bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2025–12–14
fifty-six papers selected by
Christian Frezza, Universität zu Köln
  1. Dietary restriction reprograms CD8+ T cell fate to enhance anti-tumour immunity and immunotherapy responses.
  2. An Alternative Metabolic Pathway of Glucose Oxidation Induced by Mitochondrial Complex I Inhibition: Serinogenesis and Folate Cycling.
  3. Disruption of Mitochondrial Dynamics and Integrity Drives Divergent Metabolic Flexibility and Resilience in Podocytes.
  4. Three mammalian VDAC isoforms distinctly regulate mitochondrial function and proteome to maintain cell metabolism.
  5. Somatic evolution following cancer treatment in normal tissue.
  6. The sour regulation of metabolism: acidity challenges tumor cells while fueling their metabolic survival.
  7. Ketogenesis is Dispensable for the Metabolic Adaptations to Caloric Restriction.
  8. A step-by-step guide to performing cancer metabolism research using custom-made media.
  9. Emerging dimensions of mitochondrial specialization.
  10. Targeting mitochondrial phosphatidylethanolamine alters mitochondrial metabolism and proliferation in hepatocellular carcinoma.
  11. Rapid mitochondrial repolarization upon reperfusion after cardiac ischemia.
  12. Imaging mitochondrial membrane potential via concentration-dependent fluorescence lifetime changes.
  13. A metabolic cell death program downstream of SARM1 couples NAD+ depletion to BAX activation and APAF1 degradation.
  14. Targeting ferroptosis in cancer.
  15. Metabolic costs and trade-offs of hypermetabolism in human motor neurons with ATP synthase deficiency.
  16. Epigenetic control of metabolic identity across cell types.
  17. HK1 and HK2 Beyond Glycolysis: Mitochondrial Interactions and Dual Roles in Metabolism and Cell Fate.
  18. Dynamic changes in mitochondria support phenotypic flexibility of microglia.
  19. Revisiting tryptophan metabolism in cancer: complexity, context, and spatial heterogeneity.
  20. European cancer research requires renewed urgency.
  21. Immunometabolic Gatekeeping: Reconciling Peto's & the T-cell Infiltration Prognostic Paradox.
  22. Structural transport and inhibition mechanism of the mitochondrial pyruvate carrier.
  23. Stress at the gates: Mitochondrial import dysfunctions, response pathways, and therapeutic potential.
  24. Actin dysregulation induces neuroendocrine plasticity and immune evasion: a vulnerability of small cell lung cancer.
  25. Hepatic metabolic reprogramming in male mice during short-term caloric restriction involves enhanced glucocorticoid rhythms.
  26. The exit of naive pluripotency contains a metabolism-induced checkpoint for telomere homeostasis.
  27. Fueling for the finish line: Control of human telomerase activity by nucleotide metabolism.
  28. AGPAT2 acts at the crossroads of lipid biosynthesis and DRP1-mediated ER morphogenesis.
  29. Tissue-specific mutagenesis from endogenous guanine damage is suppressed by Polκ and DNA repair.
  30. Chromosome shattering in cancer.
  31. Steroid hormone receptors through Cry2 are key players in the circadian clock response to serum.
  32. Breaking the pH Code: Acidification Triggers SASP and Inflammation in Cellular Senescence.
  33. Identification of an uncharacterized gene as a mitochondrial methionine tRNA-synthetase in Caenorhabditis elegans.
  34. Tracing NAD⁺ metabolism uncovers adaptive coordination between host and microbiome during colitis.
  35. Mutations in mitochondrial ferredoxin FDX2 suppress frataxin deficiency.
  36. Endoplasmic reticulum disruption stimulates nuclear membrane mechanotransduction.
  37. ERBB2 signaling drives immune cell evasion and resistance against immunotherapy in small cell lung cancer.
  38. INSM1 governs a neuronal progenitor state that drives glioblastoma in a human stem cell model.
  39. The inferred functional connectome underlying circadian synchronization in the mouse suprachiasmatic nucleus.
  40. The RNA-binding protein PRRC2B preserves 5' TOP mRNA during starvation to maintain ribosome biogenesis during nutrient recovery.
  41. Lysosomal activation leaves a lasting memory.
  42. Bioactive Artificial Cells as Autonomous Metabolic Actuators Enable Bidirectional Communication with Tumor Cells.
  43. The 2025 generation.
  44. The ribosome-associated complex regulates cytosolic translation upon mitoprotein-induced stress.
  45. A surprising link: TET2 clonal hematopoiesis boosts immune checkpoint therapy.
  46. Why we age.
  47. Mitochondria are absent from microglial processes performing surveillance, chemotaxis, and phagocytic engulfment.
  48. Adaptation of redox metabolism in drug-tolerant persister cells is a vulnerability to prevent relapse in pancreatic cancer.
  49. Conserved lipid metabolic reprogramming confers hypoxic and aging resilience.
  50. Neuronal fatty acid oxidation fuels memory after intensive learning in Drosophila.
  51. Bile acids regulate lipid metabolism through selective actions on fatty acid absorption.
  52. N6-Methyladenosine: an RNA modification as a central regulator of cancer.
  53. Spatial and morphological organization of mitochondria in neurons across a connectome.
  54. A lifespan clock tells the biology of time.
  55. Puromycin-sensitive aminopeptidase acts as an inhibitory auxiliary subunit of volume-regulated anion channels and regulates cGAMP transport.
  56. Space travel affects haematopoietic stem cells.
  1. Nat Metab. 2025 Dec 09.
    Dietary restriction reprograms CD8+ T cell fate to enhance anti-tumour immunity and immunotherapy responses.
    Brandon M Oswald, Lisa M DeCamp, Joseph Longo, Michael S Dahabieh, Nicholas Bunda, Benjamin K Johnson, McLane J Watson, Shixin Ma, Samuel E J Preston, Ryan D Sheldon, Michael P Vincent, Abigail E Ellis, Molly T Soper-Hopper, Christine Isaguirre, Dahlya Kamarudin, Hui Shen, Kelsey S Williams, Peter A Crawford, Susan Kaech, H Josh Jang, Evan C Lien, Connie M Krawczyk, Russell G Jones.
      Reducing calorie intake through dietary restriction (DR) slows tumour growth in mammals, yet the underlying mechanisms are poorly defined. Here, we show that DR enhances anti-tumour immunity by optimizing CD8+ T cell function within the tumour microenvironment (TME). Using syngeneic xenograft tumour models, we found that DR induces a profound reprogramming of CD8+ T cell fate in the TME, favouring the expansion of effector T cell subsets with enhanced metabolic capacity and cytotoxic potential, while limiting the accumulation of terminally exhausted T cells. This metabolic reprogramming is driven by enhanced ketone body oxidation, particularly β-hydroxybutyrate (βOHB), which is elevated in both the circulation and tumour tissues of DR-fed mice. βOHB fuels T cell oxidative metabolism under DR, increasing mitochondrial membrane potential and tricarboxylic acid cycle-dependent pathways critical for T cell effector function, including acetyl-CoA production. By contrast, T cells deficient for ketone body oxidation exhibit reduced mitochondrial function, increased exhaustion and fail to control tumour growth under DR conditions. Importantly, DR synergizes with anti-PD1 immunotherapy, further augmenting anti-tumour T cell responses and limiting tumour progression. Our findings reveal that T cell metabolic reprogramming is central to the anti-tumour effects of DR, highlighting nutritional control of CD8+ T cell fate as a key driver of anti-tumour immunity.
    DOI:  https://doi.org/10.1038/s42255-025-01415-6
  2. Int J Mol Sci. 2025 Nov 24. pii: 11349. [Epub ahead of print]26(23):
    An Alternative Metabolic Pathway of Glucose Oxidation Induced by Mitochondrial Complex I Inhibition: Serinogenesis and Folate Cycling.
    Roman Abrosimov, Ankush Borlepawar, Parvana Hajieva, Bernd Moosmann.
      Inhibition of respiratory chain complex I (NADH dehydrogenase) is a widely encountered biochemical consequence of drug intoxication and a primary consequence of mtDNA mutations and other mitochondrial defects. In an organ-selective form, it is also deployed as antidiabetic pharmacological treatment. Complex I inhibition evokes a pronounced metabolic reprogramming of uncertain purposefulness, as in several cases, anabolism appears to be fostered in a state of bioenergetic shortage. A hallmark of complex I inhibition is the enhanced biosynthesis of serine, usually accompanied by an induction of folate-converting enzymes. Here, we have revisited the differential transcriptional induction of these metabolic pathways in three published models of selective complex I inhibition: MPP-treated neuronal cells, methionine-restricted rats, and patient fibroblasts harboring an NDUFS2 mutation. We find that in a coupled fashion, serinogenesis and circular folate cycling provide an unrecognized alternative pathway of complete glucose oxidation that is mostly dependent on NADP instead of the canonic NAD cofactor (NADP:NAD ≈ 2:1) and thus evades the shortage of oxidized NAD produced by complex I inhibition. In contrast, serine utilization for anabolic purposes and C1-folate provision for S-adenosyl-methionine production and transsulfuration cannot explain the observed transcriptional patterns, while C1-folate provision for purine biosynthesis did occur in some models, albeit not universally. We conclude that catabolic glucose oxidation to CO2, linked with NADPH production for indirect downstream respiration through fatty acid cycling, is the general purpose of the remarkably strong induction of serinogenesis after complex I inhibition.
    Keywords:  NADPH-FADH2 axis; Parkinson’s disease; fatty acid cycling; futile cycle; glycolytic inhibition; metabolic reprogramming; metformin; mitochondrial disease; oxidative stress
    DOI:  https://doi.org/10.3390/ijms262311349
  3. FASEB J. 2025 Dec 31. 39(24): e71340
    Disruption of Mitochondrial Dynamics and Integrity Drives Divergent Metabolic Flexibility and Resilience in Podocytes.
    Cem Özel, Katrin M Reitmeier, Emilia Kieckhöfer, Khawla Abualia, Duc Nguyen-Minh, Mahsa Matin, Henning Hagmann, Richard J M Coward, Sebastian Brähler, Philipp Antczak, Bernhard Schermer, Thomas Benzing, Patrick Giavalisco, Paul T Brinkkoetter.
      Mitochondrial dysfunction is central to the pathogenesis of podocytopathies, yet the determinants of metabolic resilience versus failure remain elusive. We investigated how distinct disruptions of mitochondrial architecture, specifically hyperfusion via OMA1 deletion versus compromised inner mitochondrial membrane (IMM) integrity via PHB2 knockdown, influence the metabolic fate and insulin responsiveness of podocytes. To this end, we analyzed conditionally immortalized mouse podocytes with genetic OMA1 deletion or inducible PHB2 knockdown and employed an integrated approach combining bioenergetic studies, quantitative proteomics, phosphoproteomics, metabolomics, and stable isotope tracing studies with 13C6-glucose and 13C5-glutamine. We characterized metabolic remodeling at baseline and after insulin treatment and uncovered profoundly divergent metabolic states. OMA1 deficiency conferred robust metabolic resilience, characterized by a compensatory glycolytic shift and remodeling of TCA cycle flux through glutamine-driven anaplerosis while maintaining oxidative phosphorylation. OMA1-deficient podocytes sustained bioenergetic homeostasis upon insulin challenge by flexibly rerouting carbon flux, including the GABA shunt. In contrast, PHB2 deficiency led to metabolic failure, impaired respiration, and anaplerotic insufficiency. While maintaining basal ATP levels at baseline, PHB2-deficient podocytes exhibited energetic collapse upon insulin treatment, revealing profound metabolic inflexibility. Taken together, the structural integrity of the inner mitochondrial membrane, rather than mitochondrial morphology per se, is a driving determinant of metabolic competence and resilience in podocytes.
    Keywords:  OMA1; PHB2; anaplerosis; glycolysis; insulin signaling; metabolism; mitochondria; podocytes
    DOI:  https://doi.org/10.1096/fj.202502934R
  4. J Biol Chem. 2025 Dec 05. pii: S0021-9258(25)02861-3. [Epub ahead of print] 111009
    Three mammalian VDAC isoforms distinctly regulate mitochondrial function and proteome to maintain cell metabolism.
    Megha Rajendran, William M Rosencrans, Nina A Bautista, Wendy Fitzgerald, Diana Huynh, Bethel G Beyene, Baiyi Quan, Jennifer D Petersen, Julie Hwang, Tsui-Fen Chou, Sergey M Bezrukov, Tatiana K Rostovtseva.
      The Voltage Dependent Anion Channel (VDAC) is the most ubiquitous protein in the mitochondrial outer membrane. This channel facilitates the flux of water-soluble metabolites and ions like calcium across the mitochondrial outer membrane. Beyond this canonical role, VDAC has been implicated, through interactions with protein partners, in several cellular processes such as apoptosis, calcium signaling, and lipid metabolism. There are three VDAC isoforms in mammalian cells, VDAC1, VDAC2, and VDAC3, with varying tissue-specific expression profiles. From a biophysical standpoint, all three isoforms conduct metabolites and ions with similar efficiency. However, isoform knockouts (KOs) in mice lead to distinct phenotypes, which may be due to differences in VDAC isoform interactions with partner proteins. To understand the functional role of each VDAC isoform within a single cell type, we created functional KOs of each isoform in HeLa cells and performed a comparative study of their metabolic activity and proteomics. We found that each isoform KO alters the proteome differently, with VDAC3 KO dramatically downregulating key members of the electron transport chain (ETC) while shifting the mitochondria into a glutamine-dependent state. Importantly, this unexpected dependence of mitochondrial function on the VDAC3 isoform is not compensated for by the more ubiquitously expressed VDAC1 and VDAC2 isoforms. In contrast, VDAC2 KO did not affect respiration but upregulated ETC components and decreased key enzymes in the glutamine metabolic pathway. VDAC1 KO specifically reduced glycolytic activity linked to decreased hexokinase localization to mitochondria. These results reveal non-redundant roles of VDAC isoforms in cancer cell metabolic adaptability.
    Keywords:  CRISPR/Cas9 gene knockout; metabolic regulation; mitochondrial respiratory chain complex; proteomics; voltage-dependent anion channel
    DOI:  https://doi.org/10.1016/j.jbc.2025.111009
  5. Nature. 2025 Dec 10.
    Somatic evolution following cancer treatment in normal tissue.
    PEACE Consortium
      The extent to which exogenous sources, including cancer treatment, contribute to somatic evolution in normal tissue remains unclear. Here we used high-depth duplex sequencing1 (more than 30,000× coverage) to analyse 168 cancer-free samples representing 16 organs from 22 patients with metastatic cancer enroled in the PEACE research autopsy study. In every sample, we identified somatic mutations (range 305-2,854 mutations) at low variant allele frequencies (median 0.0000323). We extracted 16 distinct single-base substitution mutational signatures, reflecting processes that have moulded the genomes of normal cells. We identified alcohol-induced mutation acquisition in liver, smoking-induced mutagenesis in lung and cardiac tissue, and multiple treatment-induced processes, which correlated with therapy type and duration. Exogenous sources, including treatment, underpinned, on average, more than 40% of mutations in liver but less than 10% of mutations in brain samples. Finally, we observed tissue-specific selection, with positive selection in tissues such as lung (PTEN and PIK3CA), liver (NF2L2) and spleen (BRAF and NOTCH2), and limited selection in others, such as brain and cardiac tissue. More than 25% of driver mutations in normal tissue exposed to systemic anti-cancer therapy, including in TP53, could be attributed to treatment. Immunotherapy, although not associated with increased mutagenesis, was linked to driver mutations in PPM1D and TP53, illustrating how non-mutagenic treatment can sculpt somatic evolution. Our study reveals the rich tapestry of mutational processes and driver mutations in normal tissue, and the profound effect of lifetime exposures, including cancer treatment, on somatic evolution.
    DOI:  https://doi.org/10.1038/s41586-025-09792-4
  6. Cancer Res. 2025 Dec 11.
    The sour regulation of metabolism: acidity challenges tumor cells while fueling their metabolic survival.
    Bruna Martins Garcia, Patricia Altea-Manzano.
      The tumor microenvironment imposes diverse metabolic challenges to cancer cells. Overcoming these challenges is essential for survival, proliferation, and dissemination. However, how cancer cells cope with the harsh environment and how the different coexisting stresses affect the tumor in vivo is unknown. Recently, Groessl, Kalis and colleagues published their findings in Science showing that acidosis outweighs all other stresses and plays a major role in the adaptation to them. Mechanistically, acidosis inhibits the ERK-DRP1 pathway, resulting in mitochondria elongation, which triggers a metabolic shift from glycolysis to oxidative phosphorylation. These findings highlight the plasticity of cancer cell mitochondria and refute the previous belief that cancer mitochondria are inherently dysfunctional. Indeed, inhibition of mitochondrial fusion or oxidative phosphorylation in acidic tumors is sufficient to promote cell death. Thus, enhancing respiration under acidosis comes to light as an essential metabolic adaptation to cancer survival and proliferation and targeting how cancer cells adapt to acidosis emerges as a new avenue for therapy.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-5633
  7. Aging Cell. 2025 Dec 10. e70318
    Ketogenesis is Dispensable for the Metabolic Adaptations to Caloric Restriction.
    Chung-Yang Yeh, Alexis L Borgelt, Brynn J Vogt, Alyssa A Clark, Ted T Wong, Isaac Grunow, Michelle M Sonsalla, Reji Babygirija, Yang Liu, Michaela E Trautman, Mariah F Calubag, Bailey A Knopf, Fan Xiao, Dudley W Lamming.
      Caloric restriction (CR) extends the health and lifespan of diverse species. When fed once daily, CR-treated mice rapidly consume their food and endure a prolonged fast between meals. As fasting is associated with a rise in circulating ketone bodies, we investigated the role of ketogenesis in CR using mice with whole-body ablation of Hmgcs2, the rate-limiting enzyme producing the main ketone body β-hydroxybutyrate (βHB). Here, we report that Hmgcs2 is largely dispensable for many metabolic benefits of CR, including CR-driven changes in adiposity, glycemic control, liver autophagy, and energy balance. Although we observed sex-specific effects of Hmgcs2 on insulin sensitivity, fuel selection, and adipocyte gene expression, the overall physiological response to CR remained robust in mice lacking Hmgcs2. To gain insight into why the deletion of Hmgcs2 does not disrupt CR, we measured fasting βHB levels as mice initiated a CR diet. Surprisingly, as mice adapt to CR, they no longer engage in high levels of ketogenesis during the daily fast. Our work suggests that the metabolic benefits of long-term CR are not mediated by ketogenesis.
    Keywords:  BHB; caloric restriction; dietary restriction; ketogenesis; ketones; metabolic health; metabolism
    DOI:  https://doi.org/10.1111/acel.70318
  8. Life Sci Alliance. 2026 Feb;pii: e202503529. [Epub ahead of print]9(2):
    A step-by-step guide to performing cancer metabolism research using custom-made media.
    Sophie Seifert, Francisco Yanqui-Rivera, Tim Kühn, Lena Elise Høyland, Toman Borteçen, Bella Agranovich, Lara Elea Eckhardt, Martin Herdt, Alessa Henneberg, Verena Panitz, Faisal Hayat, Marie Migaud, Gernot Poschet, Ifat Abramovich, Eyal Gottlieb, Jeroen Krijgsveld, Mathias Ziegler, Mirja Tamara Prentzell, Christiane A Opitz.
      The preparation of custom-made media offers precise control over nutrient composition, enabling detailed studies of cellular metabolism. We demonstrate how self-made media formulations enable diverse assay designs and readouts to assess cancer metabolism. Self-made media can be used in Seahorse assays to measure mitochondrial respiration under defined conditions. In nutrient deprivation experiments, amino acid or vitamin removal can uncover how cancer cells adapt to metabolic stress. Using labeled amino acids enables analysis of nascent protein synthesis and translational regulation, while stable-isotope tracing reveals metabolic fluxes through key pathways. This guide presents a suite of metabolic assays using custom-made media, covering experimental design, the selection of controls, sample preparation, data acquisition, and interpretation. The accompanying online media calculator "Media Minds" streamlines the creation of custom media formulations, ensuring accuracy and reproducibility.
    DOI:  https://doi.org/10.26508/lsa.202503529
  9. Biol Chem. 2025 Dec 10.
    Emerging dimensions of mitochondrial specialization.
    Tslil Ast.
      The diverse, and sometimes opposing, roles of mitochondria require sophisticated organizational and regulatory strategies. This review examines emerging evidence that mitochondria can solve this challenge through functional specialization - adopting distinct bioenergetic and metabolic programs based on location, contacts, and cellular conditions. We discuss both established principles and recent technological breakthroughs that reveal this hidden complexity. Ongoing advances promise to move the field from describing mitochondrial diversity to uncovering its regulatory mechanisms and therapeutic potential.
    Keywords:  heterogeneity; metabolic specialization; mitochondria
    DOI:  https://doi.org/10.1515/hsz-2025-0210
  10. Oncogenesis. 2025 Dec 08.
    Targeting mitochondrial phosphatidylethanolamine alters mitochondrial metabolism and proliferation in hepatocellular carcinoma.
    Melina C Mancini, Cameron P McCall, Robert C Noland, Wagner S Dantas, Timothy D Heden.
      Mitochondrial metabolism is crucial for hepatocellular carcinoma (HCC) to thrive. Although phospholipids modulate mitochondrial metabolism, their impact on metabolism in HCC remains unknown. Here we report that the mitochondrial phospholipidome is unaltered in HCC mitochondria, suggesting HCC maintain their mitochondrial phospholipidome to enable efficient metabolism and promote thriftiness. Consistent with this, silencing phosphatidylserine decarboxylase (PISD), the inner mitochondrial membrane protein that generates mitochondrial phosphatidylethanolamine (PE), in HEPA1-6 cells impairs mitochondrial metabolism of fatty acid and glucose-derived substrates and reduces electron transport chain I and IV abundance. Moreover, PISD deficiency increased mitochondrial superoxide generation and altered mitochondria dynamics by augmenting mitochondrial fission, mitophagy, and mitochondrial extracellular efflux. Despite compensatory increases in anaerobic glycolysis and peroxisome fat oxidation, mitochondrial PE deficiency reduced DNA synthesis and cell proliferation, effects associated with reduced mTOR signaling and peptide levels. We conclude that targeting mitochondrial PE synthesis may be a viable therapy to slow HCC progression.
    DOI:  https://doi.org/10.1038/s41389-025-00593-y
  11. Nat Cardiovasc Res. 2025 Dec 11.
    Rapid mitochondrial repolarization upon reperfusion after cardiac ischemia.
    Abigail V Giles, Raul Covian, Hiran A Prag, Nils Burger, Bertrand Lucotte, Chak Shun Yu, Junhui Sun, Elizabeth Murphy, Thomas Krieg, Michael P Murphy, Robert S Balaban.
      The mitochondrial membrane potential (ΔΨm) drives oxidative phosphorylation and alterations contribute to cardiac pathologies, but real-time assessment of ΔΨm has not been possible. Here we describe noninvasive measurements using mitochondrial heme bL and bH absorbances, which rapidly respond to ΔΨm. Multi-wavelength absorbance spectroscopy enabled their continuous monitoring in isolated mitochondria and the perfused heart. Calibration of heme b absorbance in isolated mitochondria revealed that reduced heme bL relative to total reduced heme b (fbL = bL/(bL + bH)) exhibits a sigmoidal relationship with ΔΨm. Extrapolating this relationship to the heart enabled estimation of ΔΨm as 166 ± 18 mV (n = 25, mean ± s.d.). We used this approach to assess how ΔΨm changes during ischemia-reperfusion injury, an unknown limiting the understanding of ischemia-reperfusion injury. In perfused hearts, ΔΨm declined during ischemia and rapidly reestablished upon reperfusion, supported by oxidation of the succinate accumulated during ischemia. These findings expand our understanding of ischemia-reperfusion injury.
    DOI:  https://doi.org/10.1038/s44161-025-00752-9
  12. Nat Commun. 2025 Dec 12. 16(1): 11088
    Imaging mitochondrial membrane potential via concentration-dependent fluorescence lifetime changes.
    Dilizhatai Saimi, Luc Reymond, Tursunjan Aziz, Xuan Shen, Ziying Luo, Shuaibo Pi, Yitong Liu, Song Fu, Shuangjin Ding, Anming Meng, Liangyi Chen, Hui Jiang, Zhixing Chen.
      Mitochondria are central to cellular metabolism. Various fluorescence tools have been developed for imaging the mitochondrial environment. Yet, new reporters and imaging methods for directly reading the mitochondrial status are needed for high spatial-temporal resolution imaging. Here, we introduce PK Mito Deep Red (PKMDR), a low-phototoxicity mitochondrial probe for time-lapse imaging, whose fluorescence lifetime serves as a sensitive indicator of mitochondrial membrane potential (Δψm). The positively charged PKMDR accumulates within mitochondria under a higher Δψm, leading to concentration-induced quenching and a measurable decrease in fluorescence lifetime. Since mitochondrial respiration primarily regulates Δψm, PKMDR's fluorescence lifetime effectively reports on the status of oxidative phosphorylation. Using PKMDR with fluorescence lifetime imaging microscopy (FLIM), we visualize heterogeneous Δψm across individual cells, organoids, and tissues over time. This method reliably reveals the heterogeneity between metabolically active peripheral mitochondria and relatively inactive perinuclear mitochondria in various cell types. Overall, PKMDR-FLIM is a robust tool for directly visualizing Δψm with high spatiotemporal resolution.
    DOI:  https://doi.org/10.1038/s41467-025-66042-x
  13. Proc Natl Acad Sci U S A. 2025 Dec 16. 122(50): e2522444122
    A metabolic cell death program downstream of SARM1 couples NAD+ depletion to BAX activation and APAF1 degradation.
    Weilong Pan, Dejia Guo, Daiyuan Liu, Xiaodong Wang.
      SARM1 is a neuronal Nicotinamide adenine dinucleotide (NAD+) hydrolase that drives axonal degeneration and neuronal death by depleting NAD+, yet how NAD+ loss triggers axon loss and cell death has remained unclear. Here, we define a nonapoptotic death program downstream of endogenous SARM1 activation and NAD+ loss using a genetically tractable nonneuronal eHAP cell model. Upon NAD+ depletion, BAX is activated but caspase activation is suppressed due to APAF1 degradation via the E3 ligase HERC4, effectively uncoupling mitochondrial outer membrane permeabilization from apoptosome formation. Mechanistically, NAD+ depletion inhibits mTOR/AKT signaling, destabilizing MCL1 and relieving BAX from repression. We further identified Neurofibromatosis type II, NF2, as a regulator that promotes SARM1 transcription through the Hippo-YAP/TAZ pathway. The SARM1-dependent BAX activation and the role of NF2 in axon degradation were validated in neuronal models of axon degeneration. Together, these findings reveal how SARM1-driven metabolic collapse rewires cell death execution, positioning BAX, MCL1, APAF1, NF2, and HERC4 as core effectors in a nonapoptotic degenerative pathway linking metabolic stress to neurodegeneration.
    Keywords:  APAF1; Apoptosis; BAX; NAD+; SARM1
    DOI:  https://doi.org/10.1073/pnas.2522444122
  14. Nat Genet. 2025 Dec;57(12): 2942
    Targeting ferroptosis in cancer.
    Safia Danovi.
      
    DOI:  https://doi.org/10.1038/s41588-025-02456-z
  15. Commun Biol. 2025 Dec 11. 8(1): 1759
    Metabolic costs and trade-offs of hypermetabolism in human motor neurons with ATP synthase deficiency.
    Rubén Torregrosa-Muñumer, Jeremi Turkia, Rumeysa Ermiş, Jouni Kvist, Sandra Harjuhaahto, Jana Pennonen, Ville Hietakangas, Emil Ylikallio, Henna Tyynismaa.
      Hypermetabolism, a futile cycle of energy production and consumption, has been proposed as an adaptative response to deficiencies in mitochondrial oxidative phosphorylation. However, the cellular costs of hypermetabolism remain largely unknown. Here we studied the consequences of hypermetabolism in human motor neurons harboring a heteroplasmic mutation in MT-ATP6, which impairs ATP synthase assembly. Respirometry, metabolomics, and proteomics analyses of the motor neurons showed that elevated ATP production rates were accompanied with increased demand for acetyl-Coenzyme A (acetyl-CoA) and depleted pantothenate (vitamin B5), and the proteome was remodeled to support the metabolic adaptation. Mitochondrial membrane potential and coupling efficiency remained stable, and the therapeutic agent avanafil did not affect metabolite levels. However, a redistribution of acetyl-CoA usage resulted in metabolic trade-offs, including reduced histone acetylation and altered maintenance of the neurotransmitter acetylcholine, revealing potential vulnerabilities in motor neurons. These findings advance the understanding of cellular metabolic consequences imposed by hypermetabolic conditions.
    DOI:  https://doi.org/10.1038/s42003-025-09149-7
  16. BMC Genomics. 2025 Dec 10.
    Epigenetic control of metabolic identity across cell types.
    Maria Pires Pacheco, Déborah Gerard, Riley J Mangan, Alec R Chapman, Dennis Hecker, Manolis Kellis, Marcel H Schulz, Lasse Sinkkonen, Thomas Sauter.
       BACKGROUND: Constraint-based network modeling is a powerful genomic-scale approach for analyzing cellular metabolism, capturing metabolic variations across tissues and cell types, and defining the metabolic identity essential for identifying disease-associated transcriptional states.
    RESULTS: Using RNA-seq and epigenomic data from the EpiATLAS resource of the International Human Epigenome Consortium (IHEC), we reconstructed metabolic networks for 1,555 samples spanning 58 tissues and cell types. Analysis of these networks revealed the distribution of metabolic functionalities across human cell types and provides a compendium of human metabolic activity. This integrative approach allowed us to define, across tissues and cell types, (i) reactions that fulfil the basic metabolic processes (core metabolism), and (ii) cell type-specific functions (unique metabolism), that shape the metabolic identity of a cell or a tissue. Integration with EpiATLAS-derived cell-type-specific gene-level chromatin states and enhancer-gene interactions identified enhancers, transcription factors, and key nodes contributing to the control of core and unique metabolism. Transport and first reactions of pathways were enriched for high expression, active chromatin state, and Polycomb-mediated repression in cell types where pathways are inactive, suggesting that key nodes are targets of repression.
    CONCLUSION: Integrative analysis forms the basis for identifying putative regulation points that control metabolic identity in human cells.
    Keywords:  Chromatin state; Enhancer-gene interaction; Epigenomics; Metabolic identity; Metabolic networks
    DOI:  https://doi.org/10.1186/s12864-025-12155-y
  17. Adv Biol (Weinh). 2025 Dec 12. e00472
    HK1 and HK2 Beyond Glycolysis: Mitochondrial Interactions and Dual Roles in Metabolism and Cell Fate.
    Noemi Anna Pesce, Giulia Seminara, Giuseppe Giarrusso, Marianna Flora Tomasello.
      HK1 and HK2 are increasingly recognized not only as glycolytic enzymes but also as key modulators of mitochondrial function and cell fate through dynamic interactions with VDAC. This review explores how HK-VDAC complexes support metabolic flexibility, regulate apoptosis, and coordinate glycolytic and mitochondrial activity across diverse physiological and pathological conditions. We incorporate recent reinterpretations of the Warburg effect, emphasizing how spatial and functional reorganization of HK supports proliferative metabolism beyond classical models of mitochondrial dysfunction. Importantly, the HK-VDAC interaction is dynamically regulated by post-translational modifications and signaling pathways that control its stability and mitochondrial anchoring. Disruption of these regulatory mechanisms can impair the balance between glycolytic and mitochondrial metabolism, contributing to disease progression. Emerging evidence links altered HK-VDAC interactions to the metabolic and apoptotic imbalances observed in cancer, neurodegeneration, and aging. By integrating insights from structural biology, bioenergetics, and disease models, we highlight mitochondrial HK anchoring as a central hub for metabolic adaptation and stress response.
    Keywords:  HK‐VDAC; Warburg effect; aging; apoptosis; cancer; metabolism; mitochondria
    DOI:  https://doi.org/10.1002/adbi.202500472
  18. Nat Commun. 2025 Dec 12. 16(1): 11103
    Dynamic changes in mitochondria support phenotypic flexibility of microglia.
    Katherine Espinoza, Ari W Schaler, Daniel T Gray, Arielle R Sass, Adrian Escobar, Kamilia Moore, Megan E Yu, Casandra G Chamorro, Lindsay M De Biase.
      Microglial capacity to adapt to tissue needs is a hallmark feature of these cells. New studies show that mitochondria critically regulate the phenotypic adaptability of macrophages. To determine whether these organelles play similar roles in shaping microglial phenotypes, we generated transgenic mouse crosses to accurately visualize and manipulate microglial mitochondria. We find that brain-region differences in microglial attributes and responses to aging are accompanied by regional differences in mitochondrial mass and aging-associated mitochondrial remodeling. Microglial mitochondria are also altered within hours of LPS injections and microglial expression of inflammation-, trophic-, and phagocytosis-relevant genes is strongly correlated with expression of mitochondria-relevant genes. Finally, direct genetic manipulation of microglial mitochondria alters microglial morphology and leads to brain-region specific effects on microglial gene expression. Overall, this study advances our understanding of microglial mitochondria and supports the idea that mitochondria influence basal microglial phenotypes and phenotypic remodeling that takes place over hours to months.
    DOI:  https://doi.org/10.1038/s41467-025-66709-5
  19. Curr Opin Immunol. 2025 Dec 09. pii: S0952-7915(25)00182-7. [Epub ahead of print]98 102706
    Revisiting tryptophan metabolism in cancer: complexity, context, and spatial heterogeneity.
    Teng Teng Xu, Camille Guyot, Peter J Murray.
      Tryptophan (TRP) metabolism has long been associated with cancer immunity, primarily through the kynurenine pathway mediated by indoleamine-2,3-dioxygenase 1 (IDO1) and tryptophan-2,3-dioxygenase (TDO2). Both enzymes can deplete TRP within cells and in local microenvironments, triggering dysfunction of T cells with anti-tumor functions. This view fostered the development of IDO1/TDO2 inhibitors, which ultimately failed in clinical trials. However, we now know that TRP metabolism in tumors is far more complex than anticipated. Recent work highlights the dual, context-dependent roles of TRP-depleting enzymes. Importantly, advances in spatial profiling have uncovered that TRP-metabolizing enzymes are not uniformly expressed but instead form distinct metabolic niches within tumors. These niches shape local TRP availability, metabolite gradients, downstream metabolic signaling, and immune responses in ways that cannot be captured by bulk or single-cell approaches alone. This review synthesizes emerging insights into the diverse and spatially defined functions of TRP metabolism in cancer and discusses how integrating spatial omics may guide next-generation therapeutic strategies beyond IDO1 inhibition.
    DOI:  https://doi.org/10.1016/j.coi.2025.102706
  20. Nat Cancer. 2025 Dec 10.
    European cancer research requires renewed urgency.
    René Bernards, Anton Berns, Johanna A Joyce, Michael Baumann.
      
    DOI:  https://doi.org/10.1038/s43018-025-01062-6
  21. ArXiv. 2025 Nov 25. pii: arXiv:2511.20883v1. [Epub ahead of print]
    Immunometabolic Gatekeeping: Reconciling Peto's & the T-cell Infiltration Prognostic Paradox.
    Naomi Iris van den Berg, Matouš Elphick, Kevin Mulder, Omar Bouricha, Omid Sadeghi-Alavijeh, Xiao Fu, Samra Turajlic.
      Classical models of cancer focus on tumour-intrinsic genetic aberrations and immune dynamics and often overlook how the metabolic environment of healthy tissues shapes tumour development and immune efficacy. Here, we propose that tissue-intrinsic metabolic intensity and waste-handling capacity act as an upstream gatekeeper of anti-tumour immunity, determining whether immune infiltration translates into effective immune function and safeguards the tissue from tumourigenesis. Across human cancers, tumours arising in high-metabolism tissues - like kidney, brain, and eye - tend to show high T cell infiltration but poor prognosis, suggesting pre-existing metabolic environments prior to malignant transformation may undermine immune function. This pattern is mirrored across species: large mammals with lower mass-specific metabolic rates (e.g., elephants, whales) accumulate fewer metabolic byproducts and show lower cancer incidence (Peto's paradox), while long-lived small mammals like bats and naked mole-rats resist tumourigenesis via suppressed glycolysis or altered hypoxia responses leading to lower metabolic rates and/or byproduct accumulation. Through integrative synthesis spanning human single-cell expression data and cross-species comparisons, we outline a framework of 'immunometabolic gatekeeping', where tissues with high metabolic rate and poor waste clearance foster immune-exhausting niches even before transformation. This unifying framework reconciles multiple paradoxes in cancer biology: Peto's paradox, T cell infiltration non-prognosticity, tissue tropisms, and sex-based inequalities, and suggests new principles for identifying high-risk patients and metabolic-immune combination strategies for prevention and treatment. By shifting focus from tumour-intrinsic mutations to host-tissue metabolism, this work offers a novel, integrative lens on cancer vulnerability and immune failure.
  22. Trends Biochem Sci. 2025 Dec 05. pii: S0968-0004(25)00266-X. [Epub ahead of print]
    Structural transport and inhibition mechanism of the mitochondrial pyruvate carrier.
    Denis Lacabanne, Jonathan J Ruprecht, Maximilian Sichrovsky, Lucy R Forrest, Vanessa Leone, Sotiria Tavoulari, Edmund R S Kunji.
      The mitochondrial pyruvate carrier (MPC), of the SLC54 family of solute carriers, has a critical role in eukaryotic energy metabolism by transporting pyruvate, the end-product of glycolysis, into the mitochondrial matrix. Recently, structures of the human MPC1/MPC2 and MPC1L/MPC2 heterodimers in the outward-open, occluded, and inward-open states have been determined by cryo-electron microscopy (cryo-EM) and by AlphaFold modeling. In this review we discuss the membrane orientation, substrate binding site properties, and structural features of the alternating access mechanism of the carrier, as well as the binding poses of three chemically distinct inhibitor classes, which exploit the same binding site in the outward-open state. These structural studies will support drug development efforts for the treatment of diabetes mellitus, neurodegeneration, metabolic dysfunction-associated steatotic liver disease (MASLD), and some types of cancers.
    Keywords:  alternating access transport mechanism; membrane protein structure; mitochondrion; solute carrier family SLC54; structure-based drug design; sugar and energy metabolism
    DOI:  https://doi.org/10.1016/j.tibs.2025.11.002
  23. Mitochondrion. 2025 Dec 04. pii: S1567-7249(25)00104-7. [Epub ahead of print]87 102107
    Stress at the gates: Mitochondrial import dysfunctions, response pathways, and therapeutic potential.
    Hélène Calais, Giulia Bertolin.
      Mitochondrial protein import is necessary to ensure the proper functioning of the organelle of the cell as a whole. More than 1000 proteins are synthesized on cytosolic ribosomes and then imported into mitochondria through translocases such as TOMM and TIMM complexes. Upon entry, they can reach their final mitochondrial compartment, namely the outer mitochondrial membrane (OMM), the intermembrane space (IMS), the inner mitochondrial membrane (IMM), and the matrix. In this review, we will first explore the main mitochondrial protein import mechanisms. Then, we will focus on how import deficiencies may trigger stress paradigms. Stress response pathways are activated to restore correct cellular homeostasis. We will explore four interconnected pathways at the cellular or mitochondrial scale, which can compensate for import alterations. These are the DELE1-HRI axis combined with the ISR, the UPRam, the UPRmt, and mitophagy. Their activation depends on the extent of import alteration, with ISR and UPRmt pathways activated in conditions of low stress. If stress levels are too high, the elimination of dysfunctional mitochondria by mitophagy is triggered. Last, we will explore how mitochondrial import deficiencies are a feature common to multifaceted pathologies, such as neurodegenerative diseases and cancer. We will also present pharmacological compounds mimicking stress response mechanisms and that could be used as a therapeutic option in the near future to restore efficient mitochondrial protein import rates. Overall, this review highlights the critical role of mitochondrial protein import in cellular and mitochondrial stress response, and in disease pathogenesis. It also emphasizes the potential of mitochondrial protein import as a therapeutic target, despite the surprising absence of direct pharmacological treatments to date.
    Keywords:  DELE1/HRI; ISR; Mitochondrial protein import; Pharmacological modulation; UPRam; UPRmt
    DOI:  https://doi.org/10.1016/j.mito.2025.102107
  24. Nat Commun. 2025 Dec 06.
    Actin dysregulation induces neuroendocrine plasticity and immune evasion: a vulnerability of small cell lung cancer.
    Yoojeong Seo, Shengzhe Zhang, Jinho Jang, Kyung-Pil Ko, Kee-Beom Kim, Yuanjian Huang, Dong-Wook Kim, Bongjun Kim, Gengyi Zou, Jie Zhang, Sohee Jun, Wonhong Chu, Nicole A Kirk, Ye Eun Hwang, Young Ho Ban, Shilpa S Dhar, Joseph M Chan, Min Gyu Lee, Charles M Rudin, Kwon-Sik Park, Jae-Il Park.
      Small cell lung cancer (SCLC) is an aggressive malignancy with limited therapeutic options. Capping protein inhibiting regulator of actin dynamics (CRACD) that promotes actin polymerization, is frequently inactivated in SCLC. However, the role of CRACD loss in SCLC is unknown. Here we show that CRACD depletion drives neuroendocrine (NE) cell plasticity and immune evasion in SCLC. Mechanistically, CRACD inactivation disrupts actin organization, leading to suppression of Yap1-NOTCH signaling and subsequent NE gene upregulation. Simultaneously, CRACD loss drives EZH2-mediated histone methylation via nuclear actin disruption, leading to repression of MHC-I genes and depletion of CD8⁺ T cells. Consequently, CRACD-downregulated tumors exhibit increased cellular heterogeneity and escape from immune surveillance. Conversely, pharmacological inhibition of EZH2 restores MHC-I expression, reactivates antitumor immunity, and suppresses tumor growth. These findings identify CRACD as a tumor suppressor that constrains cell plasticity and immune evasion, highlighting the CRACD-EZH2-MHC-I axis as a potential therapeutic vulnerability in SCLC.
    DOI:  https://doi.org/10.1038/s41467-025-67078-9
  25. Nat Commun. 2025 Dec 11. 16(1): 11106
    Hepatic metabolic reprogramming in male mice during short-term caloric restriction involves enhanced glucocorticoid rhythms.
    Konstantinos Makris, Vlera Fonda, Fania Feby Ramadhani, Lina Fadel, Morgane Davezac, Bertrand Payet, Ioannis K Deligiannis, Liwei Zhang, Teresa Horn, Laura Heimerl, Céline Jouffe, Marjolein Heddes, Celia P Martinez-Jimenez, Fabiana Quagliarini, N Henriette Uhlenhaut.
      Caloric restriction prolongs lifespan and preserves health across species, with feeding times synchronized to day-night cycles further maximizing benefits. However, the mechanisms linking diet, diurnal rhythms, and lifespan remain unclear. In mice, the time point most strongly tied to dietary effects on lifespan coincides with the peak of glucocorticoid secretion (ZT12, lights-off). Caloric restriction raises circulating glucocorticoid hormone levels, implicating these signals as candidate mediators for its benefits. Here we show that in the liver, the glucocorticoid receptor (GR) is required for the metabolic response to caloric restriction. Hepatocyte-specific GR mutant males fail to mount this response, indicating that increased glucocorticoid amplitude is necessary for the adaptation. Using multiomics, we find that nutrient deprivation elicits a nuclear switch from active STAT signaling to increased FOXO1 activity, enabling GR to activate diet-specific gene expression programs. Our results suggest that glucocorticoid rhythms are crucial for caloric restriction-induced metabolic reprogramming.
    DOI:  https://doi.org/10.1038/s41467-025-67228-z
  26. Cell Rep. 2025 Dec 10. pii: S2211-1247(25)01426-3. [Epub ahead of print]44(12): 116654
    The exit of naive pluripotency contains a metabolism-induced checkpoint for telomere homeostasis.
    Roshni A de Souza, David Barneda, Donja Karimlou, Nick G P Bovee, Yuhan Zheng, Eveline J E M Kahlman, Clara Lopes Novo, James K Ellis, Bryony J Leeke, Songyang Li, Megha Prakash Bangalore, Zijing Liu, Bebiana C Sousa, Andrea F Lopez-Clavijo, Joop H Jansen, Mauricio Barahona, Michelle Percharde, Hector C Keun, Mark Christian, Hendrik Marks, Véronique Azuara.
      During peri-implantation development, the pluripotent tissue of the early embryo undergoes profound cellular and biochemical reprogramming. These transformations are essential for subsequent development, yet how they are coordinated with the preservation of genome integrity remains poorly understood. Here, we uncover a telomere length checkpoint that is elicited by metabolic remodeling as mouse embryonic stem cells (ESCs) transition from the naive to formative pluripotent state. We show that the exit of naive pluripotency is marked by accelerated mitochondrial respiration and de novo lipogenesis, fueling lipid droplet accumulation required for tissue remodeling. Unexpectedly, these acute metabolic shifts trigger transient telomere shortening and activate ZSCAN4, a pluripotency-associated regulator of telomeres, followed by telomere re-elongation as cells adopt a more glycolytic metabolic profile. Our findings reveal a feedback mechanism in which metabolism-induced telomere stress engages ZSCAN4 as a protective response, thereby linking metabolic state to telomere homeostasis during early developmental progression.
    Keywords:  3D spheroids; ALT pathway; CP: stem cell research; ZSCAN4; cell state transitions; early mouse development; embryonic stem cells; lipid droplets; metabolism; pluripotency; telomeres
    DOI:  https://doi.org/10.1016/j.celrep.2025.116654
  27. DNA Repair (Amst). 2025 Dec 04. pii: S1568-7864(25)00108-9. [Epub ahead of print]156 103912
    Fueling for the finish line: Control of human telomerase activity by nucleotide metabolism.
    William Mannherz, Suneet Agarwal.
      Telomeres are repetitive DNA sequences that preserve genome integrity. Human telomere length is kept in a tight window through a balance between telomere erosion during genome replication and telomere elongation by the telomerase reverse transcriptase. In humans, genetically determined telomere length is associated with lifespan, while inherited defects in telomere length maintenance genes predispose to a spectrum of lethal diseases termed telomere biology disorders (TBDs). Recently, dNTP metabolism has emerged as a previously underappreciated pathway that is critical for human telomerase regulation and telomere length control. Genome-wide association studies have implicated variation in several dNTP metabolism genes with human telomere length. Genetic variants at the TYMS locus, which encodes the rate limiting thymidine synthesis enzyme thymidylate synthase, have been shown to cause the TBD dyskeratosis congenita. Genome-wide CRISPR/Cas9 functional screening has linked telomere length control to multiple key dNTP metabolism genes. Remarkably, mechanistic studies emerging from these genetic data have revealed a profound, bidirectional sensitivity of human telomerase activity to cellular dNTP levels, that is readily manipulated through several metabolic control nodes. Here, we review the emerging genetic evidence and mechanistic studies supporting the relationship between dNTP metabolism and telomere length control. We present an integrated model for human telomerase regulation, wherein the levels of dNTP substrates govern telomerase reverse transcriptase activity and in turn human telomere length. We discuss the therapeutic prospects and recent trials for manipulating dNTP metabolism to treat TBDs and related degenerative diseases.
    Keywords:  Metabolism; Nucleotide; SAMHD1; Telomerase; Telomere; dNTP
    DOI:  https://doi.org/10.1016/j.dnarep.2025.103912
  28. Nat Commun. 2025 Dec 12.
    AGPAT2 acts at the crossroads of lipid biosynthesis and DRP1-mediated ER morphogenesis.
    Yoshihiro Adachi, Mauricio Torres, Allen H Hunter, Woo Jung Cho, Meixia Pan, Xianlin Han, Guangwei Du, Ling Qi, Miho Iijima, Hiromi Sesaki.
      The morphology of the endoplasmic reticulum (ER), characterized by central sheets and peripheral tubules, is controlled by membrane-shaping proteins. However, the role of lipids in ER morphogenesis remains elusive, despite the ER being the major site for lipid synthesis. Here, by examining the role of eighteen phosphatidic acid (PA)-generating enzymes in ER morphology, we identify lysophosphatidic acid acyltransferase 2 (AGPAT2) as a critical factor in mouse and human cells. AGPAT2 produces PA in the glycerophospholipid/triacylglycerol biosynthesis pathway, and its mutations cause congenital generalized lipodystrophy. We find that AGPAT2-generated PA drives ER tubulation through gene knockout, 3D structural analysis by FIB-SEM, super-resolution microscopy, lipidomics, AlphaFold, and in vitro reconstitutions of ER tubulation and AGPAT2 activity. AGPAT2 interacts with and supplies PA to the PA-binding, dynamin-related GTPase, DRP1, which subsequently tubulates the ER in a manner independent of GTP hydrolysis and oligomerization, distinct from its function in mitochondrial division. Consistently, the reduction of PA levels by ectopic expression of a PA phosphatase, LIPIN1, transforms ER tubules into sheets. Our results reveal an unforeseen interplay between lipid biosynthesis and membrane organization in the ER.
    DOI:  https://doi.org/10.1038/s41467-025-66474-5
  29. Nat Commun. 2025 Dec 12.
    Tissue-specific mutagenesis from endogenous guanine damage is suppressed by Polκ and DNA repair.
    Yang Jiang, Moritz Przybilla, Linda Bakker, Foster C Jacobs, Dylan Mckeon, Roxanne van der Sluijs, Koichi Sato, Juliëtte Wezenbeek, Joeri van Strien, Jeroen Willems, Alexander E E Verkennis, Jamie Barnett, Adrian Baez Ortega, Federico Abascal, Peter W Villalta, Puck Knipscheer, Inigo Martincorena, Silvia Balbo, Juan Garaycoechea.
      Knowledge of mutational patterns has expanded significantly, but linking these patterns to specific molecular mechanisms or sources of endogenous DNA damage remains challenging. Translesion synthesis (TLS) is a key determinant of mutagenesis, yet the endogenous lesions that require TLS and how TLS polymerases shape mammalian mutational landscapes are unclear. Here, we characterize somatic mutational patterns across mouse tissues deficient in the TLS polymerase Polκ and find that Polκ suppresses a distinct tissue-specific mutational signature in the liver and kidney. This signature, enriched for C > A/G/T mutations with strong transcriptional-strand bias, indicates that Polκ performs error-free bypass of endogenous guanine adducts. Nucleotide excision repair (NER) acts in parallel, mitigating some of this damage. Targeted adductomics and biochemical analyses identify endogenous N2-dG lesions requiring Polκ-mediated bypass, while untargeted adductomics reveal new guanine lesions that engage NER. These findings uncover the nature of endogenous DNA damage and the coordinated roles of repair and tolerance pathways that limit mutagenesis in tissues.
    DOI:  https://doi.org/10.1038/s41467-025-67072-1
  30. Science. 2025 Dec 11. 390(6778): 1102-1103
    Chromosome shattering in cancer.
    Stanley Clarke, Marcin Imieliński.
      A protein that cuts double-stranded DNA contributes to chromosome scrambling in human cancer cells.
    DOI:  https://doi.org/10.1126/science.aed1825
  31. Nat Commun. 2025 Dec 07.
    Steroid hormone receptors through Cry2 are key players in the circadian clock response to serum.
    Gal Manella, Saar Ezagouri, Nityanand Bolshette, Achim Kramer, Marina Golik, Yaarit Adamovich, Gad Asher.
      Circadian clocks are cell-autonomous oscillators that are present in most cells of the body and temporally coordinate their function. Alignment of cellular clocks with each other and the environment is mediated mostly through blood borne signals. Although serum is a potent resetting signal for circadian clocks, the underlying intracellular molecular underpinnings are largely unknown. Here, we employ Circa-SCOPE, a high-throughput single-cell method for constructing Phase Transition Curves (PTCs), to classify intracellular signaling pathways and clock-components that participate in clock resetting by serum. We identify steroid hormone, including sex-hormone receptors as key mediators of serum-induced phase resetting. Unexpectedly, we discover that Cry2 plays a central role in the response to serum and specifically to steroid hormones, irrespectively of its effect on the clock period-length. Furthermore, we find that PTCs are largely unaffected by the period-length. Overall, our findings provide important insight on intracellular determinant of the clock response to serum.
    DOI:  https://doi.org/10.1038/s41467-025-67349-5
  32. J Biochem. 2025 Dec 11. pii: mvaf080. [Epub ahead of print]
    Breaking the pH Code: Acidification Triggers SASP and Inflammation in Cellular Senescence.
    Akimitsu Konishi.
      Cellular senescence is a stress-induced, stable growth arrest accompanied by marked metabolic alterations and acquisition of the senescence-associated secretory phenotype (SASP). While enhanced glycolysis, mitochondrial dysfunction, and lysosomal abnormalities are well-established features, emerging evidence identifies progressive intracellular acidification as an important yet underappreciated regulator of cellular senescence. Acidification results from suppressed NHE1-mediated proton efflux, elevated glycolytic proton production, and lysosomal membrane permeabilization. This lowered pH alters redox balance, inhibits HDAC activity, and promotes transcription of senescence-associated genes. Recent work by Kawakami et al. demonstrates that acidification activates a glycolysis-linked inflammatory circuit through accumulation of glucose-6-phosphate and induction of the MondoA targets TXNIP and ARRDC4, which correlate with SASP induction and define a highly secretory subset of senescent cells. These findings suggest that intracellular pH functions as a key metabolic cue linking altered glycolysis to inflammatory output, offering a conceptual framework that may guide future efforts to modulate age-associated chronic inflammation.
    Keywords:  Cellular senescence; Glycolysis; Inflammation; Intracellular acidification; Senescence-associated secretory phenotype (SASP)
    DOI:  https://doi.org/10.1093/jb/mvaf080
  33. G3 (Bethesda). 2025 Dec 08. pii: jkaf298. [Epub ahead of print]
    Identification of an uncharacterized gene as a mitochondrial methionine tRNA-synthetase in Caenorhabditis elegans.
    Bharat Vivan Thapa, Mohit Das, David I Taylor, James P Held, Maulik R Patel.
      Aminoacyl-tRNA synthetases (aaRSs) are essential for translation, as they charge tRNA molecules with their corresponding amino acids. Alterations in aaRSs can significantly disrupt both cytosolic and mitochondrial translation. Through a forward genetic screen for mitochondrial unfolded protein response (UPRmt) activators in C. elegans, we identified a missense mutation (P447V) in the previously uncharacterized gene Y105E8A.20, which encodes for a methionine tRNA synthetase (MetRS). Here, we characterize the UPRmt induction by Y105E8A.20, which we call mars-2, and demonstrate that the P447V allele is a loss-of-function mutation. Furthermore, we show that impaired mars-2 activity leads to reduced mitochondrial-encoded protein abundance, depletion of mitochondrial membrane potential, fragmented mitochondrial morphology, and mild developmental delay, although the animals remain viable. Hence, this hypomorphic mars-2(P447V) strain provides a valuable tool for studying mitochondrial translation and understanding how aaRSs are involved in mitochondrial homeostasis.
    Keywords:   Caenorhabditis elegans ; WormBase; mars-2; metionine tRNA-synthetase; mitochondria; mitochondrial unfolded protein response; mtDNA; tRNAs; translation
    DOI:  https://doi.org/10.1093/g3journal/jkaf298
  34. Res Sq. 2025 Dec 04. pii: rs.3.rs-8195970. [Epub ahead of print]
    Tracing NAD⁺ metabolism uncovers adaptive coordination between host and microbiome during colitis.
    Melanie McReynolds, Abrar Alsaadi, Lina Welz, Anant Pothakamury, Clara Gilloteau, Praveena Prasad, Mahmoud Yahia, Jaedon Sadler, Jaclyn Smith, Brenita Jenkins, Garret Diven, Johanna Bornhäuser, Taous Mekdoud, Shuchang Tian, Philip Rosenstiel, Stefan Schreiber, Jordan Bisanz, Konrad Aden.
      Host-microbiota metabolic interactions critically regulate nicotinamide adenine dinucleotide (NAD+) homeostasis, and their disruption is increasingly linked to chronic diseases including inflammatory bowel disease (IBD). However, it remains unclear whether NAD+ dysregulation in IBD arises from impaired production, enhanced consumption, or both. Using multi-omics approaches and stable isotope-labeled NAD+ precursors administered via intravenous infusion in a murine model of dextran sulfate sodium (DSS)-induced colitis, we mapped tissue- and lumen-specific NAD+ metabolism under inflammatory stress. Our results reveal tissue-specific rewiring of NAD+ metabolism, with increased flux through the salvage pathway compensating for reduced de novo NAD+ synthesis from tryptophan. In parallel, microbial de novo NAD+ production was elevated, highlighting a cooperative host-microbiota response to inflammatory stress. These findings demonstrate differential regulation of NAD+ biosynthesis during acute colitis and underscore the dynamic interplay between host and microbial metabolism in maintaining NAD+ homeostasis under inflammatory conditions.
    DOI:  https://doi.org/10.21203/rs.3.rs-8195970/v1
  35. Nature. 2025 Dec 10.
    Mutations in mitochondrial ferredoxin FDX2 suppress frataxin deficiency.
    Joshua D Meisel, Pallavi R Joshi, Amy N Spelbring, Hong Wang, Sandra M Wellner, Presli P Wiesenthal, Maria Miranda, Jason G McCoy, David P Barondeau, Gary Ruvkun, Vamsi K Mootha.
      Frataxin is a key component of an ancient, mitochondrial iron-sulfur cluster biosynthetic machinery, serving as an allosteric activator of the cysteine desulfurase NFS1 (refs. 1-5). Loss of frataxin levels underlies Friedreich's ataxia6, the most common inherited ataxia. Yeast, Caenorhabditis elegans and human cells can tolerate loss of frataxin when grown in 'permissive' low oxygen tensions7. Here we conducted an unbiased, genome-scale forward genetic screen in C. elegans leveraging permissive and non-permissive oxygen tensions to discover suppressor mutations that bypass the need for frataxin. All mutations act dominantly and are in the ferredoxin FDX2/fdx-2 or in the cysteine desulfurase NFS1/nfs-1 genes, resulting in amino-acid substitutions at the FDX2-NFS1 binding interface. Our genetic and biochemical analyses show that the suppressor mutations boost iron-sulfur cluster levels in the absence of frataxin. We also demonstrate that an excess of FDX2 inhibits frataxin-stimulated NFS1 activity in vitro and blocks the synthesis of iron-sulfur clusters in mammalian cell culture. These findings are consistent with structural and biochemical evidence that frataxin and FDX2 compete for occupancy at the same site on NFS1 (refs. 8,9). We show that lowering levels of wild-type FDX2 through loss of one gene copy can ameliorate the growth of frataxin mutant C. elegans or the ataxia phenotype of a mouse model of Friedreich's ataxia under normoxic conditions. These genetic and biochemical studies indicate that restoring the stoichiometric balance of frataxin and FDX2 through partial knockdown of FDX2 may be a potential therapy for Friedreich's ataxia.
    DOI:  https://doi.org/10.1038/s41586-025-09821-2
  36. Nat Cell Biol. 2025 Dec 09.
    Endoplasmic reticulum disruption stimulates nuclear membrane mechanotransduction.
    Zhouyang Shen, Zaza Gelashvili, Philipp Niethammer.
      Cytosolic phospholipase A2 (cPLA2) controls some of the most powerful inflammatory lipids in vertebrates by releasing their metabolic precursor, arachidonic acid, from the inner nuclear membrane (INM). Ca2+ and INM tension (TINM) are thought to govern the interactions and activity of cPLA2 at the INM. However, as compensatory membrane flow from the contiguous endoplasmic reticulum (ER) may prevent TINM, the conditions permitting nuclear membrane mechanotransduction by cPLA2 or other mediators remain unclear. To test whether the ER buffers TINM, we created the genetically encoded, Ca²⁺-insensitive TINM biosensor amphipathic lipid-packing domain inside the nucleus (ALPIN). Confocal time-lapse imaging of ALPIN- or cPLA2-INM interactions, along with ER morphology, nuclear shape/volume and cell lysis revealed a link between TINM and disrupted ER-nuclear membrane contiguity in osmotically or ferroptotically stressed mammalian cells and at zebrafish wound margins in vivo. By combining ALPIN imaging with Ca2+-induced ER disruption, we reveal the causality of this correlation, which suggests that compensatory membrane flow from the ER buffers TINM without preventing it. Besides consolidating the biomechanical basis of cPLA2 activation by nuclear deformation, our results identify cell stress- and cell death-induced ER disruption as an additional nuclear membrane mechanotransduction trigger.
    DOI:  https://doi.org/10.1038/s41556-025-01820-9
  37. Nat Commun. 2025 Dec 09. 16(1): 10983
    ERBB2 signaling drives immune cell evasion and resistance against immunotherapy in small cell lung cancer.
    Lydia Meder, Charlotte I Orschel, Cyrielle L Bouchez, Rahil Gholamipoorfard, Claudia V Orschel, David Stahl, Christoph Kreer, Mirjam Koker, Marieke Nill, Ilayda G Kocak, Ka-Won Noh, Xinlei Zhao, Leon Ullrich, Björn Häupl, Josefine Jakob, Marie-Lisa Eich, Alexandra Florin, Holger Grüll, Jürgen Wolf, Filippo Beleggia, Reinhard Büttner, Thomas Oellerich, Florian Klein, Johannes Brägelmann, H Christian Reinhardt, Nima Abedpour, Roland T Ullrich.
      Small cell lung cancer (SCLC) is characterized by its highly aggressive phenotype and dismal outcome. Despite the benefit of adding immune checkpoint blockade to standard chemotherapy, tumors acquire the ability to evade immunosurveillance and develop resistance. To investigate these underlying mechanisms, we perform high-dimensional profiling of human and murine SCLC specimens. In matched primary and metastatic human samples, we observe MHC-I loss in metastases, highlighting its role in immune evasion. Correspondingly, silencing MHC-I in SCLC cells drastically reduces immune infiltration and promotes metastasis in mice. Using mass spectrometry and phospho-tyrosine kinase analyses, we identify ERBB2 signaling as a suppressor of MHC-I and driver of immune-modulatory transcripts. Mechanistically, genetic and pharmacologic blockade of ERBB2 induces MHC-I in a STING-dependent manner and prevents immune evasion in autochthonous murine SCLC. Strikingly, combining ERBB2 inhibition with anti-PD-1 elicits profound synergistic responses in preclinical models, suggesting this combination for future clinical trials in SCLC patients.
    DOI:  https://doi.org/10.1038/s41467-025-66800-x
  38. Nat Commun. 2025 Dec 07.
    INSM1 governs a neuronal progenitor state that drives glioblastoma in a human stem cell model.
    Patrick A DeSouza, Matthew Ishahak, Xuan Qu, Colin McCornack, Devi Annamalai, Diane D Mao, Rajanikanth Vangipurapu, Yiwei Fu, Alexandre T Vessoni, Ryan T Cleary, Rowland H Han, Punn Augsornworawat, Timothy Woodiwiss, Darby Agovino, Braxton Sizemore, Jessica Kline, Maryam Borhani-Haghighi, Hao Chen, Sangami Pugazenthi, Hiroko Yano, Ting Wang, Luis F Z Batista, Jeffrey R Millman, Albert H Kim.
      Glioblastoma is a lethal brain cancer marked by functional plasticity driven by tumor cell-intrinsic mutations and their interplay with developmental programs. To investigate how canonical glioblastoma mutations promote functional plasticity, we have developed an isogenic human neural stem cell (NSC) model of glioblastoma by sequential addition of TERT promoter, TP53, and PDGFRA point mutations. TP53 loss-of-function increases TERT expression during serial mutagenesis, but only triple mutant NSCs reliably form lethal brain tumors in vivo that recapitulate glioblastoma. Tumor cell evolution triggers stress-related metabolic changes and transitions toward a neuronal progenitor network driven by transcription factor INSM1. INSM1 is highly expressed in human glioblastoma tumors and, during cortical development, in intermediate progenitor cells, which give rise to neurons. Remarkably, INSM1 knockdown in triple mutant NSCs and primary glioblastoma cells disrupts oncogenic gene expression and function and inhibits the in vivo tumorigenicity of triple mutant NSCs, highlighting the functional importance of an intermediate progenitor cell-like cell state in glioblastoma pathogenesis.
    DOI:  https://doi.org/10.1038/s41467-025-66371-x
  39. Proc Natl Acad Sci U S A. 2025 Dec 16. 122(50): e2520674122
    The inferred functional connectome underlying circadian synchronization in the mouse suprachiasmatic nucleus.
    K L Nikhil, Bharat Singhal, Daniel Granados-Fuentes, Jr-Shin Li, István Z Kiss, Erik D Herzog.
      Circadian rhythms in mammals arise from the spatiotemporal synchronization of ~20,000 neuronal clocks in the suprachiasmatic nucleus (SCN). Although anatomical, molecular, and genetic approaches have revealed diverse SCN cell types, how network-level wiring enables their synchronization remains unclear. To overcome the challenges of inferring functional connectivity from fixed tissue, we developed Mutual Information & Transfer Entropy (MITE), an information-theoretic framework to infer directed cell-cell connections with high fidelity from long-term live-cell imaging. Recording and analyzing 3,290 h of clock gene expression from 8,261 SCN neurons across 17 mice, we uncovered a highly conserved, sparse SCN network organized into two asymmetrically coupled modules: dorsal and ventral. Connectivity analyses revealed five functional SCN cell types independent of neurochemical identity. Notably, only ~30% of vasoactive intestinal peptide neurons exhibited Hub-like connectivity, classifying them as Generators and Broadcasters of synchrony signals. Other spatially stereotyped cell types consistently identified as Bridges, Receivers, or Sinks. Simulations based on MITE-inferred connectomes recapitulated emergent SCN dynamics, including recovery from desynchrony and the daily dorsal-to-ventral phase wave of gene expression. Together, these results demonstrate that MITE enables precise mapping of cellular network topology, revealing the circuit logic and key cell types that mediate circadian synchrony across space and time in the mammalian SCN.
    Keywords:  circadian; connectome; information theory; suprachiasmatic nucleus; vasoactive intestinal peptide
    DOI:  https://doi.org/10.1073/pnas.2520674122
  40. Nucleic Acids Res. 2025 Nov 26. pii: gkaf1334. [Epub ahead of print]53(22):
    The RNA-binding protein PRRC2B preserves 5' TOP mRNA during starvation to maintain ribosome biogenesis during nutrient recovery.
    Nadav Goldberg, Doron Bril, Miriam Eisenstein, Tsviya Olender, Alon Savidor, Shani Bialik, Shmuel Pietrokovski, Adi Kimchi.
      PRRC2B is an intrinsically disordered RNA-binding protein that is part of the cell's translation machinery. Here, we show that PRRC2B has two alternatively spliced mRNA transcripts producing major long and minor short isoforms. Mass spectrometry-based interaction studies indicated that both isoforms associate with the 40S ribosomal subunit and translation initiation factors. Importantly, the long isoform also interacted with additional RNA-binding proteins through its unique Arg/Gly-rich region. Among these is LARP1, a regulator of 5' terminal oligopyrimidine (TOP) mRNAs under conditions of mTOR inhibition. We discovered that, like LARP1, PRRC2B-long isoform binds to 5' TOP mRNAs. Moreover, it is necessary for the post-transcriptional preservation of their mRNA levels, particularly those encoding ribosomal proteins, during amino acid starvation. In its absence, the rapid de novo translation of ribosomal proteins that takes place upon nutrient recovery is impeded. Overall, our study elucidates a newly discovered function for PRRC2B as an RNA-binding protein that regulates ribosomal biogenesis upon metabolic shift, in addition to its established function in initiating translation of specific mRNA targets.
    DOI:  https://doi.org/10.1093/nar/gkaf1334
  41. Trends Genet. 2025 Dec 05. pii: S0168-9525(25)00287-2. [Epub ahead of print]
    Lysosomal activation leaves a lasting memory.
    Amaresh Chaturbedi, Charles Lowell Heinke, Siu Sylvia Lee.
      Beyond their degradative role, lysosomes help prepare Caenorhabditis elegans offspring for stress. In a recent study, Zhang et al. show that lysosomal activation induces somatic histone H3.3 production, which moves to the germline and is methylated at K79 to transmit longevity. Thus, this work establishes lysosomes as a conduit linking metabolism, chromatin, and epigenetic inheritance.
    Keywords:  H3.3 (HIS-71); H3K79 methylation; aging; lysosomal lipolysis; transgenerational inheritance
    DOI:  https://doi.org/10.1016/j.tig.2025.11.005
  42. J Am Chem Soc. 2025 Dec 12.
    Bioactive Artificial Cells as Autonomous Metabolic Actuators Enable Bidirectional Communication with Tumor Cells.
    Lifan Hu, Wenwu Peng, Jiyao Yu, Lisa Förch, Stephen Mann, Seah Ling Kuan, Tanja Weil.
      Artificial cells (ACs) offer a powerful platform to reprogram metabolic signaling in complex tissue environments by replicating key biological functions without the full complexity of living cells. However, achieving autonomous metabolite exchange and stable integration with living tissues remains a major challenge. Here, we report the development of proteinosome-based ACs equipped with a minimal metabolism to mediate bidirectional communication with glycolytic tumor cells. These tumors accumulate lactate, a metabolic byproduct that promotes immunosuppression and metastasis. Although lactate oxidase (LOx) can degrade lactate, its oxidation product, pyruvate, may inadvertently fuel tumor growth. To overcome this limitation, we engineered dual-processor ACs coencapsulating LOx and pyruvate decarboxylase (PDC), enabling selective conversion of lactate into cytotoxic acetaldehyde while suppressing pyruvate and hydrogen peroxide accumulation. These ACs demonstrate sustained catalytic activity, maintain reactive oxygen species homeostasis, and remain functional when integrated in 3D tumor spheroids. Crucially, they engage in autonomous, bidirectional metabolite exchange, preferentially with cancer cells over normal cells, dynamically rewiring important metabolites of the tumor microenvironment and suppressing cell viability. This work establishes synthetic metabolic biointerfaces as programmable actuators capable of reshaping pathological signaling in cancer tissues.
    DOI:  https://doi.org/10.1021/jacs.5c14609
  43. Nat Cancer. 2025 Dec 10.
    The 2025 generation.
    Hana Aliee, Leire Bejarano-Bosque, Roger Castells-Graells, Deborah Caswell, Mirco Julian Friedrich, Carino Gurjao, Li Ren Kong, Shuang Liu, Simone Minnie, Reineke A Schoot, Zefang Tang.
      
    DOI:  https://doi.org/10.1038/s43018-025-01086-y
  44. FEBS J. 2025 Dec 07.
    The ribosome-associated complex regulates cytosolic translation upon mitoprotein-induced stress.
    Jiaxin Qian, Annika Nutz, Katja Hansen, Lea Bertgen, Mirita Franz-Wachtel, Boris Macek, Johannes M Herrmann, Doron Rapaport.
      The biogenesis of mitochondria relies on the import of newly synthesized precursor proteins from the cytosol. Tom70 is a mitochondrial surface receptor which recognizes precursors and serves as an interface between mitochondrial protein import and the cytosolic proteostasis network. Mitochondrial import defects trigger a complex stress response, in which compromised protein synthesis rates are a characteristic element. The molecular interplay that connects mitochondrial (dys)function to cytosolic translation rates in yeast cells is however poorly understood. Here, we show that the deletion of the two Tom70 paralogs of yeast (TOM70 and TOM71) leads to defects in mitochondrial biogenesis and slow cell growth. Surprisingly, upon heat stress, the deletion of ZUO1, a chaperone of the ribosome-associated complex (RAC), largely prevented the slow growth and the reduced translation rates in the tom70Δ/tom71Δ double deletion mutant. In contrast, the mitochondrial defects were not cured but even enhanced by ZUO1 deletion. Our study shows that Zuo1 is a critical component in the signaling pathway that mutes protein synthesis upon mitochondrial dysfunction. We propose a novel paradigm according to which RAC serves as a stress-controlled regulatory element of the cytosolic translation machinery.
    Keywords:  Tom70; mitochondria; protein import; proteostasis; ribosome‐associated complex
    DOI:  https://doi.org/10.1111/febs.70356
  45. Immunity. 2025 Dec 09. pii: S1074-7613(25)00514-X. [Epub ahead of print]58(12): 2931-2933
    A surprising link: TET2 clonal hematopoiesis boosts immune checkpoint therapy.
    Qiang Dong, Chengcheng Jin.
      TET2 mutations can drive clonal hematopoiesis (CH), but their impact on tumor immunity remains unresolved. Recently in Cancer Cell, Herbrich et al. reported that TET2-mutant CH reprograms tumor-associated macrophages to enhance antigen presentation and immune-checkpoint therapy efficacy in solid tumors.
    DOI:  https://doi.org/10.1016/j.immuni.2025.11.012
  46. Biol Rev Camb Philos Soc. 2025 Dec 09.
    Why we age.
    Michael S Ringel.
      Three categories of explanations exist for why we age: mechanistic theories, which omit reference to evolutionary forces; weakening force of selection theories, which posit that barriers exist that prevent evolutionary forces from optimising fitness in ageing; and optimisation theories, which posit that evolutionary forces actually select for ageing under the constraints that exist due to limited energy and other resources. We now have a broad data set of observed features of ageing against which these categories of theories can be tested, including results of interventions like caloric restriction, features of long-lived organisms, the existence of mortality rate plateaus, longevity of eusocial insect queens, and the malleability of lifespan. Optimisation theories are the only ones that fit all the observed data. Moreover, this category of theory makes a very ordinary claim, consistent with significant other data: evolution by natural selection is operating in ageing. It is actually quite extraordinary, either implicitly or explicitly, to claim that natural selection fails to operate, as the other categories of theories do. A key prediction of optimisation theories that differs from other theories is that mutations that extend lifespan should generally reduce fitness under natural conditions. Contrary to some suggestions in the literature, to date the available evidence supports this prediction. Optimisation theories have several implications, including that lifespan should be relatively easy to manipulate by tapping into existing biological mechanisms, and that the geroscience hypothesis, which states that intervention on the rate of ageing should also modulate the incidence of age-related diseases, is likely to be correct.
    Keywords:  ageing; aging; antagonistic pleiotropy; disposable soma; healthspan; hyperfunction; lifespan; longevity; mutation accumulation
    DOI:  https://doi.org/10.1002/brv.70109
  47. Nat Commun. 2025 Dec 12. 16(1): 11104
    Mitochondria are absent from microglial processes performing surveillance, chemotaxis, and phagocytic engulfment.
    Alicia N Pietramale, Xhoela Bame, Megan E Doty, Kiera E Schwarz, Robert A Hill.
      Microglia continually surveil the brain allowing for rapid detection of tissue damage or infection. Microglial metabolism is linked to tissue homeostasis, yet how mitochondria are subcellularly partitioned in microglia and dynamically reorganize during surveillance, injury responses, and phagocytic engulfment in the intact brain are not known. Here, we performed intravital imaging and ultrastructural analyses of microglia mitochondria in mice and human tissue, revealing that microglial processes diverge in their mitochondrial content, with some containing multiple mitochondria while others are completely void. Microtubules and hexokinase 2 mirror this uneven mitochondrial distribution indicating that these cytoskeletal and metabolic components are linked to mitochondrial organization in microglia. Microglial processes that engage in minute-to-minute surveillance typically do not have mitochondria. Moreover, unlike process surveillance, mitochondrial motility does not change with animal anesthesia. Likewise, the processes that acutely chemoattract to a lesion site or initially engage with a neuron undergoing programmed cell death do not contain mitochondria. Rather, microglia mitochondria have a delayed arrival into the responding cell processes. Thus, there is subcellular heterogeneity of mitochondrial partitioning. Moreover, microglial processes that surveil and acutely respond to damage do not contain mitochondria.
    DOI:  https://doi.org/10.1038/s41467-025-66708-6
  48. Oncogenesis. 2025 Dec 09. 14(1): 48
    Adaptation of redox metabolism in drug-tolerant persister cells is a vulnerability to prevent relapse in pancreatic cancer.
    Nadine Abdel Hadi, Gabriela Reyes-Castellanos, Tristan Gicquel, Scarlett Gallardo-Arriaga, Emma Cosialls, Emeline Boet, Jean-Emmanuel Sarry, Rawand Masoud, Juan Iovanna, Alice Carrier.
      Pancreatic Ductal Adenocarcinoma (PDAC) remains a major unresolved disease because of its remarkable therapeutic resistance. Even patients who respond to initial therapy experience relapse in most cases. The mechanisms underlying therapy-acquired resistance supporting relapse are poorly understood. In this study, we aimed to determine the metabolic features of PDAC during relapse, specifically adaptations of mitochondrial oxidative metabolism. We used preclinical PDAC mouse models (patient-derived xenografts and murine syngeneic allografts) that present regression under initial chemotherapeutic treatment but relapse after a certain time. Relapsed tumors were analyzed ex vivo by flow cytometry to measure mitochondrial and redox characteristics. Molecular mechanisms were investigated by quantification of ATP and antioxidants levels, bulk RNA-sequencing and RT-qPCR. We show increased mitochondrial mass, ATP levels, mitochondrial superoxide anions, and total ROS levels, in relapsed compared to control tumors in both models; mitochondrial membrane potential is increased in the xenografts model only. These metabolic features are also observed in tumors during treatment-induced regression and at relapse onset. At the molecular level, antioxidant defenses are increased in relapsed tumors and during treatment. These data suggest that metabolic adaptations occurring during treatment-induced regression may favor the survival of drug-tolerant persister (DTP) cells, which persist during the subsequent minimal residual disease and are responsible for cancer relapse. Finally, the combined treatment of arsenic trioxide (ROS inducer) and buthionine sulfoximine (glutathione synthesis inhibitor) is able to completely prevent relapse in PDAC xenografts. In conclusion, redox metabolism is a vulnerability of pancreatic DTP cancer cells that can be targeted to prevent relapse.
    DOI:  https://doi.org/10.1038/s41389-025-00591-0
  49. EMBO Rep. 2025 Dec 11.
    Conserved lipid metabolic reprogramming confers hypoxic and aging resilience.
    Wei I Jiang, Goncalo Dias do Vale, Quentinn Pearce, Kaitlyn Kong, Wenbin Zhou, Jeffrey G McDonald, James E Cox, Neel S Singhal, Dengke K Ma.
      The Arctic ground squirrel (AGS, Urocitellus parryii), an extreme hibernator, exhibits remarkable resilience to stressors like hypoxia and hypothermia, making it an ideal model for studying cellular metabolic adaptation. The underlying mechanisms of AGS resilience are largely unknown. Here, we use lipidomic and metabolomic profiling to discover specific downregulation of triglyceride lipids and upregulation of the lipid biosynthetic precursor malonic acid in AGS neural stem cells (NSC) versus murine NSCs. Inhibiting lipid biosynthesis recapitulates hypoxic resilience of squirrel NSCs. Extending this model, we find that acute exposure to hypoxia downregulates key lipid biosynthetic enzymes in C. elegans, while inhibiting lipid biosynthesis reduces mitochondrial fission and facilitates hypoxic survival. Moreover, inhibiting lipid biosynthesis protects against APOE4-induced pathologies and aging trajectories in C. elegans. These findings suggest triglyceride downregulation as a conserved metabolic resilience mechanism, offering insights into protective strategies for neural tissues under hypoxic or ischemic conditions, APOE4-induced pathologies and aging.
    Keywords:   C. elegans ; Arctic Ground Squirrel; Hypoxia; Lipid Biosynthetic Enzymes; Triglyceride Lipids
    DOI:  https://doi.org/10.1038/s44319-025-00664-6
  50. Nat Metab. 2025 Dec 10.
    Neuronal fatty acid oxidation fuels memory after intensive learning in Drosophila.
    Alice Pavlowsky, Bryon Silva, Ruchira Basu, Amandine Correia Delecourt, David Geny, Lydia Danglot, Pierre-Yves Plaçais, Thomas Preat.
      Metabolic flexibility allows cells to adapt to different fuel sources, which is particularly important for cells with high metabolic demands1-3. In contrast, neurons, which are major energy consumers, are considered to rely essentially on glucose and its derivatives to support their metabolism. Here, using Drosophila melanogaster, we show that memory formed after intensive massed training is dependent on mitochondrial fatty acid (FA) β-oxidation to produce ATP in neurons of the mushroom body (MB), a major integrative centre in insect brains. We identify cortex glia as the provider of lipids to sustain the usage of FAs for this type of memory. Furthermore, we demonstrate that massed training is associated with mitochondria network remodelling in the soma of MB neurons, resulting in increased mitochondrial size. Artificially increasing mitochondria size in adult MB neurons increases ATP production in their soma and, at the behavioural level, strikingly results in improved memory performance after massed training. These findings challenge the prevailing view that neurons are unable to use FAs for energy production, revealing, on the contrary, that in vivo neuronal FA oxidation has an essential role in cognitive function, including memory formation.
    DOI:  https://doi.org/10.1038/s42255-025-01416-5
  51. Cell Metab. 2025 Dec 11. pii: S1550-4131(25)00494-2. [Epub ahead of print]
    Bile acids regulate lipid metabolism through selective actions on fatty acid absorption.
    Alvin P Chan, Kelsey E Jarrett, Rochelle W Lai, Madelaine C Brearley-Sholto, Angela S Cheng, Maria O Taveras, Anne M Iwata, Michelle E Steel, Andrew Lau, Emily C Whang, John P Kennelly, Yajing Gao, Gabriella E Rubert, Heidi M Schmidt, Emily P Smith, Baolong Su, Kevin J Williams, Elizabeth J Tarling, Thomas Q de Aguiar Vallim.
      Intestinal lipid absorption, the entry point for fats into the body, requires the coordinated actions of bile acids and lipases. Here, we uncover distinct yet cooperative roles of bile acids in driving the differential uptake of dietary fatty acids. We first decreased the bile acid pool size by disrupting the rate-limiting enzyme in bile acid synthesis, Cyp7a1, using liver-directed gene editing in mice. Compared with lipase inhibition, reduced bile acids prevented diet-induced obesity, increased anorectic hormones, suppressed excessive eating, and improved systemic lipid metabolism. Remarkably, decreasing bile acids selectively reduced the absorption of saturated fatty acids but preserved polyunsaturated fatty acids. By targeting additional bile acid enzymes, we identified specific functions of individual bile acid species. Mechanistically, we show that cholic acid preferentially solubilizes polyunsaturated fatty acids into mixed micelles for intestinal uptake. Our studies demonstrate that bile acids can selectively control fatty acid uptake, revealing insights for future interventions in metabolic diseases.
    Keywords:  CYP2A12; CYP2C70; CYP7A1; CYP8B1; GLP-1; bile acids; fatty acids; lipid absorption; lipogenesis
    DOI:  https://doi.org/10.1016/j.cmet.2025.11.010
  52. Nat Rev Cancer. 2025 Dec 08.
    N6-Methyladenosine: an RNA modification as a central regulator of cancer.
    Hanzhi Luo, Michael G Kharas, Samie R Jaffrey.
      N6-Methyladenosine (m6A) is a modified nucleotide in mRNAs and non-coding RNAs that influences gene expression, primarily by promoting the degradation of specific transcripts. Recent studies have highlighted the dynamic and context-dependent roles of this RNA modification in cancer, implicating it in tumorigenesis, immune evasion and therapeutic resistance. In this Review, we discuss the functional roles of m6A writers, erasers and readers in cancer. We highlight how m6A dysregulation contributes to oncogenic processes, including cell differentiation and immune microenvironment remodelling. Using haematological malignancies as an example, we highlight the principles of m6A-dependent regulation that may be broadly relevant across cancer types. Notably, inhibitors targeting the m6A writer methyltransferase-like 3 (METTL3) have emerged as potential cancer therapeutics. METTL3 inhibitors not only disrupt m6A-dependent pathways but also elevate double-stranded RNA levels, activating innate immune responses and antitumour immunity. We emphasize the need for high-resolution quantitative m6A mapping in cancer and mechanistic studies to better understand the specific transcripts that exhibit altered patterns of m6A in cancer and to identify patient subgroups most likely to benefit from METTL3 inhibitors.
    DOI:  https://doi.org/10.1038/s41568-025-00889-6
  53. Science. 2025 Dec 11. eads6674
    Spatial and morphological organization of mitochondria in neurons across a connectome.
    Garrett Sager, Paul Pfeiffer, Heng Wu, Fabian Pallasdies, Robert Gowers, Snusha Ravikumar, Elizabeth Wu, Daniel Colón-Ramos, Susanne Schreiber, Damon A Clark.
      Neuronal function depends on mitochondria, but little is known about their organization across neurons. Using an electron microscopy Drosophila connectome, we uncovered quantitative rules governing the morphology and positioning of hundreds of thousands of mitochondria across thousands of neurons. We discover that mitochondrial morphological features are specific to cell and neurotransmitter type, providing fingerprints to identify neurons. Mitochondria are positioned with 2-3 μm precision relative to synaptic and structural features, with systematic differences across neuron types and compartments. Mitochondrial localization correlates with regional activity and postsynaptic targets. Analysis of a mouse visual cortex connectome confirms cell-type specific morphology and identifies partially divergent positioning rules. These results establish mitochondria as circuit-embedded organelles whose distribution links subcellular architecture to brain connectivity.
    DOI:  https://doi.org/10.1126/science.ads6674
  54. Nat Med. 2025 Dec 08.
    A lifespan clock tells the biology of time.
    Noa Rappaport, Annalise Schweickart, Nathan D Price.
      
    DOI:  https://doi.org/10.1038/s41591-025-04095-7
  55. Mol Cell. 2025 Dec 09. pii: S1097-2765(25)00931-1. [Epub ahead of print]
    Puromycin-sensitive aminopeptidase acts as an inhibitory auxiliary subunit of volume-regulated anion channels and regulates cGAMP transport.
    Wenqiang Zheng, Tatsuya Hagino, Hao Wang, Henry Yi Cheng, Nicholas Koylass, Kevin Hong Chen, Haobo Wang, Sepehr Mani, Anish Kumar Mondal, Edward C Twomey, Zhaozhu Qiu.
      Volume-regulated anion channels (VRACs) are large-pore channels expressed in most vertebrate cells and are critical for cell volume regulation and autocrine/paracrine signaling. Here, we identify the ubiquitously expressed puromycin-sensitive aminopeptidase (PSA) as a binding partner of the obligatory VRAC subunit SWELL1 (also known as LRRC8A) and determine the cryo-electron microscopy structure of the SWELL1-PSA complex. Three PSA molecules bind a single SWELL1 hexamer, coupling adjacent leucine-rich repeat (LRR) domains into local dimers. Functionally, PSA overexpression suppresses VRAC activation, whereas PSA deletion dramatically elevates basal channel activity. Notably, PSA's modulation of VRACs requires physical binding but not aminopeptidase activity, indicating a structural mechanism. Our findings identify PSA as an auxiliary subunit of VRACs, highlight the role of intracellular LRR domains in allosteric channel gating, and suggest a strategy to tune VRAC function in diverse physiological contexts, including 2'3'-cyclic GMP-AMP (cGAMP) transport and downstream stimulator of interferon genes (STING) signaling.
    Keywords:  LRRC8; LRRC8A; NPEPPS; STING; SWELL1; cGAMP
    DOI:  https://doi.org/10.1016/j.molcel.2025.11.014
  56. Nat Rev Mol Cell Biol. 2025 Dec 08.
    Space travel affects haematopoietic stem cells.
    Kim Baumann.
      
    DOI:  https://doi.org/10.1038/s41580-025-00941-1
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