissect their functional interplay, we analyzed single- and double-knockout strains generated by CRISPR/Cas9 alongside the classical allele. Fahd-1 mutants exhibit impaired mitochondrial respiration, reduced motility, and early egg-laying onset, whereas pyc-1 mutants display increased locomotion and enhanced metabolic flexibility. Paradoxically, although each single mutantion extended lifespan, combining them restored wild-type lifespan and partially normalized respiratory function, suggesting a compensatory interaction. These findings establish FAHD-1 and PYC-1 as antagonistic mitochondrial enzymes whose balance governs locomotion, reproduction, and lifespan in C. elegans, providing a conceptual framework for conserved links between mitochondrial metabolism and aging.
    Keywords:  caenorhabditis elegans; cell biology; citric acid cycle; mitochondrion; motility
    DOI:  https://doi.org/10.1002/adbi.202500410
  19. bioRxiv. 2025 Dec 10. pii: 2025.12.07.692828. [Epub ahead of print]
    Bioinformatic analysis of metastasis-associated metabolic landscape reveals an oncogenic role for the transsulfuration pathway.
    Jonathan K Yan, Ying Yang, Wenqi Wang.
      Cancer metastasis is a leading cause of cancer-related deaths, while its underlying mechanisms remain incompletely understood. To colonize distant organs, cancer cells reprogram their metabolism to adapt to diverse environmental challenges. Therefore, elucidating the metabolic pathways that drive cancer metastasis will uncover novel biomarkers and therapeutic targets. In this study, we integrated published datasets and systematically analyzed metabolites across multiple cancer cell lines. This large-scale bioinformatic analysis revealed distinct metabolites and metabolic pathways associated with organ-specific metastasis, and underscored the crucial role of tissue of origin in shaping the metabolic landscape of metastatic tumors. Notably, the transsulfuration pathway (also known as the cysteine and methionine metabolism) was strongly enriched in cancer cells with high metastatic potential. We validated this finding in pancreatic cancer, where the pathway enzyme cystathionine β-synthase (CBS) and its metabolic products were highly expressed in metastatic cancer cells. Targeting the transsulfuration pathway either by methionine deprivation or pharmacological inhibition of CBS significantly impaired the migration and invasion of metastatic pancreatic cancer cells. Taken together, our study not only provides a global view of the altered metabolic landscape in metastasis, but also identifies the transsulfuration pathway as an oncogenic driver and a therapeutic target for pancreatic cancer metastasis.
    DOI:  https://doi.org/10.64898/2025.12.07.692828
  20. ACS Appl Bio Mater. 2025 Dec 22.
    A Polymeric Nanocarrier Platform for Rapid and Precise Fatty Acid Tracing in Cells.
    Michael P Vincent, Abigail E Ellis, Lisa M DeCamp, Susan M Kitchen-Goosen, Thomas J Rogers, Anna R Tarach, Christine Isaguirre, Shelby E Compton, Evan C Lien, Kelsey S Williams, Russell G Jones, Ryan D Sheldon.
      Stable isotope tracing provides insights into metabolism by tracking the movement of isotopically labeled precursors through metabolic networks. Fatty acid tracers, such as uniformly labeled 13C-palmitate, are used to study lipid biosynthesis, energy storage, and/or signaling. These tracers are complexed with BSA to improve solubility; yet, this approach is limited by transport bottlenecks, toxicity, and immunogenicity. Here, we developed biodegradable nanocarriers that improve hydrophobic tracer delivery and benchmarked performance against BSA with metabolomics and lipidomics. Nanocarriers accumulated U-13C-palmitate to higher intracellular levels, and more rapidly, than BSA-conjugated controls. Once inside the cell, nanocarrier-delivered tracers exhibited first-order depletion kinetics, ensuring predictable and efficient metabolism. In contrast, BSA produced delayed or biphasic tracer depletion due to transport limitations, which hindered the bioavailability. Entrance of nanocarrier-delivered U-13C-palmitate into the cellular metabolic network manifested through 13C-labeled desaturated and elongated fatty acids and incorporation into complex lipids without material-mediated aberrations. Our results demonstrate that nanocarrier-assisted tracing captures key metabolic trends with enhanced labeling while overcoming limitations of BSA-mediated delivery. This versatile, customizable platform enables opportunities for metabolic tracing in complex systems.
    Keywords:  BSA; lipidomics; metabolism; metabolomics; nanocarrier; nanoparticle; palmitate; tracing
    DOI:  https://doi.org/10.1021/acsabm.5c01770
  21. Biochemistry (Mosc). 2025 Dec;90(12): 1849-1861
    Turnover and Quality Control of Mitochondrial DNA.
    Wolfram S Kunz.
      The quantitative content of mitochondrial DNA (mtDNA) - a multicopy circular genome - is an important parameter relevant for function of mitochondrial oxidative phosphorylation (OxPhos) in cells, since mtDNA encodes 13 essential OxPhos proteins, 22 tRNAs, and 2 rRNAs. In contrast to the nuclear genome, where almost all lesions have to be repaired, the multicopy nature of mtDNA allows the degradation of severely damaged genomes. Therefore, cellular mtDNA maintenance and its copy number not only depend on replication speed and repair reactions. The speed of intramitochondrial mtDNA degradation performed by a POLGexo/MGME1/TWNK degradation complex and the breakdown rate of entire mitochondria (mitophagy) are also relevant for maintaining the required steady state levels of mtDNA. The present review discusses available information about the processes relevant for turnover of mitochondrial DNA, which dysbalance leads to mtDNA maintenance disorders. This group of mitochondrial diseases is defined by pathological decrease of cellular mtDNA copy number and can be separated in diseases related to decreased mtDNA synthesis rates (due to direct replication defects or mitochondrial nucleotide pool dysbalance) or diseases related to increased breakdown of entire mitochondria (due to elevated mitophagy rates).
    Keywords:  determinants of cellular mtDNA content; mtDNA degradation; mtDNA maintenance; mtDNA maintenance disorders; mtDNA replication
    DOI:  https://doi.org/10.1134/S0006297925602485
  22. Nat Commun. 2025 Dec 20.
    Reconstructing the three-dimensional architecture of extrachromosomal DNA with ec3D.
    Biswanath Chowdhury, Kaiyuan Zhu, Chaohui Li, Jessica Alsing, Jens Luebeck, Maria E Stefanova, Owen S Chapman, Katerina Kraft, Shu Zhang, Jun Yi Stanley Lim, Yipeng Xie, Yoon Jung Kim, Sihan Wu, Lukas Chavez, Guy Nir, Anton G Henssen, Paul S Mischel, Howard Y Chang, Vineet Bafna.
      Extrachromosomal DNAs (ecDNAs) are circular DNA molecules prevalent in human cancers that drive tumor evolution and drug resistance. Their circular topology, which disrupts topological domains and rewires regulatory circuits, has typically been studied via pairwise interactions. Here we develop ec3D, a computational method for reconstructing three-dimensional ecDNA structures from Hi-C data. Given a candidate ecDNA sequence and whole-genome Hi-C data, ec3D reconstructs spatial structures by maximizing the Poisson likelihood of observed interactions. We validate ec3D using simulated structures, previously characterized cancer cell lines, and microscopy imaging. Our reconstructions reveal that ecDNAs occupy spherical configurations and mediate unique long-range regulatory interactions involved in gene regulation. Through algorithmic innovations, ec3D can resolve complex structures with duplicated segments, identify multi-way interactions, and identify potential intermolecular (trans) interactions. Our findings provide insights into how ecDNA's spatial organization bypasses normal chromosomal constraints and contributes to increased oncogene expression.
    DOI:  https://doi.org/10.1038/s41467-025-67614-7
  23. Cell Death Dis. 2025 Dec 20.
    Transsulfuration metabolism is essential for ferroptosis resistance in quiescent endothelial cells.
    Roxana Elena Oberkersch, Jacopo Lidonnici, Sebastiano Andreuzza, Eleonora Zambon, Gabriele Imperato, Silvia Pedretti, Nico Mitro, Massimo Mattia Santoro.
      Angiogenesis, the formation of new blood vessels from pre-existing ones, is a crucial process involved in both physiological and pathological contexts. During angiogenesis, quiescent endothelial cells (QECs) forming the vascular bed begin to proliferate and switch their metabolism to support anabolic and energetic needs in response to growth factors and hypoxic conditions. Recent research has demonstrated that ferroptosis, an iron-dependent form of cell death mediated by lipid peroxidation, can affect angiogenesis. Cysteine, a thiol-containing amino acid, is crucial for the synthesis of sulfur-containing biomolecules that control ferroptosis. Glutathione (GSH), a reducing tripeptide containing a cysteine residue, serves as a cofactor for the enzyme glutathione peroxidase 4 (GPX4) to donate electrons to peroxides of polyunsaturated fatty acyl phospholipids. Cysteine can be acquired from its extracellular oxidized form, cystine, via the glutamate-cystine antiporter (system xCT) or synthesized de novo via the transsulfuration pathway (TSP). However, whether proliferating ECs (PECs) and QECs differentially modulate the cysteine/GSH/GPX4 axis to protect themselves from ferroptosis is still unknown. Our findings revealed that PECs primarily utilize extracellular cystine to synthesize GSH, which is essential for avoiding ferroptosis. In contrast, QECs exhibit a resilient response to cystine starvation by activating the TSP. Interestingly, chronic and severe hypoxia induces ferroptosis resistance in PECs exposed to cystine limitation, mimicking the metabolic profile of QECs. Molecularly, QECs exhibit high NRF2 expression necessary to support TSP under cystine limitation and protect QECs from ferroptosis. In vivo experiments confirm the susceptibility of ECs to cell death by xCT inhibition in a retinal model of sprouting angiogenesis. These findings highlight differential regulation of cysteine metabolism in PECs and QECs and suggest that the cysteine/GSH/GPX4 axis could be a potential therapeutic target for diseases involving angiogenesis.
    DOI:  https://doi.org/10.1038/s41419-025-08333-1
  24. Aging Cell. 2026 Jan;25(1): e70346
    Preliminary Evidence for Increased Histone Succinylation as a Potential Epigenetic Marker for Longevity.
    Stephanie Stransky, Sarah Graff, Kai Mao, Derek M Huffman, Sofiya Milman, Nir Barzilai, Simone Sidoli.
      Histone post-translational modifications (PTMs) are critical regulators of chromatin structure and gene expression, with broad implications for development, metabolism, and aging. While canonical modifications such as methylation and acetylation are well characterized, the role of histone succinylation remains poorly understood. Here, we investigated histone succinylation in the context of aging and exceptional longevity. Using mass spectrometry-based proteomics, we quantified histone succinylation in B-cells from four groups: young individuals, older individuals without parental longevity (OPUS), long-lived individuals, and offspring of long-lived individuals (OPEL). We found that histone succinylation was significantly elevated in the OPEL group compared to both young and OPUS cohorts. Nuclear proteomics further revealed enrichment of succinylated proteins in OPEL samples, supporting a role for succinylation in chromatin organization. To test whether succinate availability impacts healthspan, we supplemented middle-aged mice with succinic acid. While body weight, frailty index, and cognition were unaffected, succinic acid improved motor coordination and muscle strength. Together, our findings provide preliminary evidence that enhanced histone succinylation may serve as a protective epigenetic mechanism in individuals predisposed to exceptional longevity, and that succinate supplementation can selectively improve aspects of physical performance during aging.
    Keywords:  aging; chromatin modifications; epigenetics; healthspan; histone succinylation; longevity; progeny of long‐lived individuals
    DOI:  https://doi.org/10.1111/acel.70346
  25. Nat Commun. 2025 Dec 21.
    Deep Mutational Scanning of FDX1 Identifies Key Structural Determinants of Lipoylation and Cuproptosis.
    Jeffrey C Hsiao, Douglas M Warui, Jason J Kwon, Margaret B Dreishpoon, Nolan R Bick, Tamra Blue-Lahom, David E Root, Squire J Booker, Peter Tsvetkov.
      Cuproptosis is a recently described form of regulated cell death triggered by ionophore-induced copper (Cu) overload in mitochondria. It is critically dependent on ferredoxin 1 (FDX1), a mitochondrial iron-sulfur cluster containing protein that acts as an electron shuttle. FDX1 reduces ionophore-bound Cu(II) to Cu(I), thereby triggering its release, and promotes mitochondrial protein lipoylation, which is directly targeted by the released copper to drive cell death. Despite the pivotal role of FDX1 in cuproptosis, the structural determinants underlying its distinct functions remain unclear. To address this, we performed deep mutational scanning on FDX1 and find that two conserved solvent-exposed residues, D136 and D139, on alpha helix 3 are essential for both cuproptosis and lipoylation. Charge-reversal mutations at these positions abolish FDX1's ability to induce cuproptosis and support lipoylation in cells, despite retaining full enzymatic activity in vitro. Guided by structural and genomic analyses, we further identify dihydrolipoamide dehydrogenase (DLD), the E3 subunit of lipoylated complexes as an alternative FDX1 reductase both in cells and in vitro. Together, these findings establish the acidic alpha helix 3 of FDX1 as a critical interface for its upstream regulation and suggest that FDX1's roles in cuproptosis and in lipoylation are both structurally and functionally linked.
    DOI:  https://doi.org/10.1038/s41467-025-67869-0
  26. bioRxiv. 2025 Dec 18. pii: 2025.12.16.693850. [Epub ahead of print]
    Systematic screening of tryptophan metabolism identifies site- and microbial-specific signatures of tryptophan utilization in experimental colitis.
    Lina Welz, Abrar I Alsaadi, Danielle Mm Harris, Meiping Yu, Taous Mekdoud, Johanna Bornhäuser, Eva Springer, Clara Gilloteau, Anant A Pothakamury, Jaclyn D Smith, Brenita C Jenkins, Felix Sommer, Silvio Waschina, Philip Rosenstiel, Stefan Schreiber, Melanie R McReynolds, Konrad Aden.
       Background: Altered tryptophan (Trp) metabolism and disrupted nicotinamide adenine dinucleotide (NAD⁺) synthesis are hallmarks of IBD, yet how intestinal microbiota contribute to these metabolic shifts during intestinal inflammation remains poorly understood.
    Methods: We used targeted metabolomics to systematically profile Trp- and NAD⁺-related metabolites across multiple biological compartments - including tissues, luminal contents, stool, and serum - in mice treated with dextran sulfate sodium (DSS) alone or in combination with a broad-spectrum antibiotic (ABX) cocktail.
    Results: Microbial depletion significantly attenuated colitis and increased host Trp bioavailability, implicating the gut microbiota as a competitive Trp consumer. In DSS colitis, Trp degradation along the kynurenine pathway (KP) was exaggerated but blocked at the key KP enzyme quinolinate phosphoribosyltransferase (QPRT), resulting in mucosal NAD(H) depletion. ABX co-treatment normalized metabolite conversion along the KP and restored mucosal NAD(H) levels, revealing a dual role of the gut microbiota during colitis: while they compete with the host for Trp utilization, they simultaneously shape host KP regulation and NAD⁺ de novo synthesis, supporting host energy homeostasis.
    Conclusion: Our findings demonstrate that mucosal NAD⁺ de novo synthesis is a microbially regulated metabolic process that alleviates intestinal inflammation and may represent a novel therapeutic target in IBD through modulation of the gut microbiota or their metabolites.
    DOI:  https://doi.org/10.64898/2025.12.16.693850
  27. Biochemistry (Mosc). 2025 Dec;90(12): 1929-1943
    ATP in Mitochondria: Quantitative Measurement, Regulation, and Physiological Role.
    Anna S Lapashina, Danila O Tretyakov, Boris A Feniouk.
      Oxidative phosphorylation in mitochondria is the main source of ATP in most eukaryotic cells. Concentrations of ATP, ADP, and AMP affect numerous cellular processes, including macromolecule biosynthesis, cell division, motor protein activity, ion homeostasis, and metabolic regulation. Variations in ATP levels also influence concentration of free Mg2+, thereby extending the range of affected reactions. In the cytosol, adenine nucleotide concentrations are relatively constant and typically are around 5 mM ATP, 0.5 mM ADP, and 0.05 mM AMP. These concentrations are mutually constrained by adenylate kinases operating in the cytosol and intermembrane space and are further linked to mitochondrial ATP and ADP pools via the adenine nucleotide translocator. Quantitative data on absolute adenine nucleotide concentrations in the mitochondrial matrix are limited. Total adenine nucleotide concentration lies in the millimolar range, but the matrix ATP/ADP ratio is consistently lower than the cytosolic ratio. Estimates of nucleotide fractions show substantial variability (ATP 20-75%, ADP 20-70%, AMP 3-60%), depending on the organism and experimental conditions. These observations suggest that the 'state 4' - inhibition of oxidative phosphorylation in the resting cells due to the low matrix ADP and elevated proton motive force that impedes respiratory chain activity - is highly unlikely in vivo. In this review, we discuss proteins regulating ATP levels in mitochondria and cytosol, consider experimental estimates of adenine nucleotide concentrations across a range of biological systems, and examine the methods used for their quantification, with particular emphasis on the genetically encoded fluorescent ATP sensors such as ATeam, QUEEN, and MaLion.
    Keywords:  ADP; ATP; ATP synthase; ATeam; adenine nucleotide translocator (ANT); mitochondria
    DOI:  https://doi.org/10.1134/S0006297925603338
  28. Nat Commun. 2025 Dec 23. 16(1): 11338
    Clonal evolution and transcriptional plasticity shape metastatic dissemination routes in prostate cancer.
    Migle Mikutenaite, Evdoxia Karadoulama, Francesco Favero, Alessio Locallo, Francisco German Rodriguez Gonzalez, Daria Kiriy, Tina Keshavarzian, Kira Furlano, Markus Graefen, Robert G Bristow, Clarissa Gerhäuser, Christoph Plass, Guido Sauter, Ronald Simon, Mathieu Lupien, Sarah Minner, Thorsten Schlomm, Joachim Weischenfeldt.
      Prostate cancer is a highly heterogeneous disease, driven by genomic and transcriptional changes that impact disease progression and metastatic potential. The interplay between clonal evolution, transcriptional plasticity, and tumour microenvironment is, however, poorly understood. Here, we leverage and integrate single-nuclei RNA sequencing and whole-genome sequencing from 43 spatially distinct tumour samples from five patients with locally advanced prostate cancer to reconstruct clonal evolution trajectories and transcriptional changes driving metastasis at single-cell resolution. We find extensive clonal heterogeneity, including both monophyletic and polyphyletic metastatic dissemination, and ongoing clonal evolution in the primary tumour after metastatic spread. Metastatic seeding converges on disease trajectories involving both genomic and transcriptional changes, including androgen receptor independence and activation of estrogen-, WNT- and JAK-STAT- pathway activity, in spatially distinct areas. Our findings suggest an intricate interplay between clonal evolution and cellular plasticity driving metastatic seeding and point toward more integrative prognostic markers for improved patient management.
    DOI:  https://doi.org/10.1038/s41467-025-66704-w
  29. Cancer Cell. 2025 Dec 24. pii: S1535-6108(25)00536-7. [Epub ahead of print]
    Targeting STING to generate therapeutic anti-tumor immunity.
    Caroline G Fahey, Anthony F Cordova, Patrick C Gedeon, David A Barbie.
      The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway bridges cytosolic DNA sensing with type I interferon activation in cancer. Despite promising preclinical results, generating clinically meaningful anti-tumor immunity with STING agonists has faced substantial challenges, highlighting gaps in model systems and the biologic complexity of STING signaling. In the tumor microenvironment (TME), STING activation elicits highly context- and cell type-dependent outcomes, with divergent effects on tumor cells, myeloid cells, T cells, and other cell types. Furthermore, the downstream induction of type I interferon and other cytokines in the TME can have both pro- and anti-tumorigenic consequences, with emerging interferon-independent functions of STING signaling adding further complexity. In this review, we chart the diverse impact of STING activation across the TME and discuss how recent insights can inform the design of next-generation therapeutic strategies that more effectively harness STING-driven innate immunity to promote durable anti-tumor activity in humans.
    Keywords:  STING; anti-tumor immunity; cGAS; innate immunity; interferon; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.ccell.2025.12.002
  30. bioRxiv. 2025 Dec 12. pii: 2025.12.09.693280. [Epub ahead of print]
    Lysosomal swelling triggers LRRK2 activity.
    Tuyana Malankhanova, Zhiyong Liu, Samuel Strader, Weiping Wang, Kiwoon Sung, Zhong Li, Shawn M Ferguson, Andrew B West.
      LRRK2 is implicated in lysosomal functions, but the physiological upstream cues that engage endogenous LRRK2 activity are incompletely defined. Here we show that lysosomal swelling serves as a selective and reversible trigger for LRRK2-mediated Rab phosphorylation, without requiring membrane damage. Acute inhibition of PIKfyve, but not the general disruption of phosphoinositide signaling, induces the robust accumulation of phosphorylated Rabs across endolysosomal membranes. Rescue of swelling through pharmacological restoration of lysosomal ionic imbalances from PIKfyve inhibition suppresses LRRK2 activation without restoring lysosomal function. Mechanical lysosomal swelling from indigestible osmolyte uptake causes a dose-dependent increase in LRRK2-mediated Rab phosphorylation on both swollen and non-swollen lysosomes. Together, these findings identify LRRK2 as a sensor of lysosomal volume and mechanical stress, not specifically membrane damage or PIKfyve inhibition. As lysosomal swelling is a shared pathological feature across LRRK2 -linked diseases, these results reframe LRRK2 as part of an endolysosomal surveillance system responsive to lysosomal distension.
    DOI:  https://doi.org/10.64898/2025.12.09.693280
  31. Nat Commun. 2025 Dec 21.
    Single cell profiling framework reveals metabolic subpopulations as drivers of bioproduction heterogeneity.
    Juline Savigny, Kiyan Shabestary, Maria Portela, Cinzia Klemm, Yvette Sum, Piotr Hapeta, Marko Storch, Christopher Rowlands, Rodrigo Ledesma-Amaro.
      Heterogeneity within clonal cell populations remains a critical bottleneck within bioprocess engineering, notably by undermining bioproduction yields. Efforts to mitigate its impact have, however, been hampered by technological difficulties quantifying metabolism at the single-cell level. Here, we propose a framework based on single-cell biosensor analysis that enables robust characterisation of cell's metabolic states, leveraging it to detect and isolate isogeneic heterogeneity in response to environmental perturbations and within microbial cell factories. We identify acute and gradual glucose depletion to induce differentiation of metabolically distinct subpopulations and reveal these subpopulations to exhibit differential production capabilities, with lower intracellular pH subpopulations exhibiting enhanced product accumulation within violacein-producing strains but reduced yields within lycopene-producing strains. Lastly, we highlight galactose cultivation as a method to modulate subpopulation dynamics towards higher-producing lycopene phenotypes. Altogether, our research provides insights into subpopulation differentiation and establishes promising avenues for the engineering of more robust and higher-producing strains.
    DOI:  https://doi.org/10.1038/s41467-025-67408-x
  32. Nat Methods. 2025 Dec 23.
    Glutamate indicators with increased sensitivity and tailored deactivation rates.
    Abhi Aggarwal, Adrian Negrean, Yang Chen, Rishyashring Iyer, Daniel Reep, Anyi Liu, Anirudh Palutla, Michael E Xie, Bryan J MacLennan, Kenta M Hagihara, Lucas W Kinsey, Julianna L Sun, Pantong Yao, Jihong Zheng, Arthur Tsang, Getahun Tsegaye, Yonghai Zhang, Ronak H Patel, Benjamin J Arthur, Julien Hiblot, Philipp Leippe, Miroslaw Tarnawski, Jonathan S Marvin, Jason D Vevea, Srinivas C Turaga, Alison G Tebo, Matteo Carandini, L Federico Rossi, David Kleinfeld, Arthur Konnerth, Karel Svoboda, Glenn C Turner, Jeremy P Hasseman, Kaspar Podgorski.
      Understanding how neurons integrate signals from thousands of input synapses requires methods to monitor neurotransmission across many sites simultaneously. The fluorescent protein glutamate indicator iGluSnFR enables visualization of synaptic signaling, but the sensitivity, scale and speed of such measurements are limited by existing variants. Here we developed two highly sensitive fourth-generation iGluSnFR variants with fast activation and tailored deactivation rates: iGluSnFR4f for tracking rapid dynamics, and iGluSnFR4s for recording from large populations of synapses. These indicators detect glutamate with high spatial specificity and single-vesicle sensitivity in vivo. We used them to record natural patterns of synaptic transmission across multiple experimental contexts in mice, including two-photon imaging in cortical layers 1-4 and hippocampal CA1, and photometry in the midbrain. The iGluSnFR4 variants extend the speed, sensitivity and scalability of glutamate imaging, enabling direct observation of information flow through neural networks in the intact brain.
    DOI:  https://doi.org/10.1038/s41592-025-02965-z
  33. Cell Rep. 2025 Dec 24. pii: S2211-1247(25)01569-4. [Epub ahead of print]45(1): 116797
    Activated T cells degrade extracellular proteins to enhance effector functions.
    Yunxue Yin, Xiaorong Lin, Linlin Li, Shuo Kan, Wenrong Jiang, Yuchen Han, Lixin Wang, Shiwen Wang, Jun Jin.
      Proteins are the most abundant source of amino acids in body fluids. However, the potential contribution of extracellular protein catabolism to the regulation of T cell immunity remains poorly understood. In this study, we show that endocytosed extracellular proteins function as an amino acid source in activated T cells, maintaining mTORC1 activity and sustaining cytokine production following T cell activation. Genetic ablation of Tfe3 impairs the activation-induced upregulation of lysosomal genes and disrupts extracellular protein catabolism, resulting in attenuated mTORC1 signaling and compromised anti-viral and anti-tumor T cell responses. The TFE3-protein-mTORC1 signaling axis demonstrates clinical relevance. CD8+PD-1+ tumor-infiltrating T cells from older patients with lung cancer display reduced lysosomal degradation capacity and impaired cytokine secretion compared to their middle-aged counterparts. This functional defect is rescued by treatment with Vismodegib, a TFE3-inducing drug. Our findings reveal lysosome-mediated extracellular protein catabolism as an important metabolic pathway supporting T cell immunity.
    Keywords:  CP: immunology; CP: metabolism; activated T cells; amino acids; extracellular proteins; lysosomal proteolysis; mTORC1; protein degradation
    DOI:  https://doi.org/10.1016/j.celrep.2025.116797
  34. bioRxiv. 2025 Dec 19. pii: 2025.12.18.695286. [Epub ahead of print]
    Mitochondrial membrane junction-mediated ATP channeling drives activity-dependent glucose metabolism.
    Dengbao Yang, Gemma Molinaro, Nadine Nijem, Chuanhai Zhang, Dylen Penny, Meijuan Bai, Mei-Jung Lin, Xiaodong Wen, Salvador Pena, Janaka Wansapura, Maria Gaitanou, Rebecca Matsas, Boyuan Wang, Hamid Baniasadi, Yan Han, Jay Gibson, Kimberly Huber, Xing Zeng.
      Neurons and brown adipocytes rely on rapid ATP production from accelerated glucose metabolism to sustain bursts of activity upon stimulation, a process known as activity-dependent glucose metabolism. The first committed step in this pathway, the hexokinase I (HK1)-catalyzed phosphorylation of glucose, consumes ATP, raising the question of how this reaction can be accelerated when cytosolic ATP becomes limiting during stimulation. We identify Cell Cycle Exit and Neuronal Differentiation protein 1 (CEND1), expressed in both cell types, as a critical regulator of this process. Loss of CEND1 impairs activity-dependent glucose utilization, ATP generation, and stimulation-evoked activity both in vitro and in vivo . Mechanistically, CEND1 assembles a complex with HK1, voltage-dependent anion channel 1 (VDAC1), and adenine nucleotide translocase 1 (ANT1) at hemifusion-like membrane junction between the outer/inner mitochondrial membrane, channeling mitochondrially derived ATP directly to HK1. These findings uncover a previously unrecognized mechanism that sustains activity-dependent glucose metabolism, with broad implications for energy homeostasis in specialized cell types.
    DOI:  https://doi.org/10.64898/2025.12.18.695286
  35. bioRxiv. 2025 Dec 21. pii: 2025.12.19.694894. [Epub ahead of print]
    T CELLS promote the growth of small-cell lung carcinoma via an IL-6/CD74 axis.
    Maya Baron, Zoe Ginestet, Debadrita Bhattacharya, Myung Chang Lee, Alexandros P Drainas, Clara L Poupault, Yoko Nishiga, Alec E Dallas, Barxin Y Nabet, Julien Sage.
      A central challenge in immuno-oncology is overcoming the limited efficacy and durability of immune checkpoint inhibition (ICI). This is particularly true in small-cell lung cancer (SCLC), where chemotherapy plus ICI is standard of care but rarely curative. Here, we found that T cells are surprisingly both necessary and sufficient for optimal tumor growth in mouse models of SCLC. These pro-tumoral effects are mediated by interleukin-6 (IL-6) production, which induces the pro-survival factor CD74 in SCLC cells. Notably, T cells within human SCLC tumors express IL-6, and low IL-6 signaling correlates with improved survival following chemotherapy plus ICI in patients. Accordingly, IL-6 blockade synergizes with ICI to inhibit SCLC growth in vivo. These findings reveal a paradoxical role for T cells in SCLC, uncovering an unexpected T cell-IL-6-CD74 axis that promotes tumor survival, and identify IL-6 as a promising target to help unleash the full potential of immunotherapy in this aggressive cancer.
    DOI:  https://doi.org/10.64898/2025.12.19.694894
  36. Trends Mol Med. 2025 Dec 23. pii: S1471-4914(25)00292-8. [Epub ahead of print]
    Lymph node microenvironment rewires ferroptosis redox defenses.
    Jillian Stark, Jia-Shu Yang, Victor W Hsu, Whitney S Henry.
      Palma et al. show that melanoma cells adapt to oxidative stress imposed by the lymphatic niche by shifting their dependency from glutathione peroxidase 4 (GPX4) to ferroptosis suppressor protein 1 (FSP1), to protect from ferroptosis. This highlights the importance of the microenvironment in shaping ferroptosis defenses and supports FSP1 as a targetable vulnerability for lymph node metastases.
    Keywords:  FSP1; GPX4; ferroptosis; hypoxia; lymph node; melanoma; oxidative stress; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.molmed.2025.12.005
  37. bioRxiv. 2025 Dec 10. pii: 2025.12.08.692638. [Epub ahead of print]
    Oncometabolite fumarate impairs ATR-CHK1 signaling by succinating RPA1 in Fumarate Hydratase-deficient renal cell carcinoma cells.
    Nian Liu, Changxian Shen, Tingting Zhou, Yu Zhou, Hang Yuan, Hongjie Bi, Yingying Wang, Xinyu Pei, Rui Su, Li Zheng, Yihui Shi, Binghui Shen.
      Abnormal accumulation of oncometabolite fumarate drives susceptibility in fumarate hydratase-deficient renal cell carcinoma (FH-dRCC), but the precise mechanisms remain not fully understood. In this study, we demonstrate that high fumarate levels impair activation of ATR-CHK1 signaling in response to replication stress and DNA damage. Mechanistically, fumarate modifies RPA1, an essential factor for ATR-CHK1 activation through succination, a post-translational modification. Succination of RPA1 occurs mainly at cysteine residues 481 and 486, which reduces its binding affinity for single-stranded DNA (ssDNA). RPA1 succination leads to deficient recruitment of TOPBP1 to ssDNA, resulting in attenuated CHK1 activation and defective cell cycle arrest in response to DNA damage. Succinated RPA1 compromises homologous recombination-mediated DNA repair. Our findings establish that fumarate-induced succination of RPA1 impairs DNA repair and cell cycle control, promoting genomic instability in FH-dRCC. This work reveals a novel mechanism by which oncometabolites contribute to genomic instability.
    DOI:  https://doi.org/10.64898/2025.12.08.692638
  38. J Clin Invest. 2025 Dec 23. pii: e195189. [Epub ahead of print]
    Mismatch repair deficiency drives malignant progression and alters the tumor immune microenvironment in glioblastoma models.
    Montserrat Puigdelloses Vallcorba, Nishant Soni, Seung-Won Choi, Kavita Rawat, Tanvi Joshi, Sam Friedman, Alice Buonfiglioli, Angelo Angione, Zhihong Chen, Gonzalo Piñero, Gabrielle Price, Mehek Dedhia, Raina Roche, Emir Radkevich, Anne M Bowcock, Deepti Bhatt, Winfried Edelmann, Robert M Samstein, Timothy E Richardson, Nadejda M Tsankova, Alexander M Tsankov, Ranjit S Bindra, Raul Rabadan, Juan C Vasquez, Dolores Hambardzumyan.
      Mutations in DNA mismatch repair (MMR) pathway genes (MSH2, MSH6, MLH1, and PMS2) are linked to acquired resistance to temozolomide (TMZ) and high tumor mutation burden (TMB) in high-grade gliomas (HGG), including glioblastoma (GBM). However, the specific roles of individual MMR genes in the initiation, progression, TMB, microsatellite instability (MSI), and resistance to TMZ in glioma remain unclear. Here, we developed de novo mouse models of germline and somatic MMR-deficient (MMRd) HGG. Surprisingly, loss of Msh2 or Msh6 does not lead to high TMB, MSI, nor confer response to anti-PD-1 in GBM. Similarly, human GBM shows discordance between MMR gene mutations and TMB/MSI.Germline MMRd leads to promoted progression from low-grade to HGG and reduced survival compared to MMR-proficient (MMRp) tumor-bearing mice. This effect is not tumor cell intrinsic but is associated with MMRd in the tumor immune microenvironment, driving immunosuppressive myeloid programs, reduced lymphoid infiltration, and CD8+ T cell exhaustion. Both MMR-reduced (MMRr) and MMRd GBM are resistant to temozolomide (TMZ), unlike MMRp tumors. Our study shows that KL-50, a imidazotetrazine-based DNA targeting agent inducing MMR-independent cross-link-mediated cytotoxicity, was effective against germline and somatic MMRr/MMRd GBM, offering a potential therapy for TMZ-resistant HGG with MMR alterations.
    Keywords:  Brain cancer; Cell biology; DNA repair; Immunology; Immunotherapy; Neuroscience; Oncology
    DOI:  https://doi.org/10.1172/JCI195189
  39. bioRxiv. 2025 Dec 16. pii: 2025.12.12.693842. [Epub ahead of print]
    Mitochondria-derived PEP licenses glycerolipid synthesis via SLC25A35.
    Tadashi Yamamuro, Daisuke Katoh, Guilherme Martins Silva, Hiroshi Nishida, Satoshi Oikawa, Yusuke Higuchi, Dandan Wang, Masanori Fujimoto, Naofumi Yoshida, Mark Li, Jihoon Shin, Zezhou Zhao, Jin-Seon Yook, Lijun Sun, Shingo Kajimura.
      Mitochondria provide a variety of metabolites, in addition to ATP, to meet cell-specific needs. One such metabolite is phosphoenolpyruvate (PEP), which contains the highest energy phosphate bond above ATP, and has diverse biological functions, including glycolysis, gluconeogenesis, and glyceroneogenesis. Although PEP is generally considered a cytosolic intermediate, it can also be synthesized within mitochondria by the mitochondria-localized carboxykinase (PCK2, also known as M-PEPCK). However, the mechanism by which mitochondrial PEP is delivered to the cytosolic compartment and caters to cell-specific requirements remains elusive. Here, we identify SLC25A35, a previously uncharacterized mitochondrial inner-membrane protein, as the long-sought carrier responsible for mitochondrial PEP efflux. SLC25A35 is highly expressed in lipogenic cells, such as adipocytes, which employ the mitochondrial pyruvate-to-PEP bypass, and is upregulated by lipogenic stimuli. Reconstitution studies by proteo-liposomes, together with structural analyses, demonstrated specific PEP transport by SLC25A35 in a pH gradient-dependent manner. Importantly, loss of SLC25A35 in adipocytes impaired the conversion of mitochondrial PEP into glycerol-3-phosphate, the glycerol backbone in triglyceride, resulting in reduced glycerolipid synthesis while preserving substrate oxidation in the TCA cycle. Furthermore, blockade of SLC25A35 in the liver of obese mice markedly decreased glycerolipid accumulation, ameliorated hepatic steatosis, and improved systemic glucose homeostasis. Together, the present study identifies mitochondrial PEP transport via SLC25A35 as a metabolic checkpoint of fatty acid esterification, offering a selective target for "lipogenic mitochondria" to limit glycerolipid synthesis, a pivotal step in the pathogenesis of hepatic steatosis and Type 2 diabetes.
    DOI:  https://doi.org/10.64898/2025.12.12.693842
  40. Immunity. 2025 Dec 19. pii: S1074-7613(25)00522-9. [Epub ahead of print]
    Positioning and reversible suppression of CCR7+ dendritic cells in perivascular tumor niches shape cancer immunity.
    Beatrice Zitti, Florent Duval, Pratyaksha Wirapati, Mehdi Hicham, Yuxuan Xie, Juhyun Oh, Jan Hoelzl, Philippa Meiser, Marco Varrone, Hannah M Peterson, Chiara Cianciaruso, Ruben Bill, Felix Bayerl, Evangelia Bolli, Anne-Gaëlle Goubet, Máté Kiss, Sheri McDowell, Phil Cheng, Dan Celestini, Julie Terzic, Thomas Zwahlen, Nagham Alouche, Nawel Zouggari, David Tarussio, Stephanie Tissot, Paula Nunes-Hasler, Mari Mino-Kenudson, Michael Lanuti, William C Faquin, Peter M Sadow, Jean-Christophe Tille, Sana Intidhar Labidi-Galy, Christopher S Garris, Stephanie Hugues, Tatiana V Petrova, Burkhard Ludewig, Sergio Quezada, Sanjiv Luther, Thorsten R Mempel, Giovanni Ciriello, Sara I Pai, Olivier Michielin, Jan P Böttcher, Ralph Weissleder, Mikael J Pittet.
      Tumor-resident CCR7+ dendritic cells (DCs) are key determinants of antitumor T cell responses. Here, we examined the localization of CCR7+ DCs within tumors and the impact of this positioning on antitumor immunity. Spatial, single-cell, and intravital analyses of human cancers and mouse models reveal that CCR7+ DCs form perivascular clusters. Fibroblasts surrounding venous blood vessels produced CCL19, guiding CCR7+ DCs into perivascular niches. Regulatory T (Treg) cells frequently contact perivascular CCR7+ DCs, suppressing CD40 expression and CD4+ and CD8+ T cell activation. Treg cell depletion restored CD40 expression by CCR7+ DCs, enhanced immunostimulatory programs, and improved T cell-dependent tumor control. Anti-PD-1 not only increased perivascular CCR7+ DC clustering and IL-12 production but also strengthened Treg-DC interactions through a CCL22-dependent mechanism, limiting therapeutic efficacy. CCR7+ DCs expressed both co-stimulatory and co-inhibitory molecules, which may underlie their capacity for antitumor activation and concurrent vulnerability to suppression. Modulating the mechanisms that form and restrain CCR7+ DC perivascular immune hubs may improve cancer immunotherapy.
    Keywords:  T cells; cancer immunity; cancer immunity cycle; chemokines; dendritic cells; immunotherapy; regulatory
    DOI:  https://doi.org/10.1016/j.immuni.2025.11.020
  41. Cancer Cell. 2025 Dec 24. pii: S1535-6108(25)00535-5. [Epub ahead of print]
    Epitranscriptomic control of cancer hallmarks: Functions, mechanisms, and therapeutics of RNA modifications.
    Xiaolan Deng, Dong Wu, Yingqi Zhao, Ying Qing, Huizhe Wu, Jianjun Chen.
      The epitranscriptome, comprising over 170 distinct RNA modifications, represents a dynamic and multifaceted layer of gene regulation. These chemical marks such as N6-methyladenosine (m6A), 5-methylcytosine (m5C), and pseudouridine (Ψ) modulate RNA processing, localization, stability, and translation, shaping cell identity and stress responses. In cancer, RNA modifications integrate with oncogenic signaling networks to influence cancer cell proliferation, metabolism, immune evasion, stemness, and therapeutic resistance. Recent advances in detection technologies, functional perturbation tools, and spatial profiling have accelerated our understanding of the epitranscriptome's roles and the underlying mechanisms in malignancies. In this review, we provide a mechanistic framework connecting RNA modifications and regulators to the hallmarks of cancer. We highlight emerging insights into the interface between epitranscriptomic regulators and canonical cancer pathways and evaluate their potential as biomarkers and therapeutic targets. Together, these findings underscore RNA modification as a pivotal regulatory axis in cancer biology and a promising frontier for translational intervention.
    Keywords:  ▪▪▪
    DOI:  https://doi.org/10.1016/j.ccell.2025.12.001
  42. bioRxiv. 2025 Dec 08. pii: 2025.12.04.692337. [Epub ahead of print]
    RamanOmics Decodes Spatial Vibrational-Molecular Architecture and Rewiring in Aging and Repair.
    Ke Zhang, Xingjian Chen, Francesco Monticolo, Salvatore Sorrentino, Haochun Huang, Claire Callahan, Yueqing Qiao, Judy Zhou, Sonia Brodowska, Styliani Sapantzi, Jianhuan Qi, Yinghan Wu, Thai Nam Son Dang, Francesca Viggiani, Chia-Kang Ho, Yanxin Xu, Koseki J Kobayashi-Kirschvink, Thang Mung, Hemali Phatnani, Zhixun Dou, Jeon Woong Kang, Peter T C So, Jian Shu.
      Aging and tissue repair involve multilayered and spatially heterogeneous remodeling across transcriptional, biochemical, and cellular dimensions, yet prevailing definitions rely on isolated molecular markers that obscure how biochemical and transcriptional states co-evolve in tissues. Here we present RamanOmics, a multimodal framework that integrates single-nucleus RNA sequencing (snRNA-seq), spatial transcriptomics, and label-free Raman imaging to map the spatial vibrational-biochemical and molecular architecture of aging and senescence directly in intact tissues. Applied to mouse lung and skin, RamanOmics generates spatially resolved biochemical-molecular maps revealing tissue-specific programs: lung senescent cells are enriched for extracellular matrix (ECM) remodeling and TGF-β signaling ( Serpine1, Dab2, Igfbp7 ), whereas skin senescence is dominated by keratinization and barrier homeostasis modules ( Krt10, Lor, Sbsn ). Across tissues, we identify a conserved branched-chain fatty-acid-linked biochemical profile and Raman signature (1131-1135 cm⁻¹) that robustly marks p21 ⁺ senescent cells. To unify these layers, we develop a machine learning derived "multimodal barcode" that quantitatively integrates biochemical and transcriptional features, enabling non-destructive identification of senescence in situ . In a wound-healing model, RamanOmics further reveals coordinated reactivation of barrier-repair programs in senescent cells, marked by upregulation of Krt10 , Lor , Sbsn , Sfn , and Dmkn together with matching increases in lipid-associated Raman signatures, confirming biological generalizability beyond steady-state aging. By directly integrating gene programs to spatial vibrational-biochemical states, RamanOmics provides a general framework and resource for scalable, multimodal profiling of cellular states.
    DOI:  https://doi.org/10.64898/2025.12.04.692337
  43. J Cell Sci. 2025 Dec 23. pii: jcs.264398. [Epub ahead of print]
    Macropinocytosis facilitates amino acid acquisition from extracellular fluid to support cell proliferation in macrophages.
    Biniam M Tebeje, Adam D Hoppe, Natalie W Thiex, Joel A Swanson.
      Although many cancer cells proliferate by metabolizing extracellular proteins internalized by macropinocytosis and degraded in lysosomes, the extent to which macropinocytosis contributes to the growth of other metazoan cells remains undefined. This study analyzed macropinocytosis in proliferating murine macrophages as a mechanism for extracting amino acids from growth media. Macrophages internalized the fluid-phase probe Lucifer yellow by macropinocytosis and recycled much of it from their lysosomes by a first-order process. Inhibitors of pinocytosis inhibited cell growth. Removal of the essential amino acid leucine from growth medium reduced proliferation and allowed analysis of pinocytosis and the higher growth rates achieved by supplementation with either free leucine or bovine serum albumin (BSA) as a source of leucine. Macrophages could proliferate by macropinocytosis and digestion of BSA. In contrast, growth on free leucine exceeded the capacity of macropinocytosis to extract leucine from the medium. Dye molecules released from proteins by hydrolysis in lysosomes were recycled from cells efficiently. We propose that macropinocytosis concentrates large solutes such as proteins into lysosomes but allows amino acids and other products of lysosomal hydrolases to redistribute into macropinosomes and outside of the cell.
    Keywords:  Colony stimulating factor-1; Lysosome; Macrophage; Recycling
    DOI:  https://doi.org/10.1242/jcs.264398
  44. Nat Commun. 2025 Dec 22.
    Latent brain subtypes of chronotype reveal unique behavioral and health profiles across population cohorts.
    Le Zhou, Karin Saltoun, Justin Marotta, Shambhavi Aggarwal, Jakub Kopal, Julie Carrier, Kai-Florian Storch, Robin I M Dunbar, Danilo Bzdok.
      Chronotype is shaped by the complex interplay of endogenous and exogenous factors. This time-enduring trait ties into societal behaviors and is linked to psychiatric and metabolic conditions. Despite its multifaceted nature, prior research has treated chronotype as a monolithic trait across the population, risking overlooking substantial heterogeneity in neural and behavioral fingerprints. To uncover hidden subgroups, we develop a supervised pattern-learning framework integrating three complementary brain-imaging modalities with deep behavioral and health profiling from 27,030 UK Biobank participants. We identify five distinct, biologically valid chronotype subtypes. Each demonstrates unique patterns across brain, behavioral and health profiles. External validation in 10,550 US children from the ABCD Study cohort reveals reversed age distributions and replicates sex-associated brain-behavioral patterns, suggesting that potential divergences between chronotype traits observed throughout adulthood may begin to emerge early in life. These findings highlight underappreciated sources of population variation that echo the rhythm of people's inner clock.
    DOI:  https://doi.org/10.1038/s41467-025-66784-8
  45. Bioessays. 2026 Jan;48(1): e70101
    Using Mathematical Modeling of Tumor Metabolism to Predict the Magnitude, Composition, and Hypoxic Interactions of Microenvironment Acidosis.
    Alzbeta Hulikova, Pawel Swietach.
      In well-perfused tissues, interstitial composition resembles capillary plasma. Solid tumors break this norm because cancer cell proliferation outpaces vascular expansion, leading to a diffusion-limited tumor microenvironment (TME) that is notably depleted of oxygen and enriched in acids. The magnitude of tumor acidosis; its chemical composition in terms of [CO2] and [HCO3 -] (components of the major extracellular buffer); and its relationship with hypoxia are not intuitive to predict but important to know for designing experiments and contextualising results. We address these timely questions using mathematical models of a monolayer, spheroid, and poorly-perfused tissue. Our simulations suggest a physiologically realistic TME pH range of 6.7-7.4, reveal a prominence of hypercapnia, and indicate varying levels of HCO3 - depletion or accumulation arising from fermentation and respiration, respectively. The trajectories of tumor hypoxia and acidosis depend on the balance between aerobic and anaerobic pathways, with important consequences on hypoxic signaling where many responses are pH-sensitive.
    DOI:  https://doi.org/10.1002/bies.70101
  46. Nat Cell Biol. 2025 Dec 22.
    Inheriting chromosome conformation.
    Kyle P Eagen.
      
    DOI:  https://doi.org/10.1038/s41556-025-01851-2
  47. Cell Metab. 2025 Dec 19. pii: S1550-4131(25)00526-1. [Epub ahead of print]
    Enhanced non-enzymatic H2S generation extends lifespan and healthspan in male mice.
    María Ángeles Cáliz-Molina, Raúl López-Fernández-Sobrino, Inmaculada Pino-Pérez, Concepción Panadero-Morón, María Del Carmen Vilches-Pérez, María Camacho-Cabrera, Almudena García-Ruiz, Leopoldo Pérez-Rosendo, Isabel Espadas, Alejandro Sola-García, Mario Soriano-Navarro, Franz Martin, Mónica Venegas-Calerón, Joaquín Jesús Salas, Enrique Martínez-Force, Luis C Romero, Ángeles Aroca, Román González-Prieto, Máximo Bernabeu-Wittel, Vivian Capilla-González, Christopher Hine, Alejandro Martín-Montalvo.
      Hydrogen sulfide is a gasotransmitter with biological functions, including roles in antioxidant defenses, mitochondrial bioenergetics, and cellular signaling via cysteine persulfidation. Several longevity-promoting interventions enhance endogenous hydrogen sulfide generation. However, whether enhanced hydrogen sulfide generation extends healthspan and lifespan in mammals remains unknown. Here, we investigated the in vivo effects of the non-enzymatic hydrogen sulfide generation promoted by natural diallyl sulforated compounds. Diallyl sulforated compounds extended lifespan and improved the main aspects of healthspan, including glucoregulation, locomotor function, and neurocognition in wild-type male mice across their lifespan. At the histological and molecular levels, we observed reductions in hepatic lipid-droplet size, attenuation of transcriptional and proteomic signatures associated with mTOR and immune-related pathways, and increased cysteine persulfidation in proteins. In humans, greater protein persulfidation in individuals with polypathological conditions was associated with increased muscle strength and lower triglyceride levels, supporting its physiological relevance. Our findings uncover the potential of enhanced hydrogen sulfide generation to promote healthy aging.
    Keywords:  diallyl disulfide; diallyl trisulfide; garlic; geroprotector; healthspan; hydrogen sulfide; lifespan; longevity; persulfidation
    DOI:  https://doi.org/10.1016/j.cmet.2025.11.012
  48. Nat Cell Biol. 2025 Dec 22.
    Interphase chromosome conformation is specified by distinct folding programmes inherited through mitotic chromosomes or the cytoplasm.
    Allana Schooley, Sergey V Venev, Vasilisa Aksenova, Jesse W Lehman, Emily Navarrete, Athma A Pai, Mary Dasso, Job Dekker.
      Identity-specific chromosome conformation must be re-established at each cell division. To uncover how interphase folding is inherited, we developed an approach that segregates chromosome-intrinsic mechanisms from those propagated through the cytoplasm during G1 nuclear reassembly. Inducible degradation of proteins essential for the establishment of nucleocytoplasmic transport during mitotic exit enabled analysis of folding programmes with distinct modes of inheritance. Here we show that genome compartmentalization is driven entirely by chromosome-intrinsic factors. In addition to conventional compartmental segregation, the chromosome-intrinsic folding programme leads to prominent genome-scale microcompartmentalization of mitotically bookmarked cis-regulatory elements. The microcompartment conformation forms transiently during telophase and is subsequently modulated by a second folding programme inherited through the cytoplasm in early G1. This programme includes cohesin-mediated loop extrusion and factors involved in transcription and RNA processing. The combined and interdependent action of chromosome-intrinsic and cytoplasmic inherited folding programmes determines the interphase chromatin conformation as cells exit mitosis.
    DOI:  https://doi.org/10.1038/s41556-025-01828-1
  49. Cell. 2025 Dec 24. pii: S0092-8674(25)01369-8. [Epub ahead of print]
    Tumor-produced ammonia is metabolized by regulatory T cells to further impede anti-tumor immunity.
    Jian Gu, Yu Li, Qiuyang Chen, Ziyan Song, Qufei Qian, Yuan Liang, Tianning Huang, Lei Qiao, Xiangyu Li, Miao Yu, Mu Liu, Jinren Zhou, Qing Shao, Xiaozhang Xu, Robert Zeiser, Ling Lu.
      Mechanisms of adaptation of regulatory T cells (Tregs) to harsh tumor metabolic microenvironments for suppression of anti-tumor immunity remain largely unclear. Here, using spatial metabolomics and transcriptomics, we show that human hepatocellular carcinoma harbored metabolically heterogeneous subregions characterized by high glutaminolysis and ammonia contents, where Tregs were frequently present but CD8+ and CD4+ effector T cells die. We found Tregs used the urea cycle to detoxify ammonia by upregulating argininosuccinate lyase (ASL); meanwhile, ammonia was also converted to spermine by the FOXP3 transcription factor regulated spermine synthase (SMS). A direct interaction between spermine and PPARγ was verified by X-ray crystallography, leading to comprehensively modulating the transcription of multiple mitochondrial complex proteins to enhance oxidative phosphorylation and immunosuppression of Tregs. Clinically, anti-PD-1-treated dying tumor cells used transdeamination to release ammonia, which reinforced Treg function, leading to immunotherapeutic resistance. Targeting ammonia production to suppress Tregs presents a potential strategy for anti-tumor immunotherapy.
    Keywords:  Tregs; ammonia; cancer immunotherapy; glutaminolysis; metabolic adaptation; polyamine metabolism; urea cycle
    DOI:  https://doi.org/10.1016/j.cell.2025.11.034
  50. bioRxiv. 2025 Dec 11. pii: 2025.12.08.693074. [Epub ahead of print]
    The circadian clock regulates scavenging of fluid-borne substrates by brain border-associated macrophages.
    Helena J Barr, Sydney K Caldwell, Justin M Reimertz, Constanze Depp, Alec J Walker, Samuel E Marsh, Anushree S Gupte, Maximilian Hingerl, Jasmin Patel, Sang-O Park, Sarah Ferraro, Jonathan Lipton, Beth Stevens.
      Circadian disruptions perturb the brain and immune system and increase the risk of developing Alzheimer's Disease (AD), yet whether this involves dysregulation of brain immunity remains less clear. Here, we perform single-cell RNA sequencing of the brain immune compartment around the day-night cycle and identify brain border-associated macrophages (BAMs) as highly rhythmic cells. During the rest phase, we find that BAMs exhibit coordinated upregulation of endocytic genes and enhanced uptake of extracellular fluid-borne material including amyloid-beta (Aβ). Rhythmicity in BAM scavenging is regulated by the clock gene Bmal1 , mediated by the endocytic receptor CD206, and perturbed with age. In a mouse model of AD, we show that deletion of Bmal1 in BAMs worsens perivascular and leptomeningeal Aβ plaque burden. Our results identify endocytosis as a specialized and rhythmic BAM function and identify perturbed timing of brain border immune functions as a potential mechanism by which circadian disruptions precipitate amyloidosis.
    DOI:  https://doi.org/10.64898/2025.12.08.693074
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