bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2026–02–08
seventy papers selected by
Christian Frezza, Universität zu Köln
  1. Mitochondrial superoxide signals shield the nucleus to delay ageing.
  2. SLC6A6 imports taurine into mitochondria to sustain mitochondrial translation and tumour growth.
  3. ZNF395 Is a Hypoxia-Responsive Regulator of Mitochondrial Glutaminolysis in Clear Cell Renal Cell Carcinoma.
  4. Cancer cachexia in STK11/LKB1-mutated non-small cell lung cancer is dependent on tumor-secreted GDF15.
  5. Mitochondrial SLC6A6 supports taurine transport.
  6. Mitochondria at the membrane provide a route to inflammatory cell death.
  7. ZFTA-RELA ependymomas make itaconate to epigenetically drive fusion expression.
  8. Hallmarks of nuclear metabolism: implications for genome integrity, nuclear signaling, and therapeutic targeting.
  9. Metastasis gets a little help from immune cell mitochondria.
  10. Dietary sulfur amino acid restriction improves glucose homeostasis through hepatic de novo serine synthesis.
  11. PtdIns(3,5)P2 is an endogenous ligand of STING in innate immune signalling.
  12. Proteostasis of organelles in aging and disease.
  13. Dual targeting of SLC25A51 and succinate dehydrogenase selectively depletes mitochondrial NAD+ to eradicate KRAS-driven AML.
  14. Activated ATF6α is a hepatic tumour driver restricting immunosurveillance.
  15. Tumour-brain crosstalk restrains cancer immunity via a sensory-sympathetic axis.
  16. Metabolomic profiling and stable isotope tracing of human schwannomas: A novel perspective on tumor biology and radiation response.
  17. Mitochondrial superoxide regulates nuclear envelope integrity and ageing via redox-mediated lipid metabolism.
  18. Distinct sensing of BCAAs by mTOR and c-Myc governs T cell proliferation, independent of catabolism.
  19. Ribosome-associated quality control of aberrant protein production during amino acid limitation.
  20. A p53-controlled lysosomal recycling circuit fuels phospholipid synthesis.
  21. Regulation of STING activation by phosphoinositide and cholesterol.
  22. Lifespan and Fecundity Impacts of Reduced Insulin Signalling Can Be Directed by Mito-Nuclear Epistasis in Drosophila.
  23. Glucose deprivation drives LIF-dependent lung cancer.
  24. Mitochondrial DNA release and inflammation in mitochondrial disease pathogenesis.
  25. The mitochondrial intermembrane space nuclease Nuc1 (endonuclease G) prevents mitophagy-mediated mtDNA escape in yeast.
  26. Polyamine metabolism as a regulator of cellular and organismal aging.
  27. Dying oligodendrocytes persist without mitochondria.
  28. Cytoplasmic NAD/H synthesis via NRK1 regulates inflammatory capacity and promotes survival of CD4+ T cells.
  29. A Recombinant Antibody Against Human DRP1 Serine 616 Phosphorylation Enables Detection of BRAF V600E -Associated Mitochondrial Division in Cancer.
  30. BCLAF1 links RNA splicing to ATF4-dependent metabolic adaptation in acute myeloid leukemia.
  31. Rhythmic Nuclear Import Mediated by Importins Regulates the Neurospora Circadian Clock.
  32. Cell-free DNA epigenomic profiling enables noninvasive detection and monitoring of translocation renal cell carcinoma.
  33. Glucose availability tunes latent CD8+ T cell expansion potential through a mitogen-independent, mTOR-dependent regulatory switch.
  34. Zebrafish macrophages convert physical wound signals into rapid vascular permeabilization.
  35. Aging clocks delineate neuron types vulnerable or resilient to neurodegeneration and identify neuroprotective interventions.
  36. The biological role of local and global fMRI BOLD signal variability in multiscale human brain organization.
  37. Reversible arginine methylation regulates mitochondrial IDH2 activity: coordinated control by CARM1 and KDM3A/4A.
  38. The loss of peroxiredoxin 2 in mice disrupts the biochemical aging phenotype in erythrocytes.
  39. Senescent cells secrete chromatin components via senescence-associated extracellular particles.
  40. Condensates and Cell States: A New Paradigm for Understanding Tumor Biology.
  41. Multiomic analysis of clonal development reveals new regulators of leukemic cell growth.
  42. Treatment resistance to platinum-based chemotherapy in lung and ovarian cancer is driven by a targetable TGFβ senescent secretome.
  43. Mannose metabolic pathway senses glucose supply and regulates cell fate decisions.
  44. LONP-1 deficiency causes dysregulated protein synthesis within mitochondria that is restored by mitoribosomal mutations.
  45. Acetyl-CoA availability regulates neuronal metabolism, growth, and synaptic activity.
  46. Aldehyde and seek: Toxic aldehydes drive exhaustion in tumor-infiltrating T cells.
  47. Multiple Adenylate-Forming Enzymes Contribute to Biosynthesis of the DPO Quorum-Sensing Autoinducer.
  48. The second mitochondrial activator of caspases (SMAC) regulates growth, inflammation and mitochondrial integrity in cancer cells.
  49. Kras G12C- and G12D-driven lung cancers differ in oncogenic potency, immunogenicity, and relapse after Kras inhibition in mouse models.
  50. Brief pulses of high-level fluid shear stress enhance metastatic potential and rapidly alter the metabolism of cancer cells.
  51. Fungal infection drives metabolic reprogramming in epithelial cells via aerobic glycolysis and an alternative TCA cycle shunt.
  52. Adaptive regulation of glycerophospholipid metabolism.
  53. Mendelian randomization linking metabolites with enzymes reveals pathway regulation and therapeutic avenues.
  54. The human pathome shows sex and tissue specific aging patterns.
  55. Aerobic glycolysis promotes NLRP3 inflammasome activation via NLRP3 lactylation.
  56. Suppression of interferon signaling via small-molecule modulation of TFAM.
  57. Five energy metabolism pathways show distinct regional distributions and lifespan trajectories in the human brain.
  58. An mTurquoise2-Based Glucose Biosensor.
  59. Timing of NAD Deficiency During Organogenesis Dictates Defect Type and Penetrance.
  60. Quantitative and temporal analysis of autophagy: Differential Response to amino acid and glucose starvation.
  61. Functional characterisation of tumour suppressor PDCD4 reveals previously undisclosed role in the control of cell adhesion.
  62. Early-life NAD+ deficiency programs skeletal muscle aging by sustained suppression of hyaluronic acid synthesis beginning in childhood.
  63. Illuminating spatial dynamics of glutamine metabolism with a sensitive genetically encoded biosensor.
  64. Cellular quiescence uncouples the proteome from the transcriptome in neural stem cells.
  65. B cells drive CD4 T cell immunosenescence and age-associated health decline.
  66. AHCY: A Metabolic Gatekeeper at the Interface of Methylation, Redox Balance, and Cellular Stress Response.
  67. Butyrate extends health and lifespan in mice with mitochondrial deficiency.
  68. CCL3 is produced by aged neutrophils across cancers and promotes tumor growth.
  69. Hallmarks of cancer-Then and now, and beyond.
  70. Metabolite control of enzyme activity links stress to biosynthetic regulation.
  1. Nat Metab. 2026 Feb 03.
    Mitochondrial superoxide signals shield the nucleus to delay ageing.
      
    DOI:  https://doi.org/10.1038/s42255-026-01461-8
  2. Nat Metab. 2026 Feb 06.
    SLC6A6 imports taurine into mitochondria to sustain mitochondrial translation and tumour growth.
    Liucheng Li, Jianwei You, Zi-Qing Chai, Xueshan Li, Xinlei Cai, Lin Wang, Fang Yang, Lingzhi Zhu, Wen Mi, Xinyi Xia, Haohang Yan, Fei Li, Juan Wang, Tong-Jin Zhao, Ligong Chen, Hongbin Ji, Pingyu Liu, Xiao-Long Zhou, Li Chen, Fuming Li.
      Taurine plays a crucial role in mitochondrial translation. Mammalian cells obtain taurine via exogenous uptake mediated by the plasma membrane transporter SLC6A6 or via cytosolic biosynthesis. However, it remains unclear how taurine enters mitochondria and impacts cellular metabolism. Here we show that SLC6A6, but not exogenous taurine, is essential for mitochondrial metabolism and cancer cell growth. We discover that SLC6A6 also localizes to mitochondria and imports taurine for mitochondrial transfer RNA modifications. SLC6A6 deficiency specifically reduces mitochondrial taurine abundance and abrogates mitochondrial translation and cell proliferation. We identify protein kinase A as a regulator of SLC6A6 subcellular localization, as it promotes SLC6A6 presence at the plasma membrane while inhibiting its mitochondrial localization. Furthermore, we identify NFAT5 as a key regulator of mitochondrial function through SLC6A6 and demonstrate that targeting the NFAT5-SLC6A6 axis markedly impairs mitochondrial translation and tumour growth. Together, these findings suggest that SLC6A6 is a mitochondrial taurine transporter and an exploitable metabolic dependency in cancer.
    DOI:  https://doi.org/10.1038/s42255-026-01455-6
  3. Cancer Res. 2026 Feb 04. OF1-OF14
    ZNF395 Is a Hypoxia-Responsive Regulator of Mitochondrial Glutaminolysis in Clear Cell Renal Cell Carcinoma.
    Joanna Koh, Chengheng Liao, Michelle Shu Wen Ng, Jing Han Hong, Hong Lee Heng, Dan Y Gui, Zhenxun Wang, Benjamin Yan-Jiang Chua, Zhimei Li, Radoslaw M Sobota, Lye Siang Lee, Jabed Iqbal, Kevin Junliang Lim, Divya Bezwada, Ralph J DeBerardinis, Gertrud Steger, Jianhong Ching, Patrick Tan, Bin Tean Teh, Qing Zhang, Xiaosai Yao.
      Hypoxia signaling induced by VHL deficiency fuels growth but also imposes metabolic stress on clear cell renal cell carcinomas (ccRCC). Many ccRCC cells depend on glutamine as the primary source of tricarboxylic acid (TCA) anaplerosis. Hypoxia-inducible factor α (HIFα) governs glycolysis but does not directly regulate glutamine metabolism; instead, the factor responsible for orchestrating glutamine metabolism and mitochondrial adaptations to hypoxia remains elusive. In this study, we showed that ZNF395 is a hypoxia-responsive factor that regulates glutamine metabolism in the mitochondria. When activated by a HIF2α-modulated superenhancer, ZNF395 facilitated the transcription of enzymes essential for glutaminolysis, including glutaminase (GLS) and isocitrate dehydrogenase 2. Functionally, ZNF395 depletion resulted in reduced TCA cycle intermediates and their derivatives, including amino acids, glutathione, and pyrimidine nucleotides, leading to impaired mitochondrial respiration. Restoration of mitochondrial complex I function and GLS expression partially rescued the effects of ZNF395 depletion on ccRCC tumor growth. Together, this study underscores the coordinated role of HIFα and ZNF395 in shaping metabolic adaptations in response to hypoxia in VHL-deficient ccRCCs.
    SIGNIFICANCE: ZNF395 and HIF are complementary mediators of hypoxia-induced metabolic reprogramming and therapeutic targets in VHL-deficient kidney cancer, with the former regulating glutamine metabolism and the latter regulating glucose metabolism.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-4745
  4. Nat Commun. 2026 Jan 30.
    Cancer cachexia in STK11/LKB1-mutated non-small cell lung cancer is dependent on tumor-secreted GDF15.
    Jinhai Yu, Tong Guo, Arun Gupta, Ernesto M Llano, Thomas Salisbury, Naureen Wajahat, Dianne Zhao, Sean Slater, Qing Deng, Esra A Akbay, Beverly A Rothermel, John M Shelton, Bret M Evers, Zhidan Wu, Iphigenia Tzameli, Evanthia Pashos, James Kim, John D Minna, Puneeth Iyengar, Rodney E Infante.
      Cachexia is a wasting syndrome involving adipose, muscle, and body weight loss in cancer patients. Tumor loss-of-function mutations in STK11/LKB1, a regulator of AMP-activated protein kinase, induce cancer cachexia (CC) in preclinical models and are linked to weight loss in non-small cell lung cancer (NSCLC) patients. This study examines the role of the integrated stress response (ISR) cytokine growth differentiation factor 15 (GDF15) in regulating cachexia using patient-derived and engineered STK11/LKB1-mutant NSCLC lines. Tumor cell-derived serum GDF15 levels are elevated in mice bearing these tumors. Treatment with a GDF15-neutralizing antibody or silencing GDF15 from tumor cells prevents adipose/muscle loss, strength decline, and weight reduction, identifying tumors cells as the GDF15 source. Restoring wild-type STK11/LKB1 in NSCLC lines with endogenous STK11/LKB1 loss reverses the ISR and reduces GDF15 expression rescuing the cachexia phenotype. Collectively, these findings implicate tumor-derived GDF15 as a key mediator and therapeutic target in STK11/LKB1-mutant NSCLC-associated cachexia.
    DOI:  https://doi.org/10.1038/s41467-026-68702-y
  5. Nat Metab. 2026 Feb 06.
    Mitochondrial SLC6A6 supports taurine transport.
    Katsuhisa Inoue.
      
    DOI:  https://doi.org/10.1038/s42255-026-01471-6
  6. Cell Metab. 2026 Feb 03. pii: S1550-4131(25)00550-9. [Epub ahead of print]38(2): 260-262
    Mitochondria at the membrane provide a route to inflammatory cell death.
    Zezhao Chen, Daichao Xu.
      In a recent issue of Cell, Wang et al. identify "mitoxyperilysis," a previously unknown lytic cell death pathway where combined innate immune and metabolic stress triggers prolonged mitochondria-plasma membrane contact, causing local oxidative damage and membrane rupture. This mTORC2-regulated process identifies a therapeutic axis for inflammatory diseases and cancer.
    DOI:  https://doi.org/10.1016/j.cmet.2025.12.019
  7. Nature. 2026 Feb 04.
    ZFTA-RELA ependymomas make itaconate to epigenetically drive fusion expression.
    Siva Kumar Natarajan, Joanna Lum, James Haggerty Skeans, Minal Nenwani, Sanjana Eyunni, Mateus Mota, Jill M Bayliss, Akash Deogharkar, Erin Taya Hamanishi, Matthew Pun, Stefan R Sweha, Simon Hoffman, Eleanor Young, Qiuyang Zhang, Rijul Mehta, Olamide Animasahun, Pranav Narayanan, Sushanth Sunil, Abhijit Parolia, Peter Sajjakulnukit, Pooja Panwalkar, Robert Doherty, Madison Clausen, Derek Dang, Debra Hawes, Fusheng Yang, Mariarita Santi, Alexander R Judkins, Yelena Wilson, Thomas Vigil, Andrea Franson, Richard M Mortensen, Tatsuya Ozawa, Andrea Griesinger, Eric C Holland, Nicholas K Foreman, Kulandaimanuvel Antony Michealraj, Sameer Agnihotri, Michael Taylor, Richard J Gilbertson, Carl Koschmann, Arul M Chinnaiyan, Costas A Lyssiotis, Deepak Nagrath, Sriram Venneti.
      ZFTA-RELA+ ependymomas are malignant brain tumours defined by fusions formed between the putative chromatin remodeller ZFTA and the NF-κB mediator RELA1. Here we show that ZFTA-RELA+ cells produce itaconate, a key macrophage-associated immunomodulatory metabolite2. Itaconate is generated by cis-aconitate decarboxylase 1 (ACOD1; also known as IRG1). However, the production of itaconate by tumour cells and its tumour-intrinsic role are not well established. ACOD1 is upregulated in a ZFTA-RELA-dependent manner. Functionally, itaconate enables a feed-forward system that is crucial for the maintenance of pathogenic ZFTA-RELA levels. Itaconate epigenetically activates ZFTA-RELA transcription by enriching for activating H3K4me3 via inhibition of the H3K4 demethylase KDM5. ZFTA-RELA+ tumours enhance glutamine metabolism to supply carbons for itaconate synthesis. Antagonism of ACOD1 or glutamine metabolism reduces pathogenic ZFTA-RELA levels and is potently therapeutic in multiple in vivo models. Mechanistically, ZFTA-RELA epigenetically suppresses PTEN expression to upregulate PI3K-mTOR signalling, a known driver of glutaminolysis. Finally, suppression of ACOD1 or a combination of glutamine antagonism with PI3K-mTOR inhibition abrogates spinal metastasis. Our data demonstrate that ZFTA-RELA+ ependymomas subvert a macrophage-like itaconate metabolic pathway to maintain expression of the ZFTA-RELA driver, which implicates itaconate as a candidate oncometabolite. Taken together, our results position itaconate upregulation as a previously unappreciated driver of ZFTA-RELA+ ependymomas. Our work has implications for future drug development to reduce pathogenic ZFTA-RELA expression for this brain tumour, and will advance our understanding of oncometabolites as a new class of therapeutic dependencies in cancers.
    DOI:  https://doi.org/10.1038/s41586-025-10005-1
  8. NPJ Metab Health Dis. 2026 Feb 02. 4(1): 6
    Hallmarks of nuclear metabolism: implications for genome integrity, nuclear signaling, and therapeutic targeting.
    Alisa Schmidt, Matilda Pfeiffer, Sara Sdelci.
      Certain metabolic enzymes localize to the nucleus, where they perform regulatory functions that extend far beyond canonical metabolism. Once inside, they influence chromatin organization, transcription, DNA repair, and cell cycle progression. This review summarizes recent advances that redefine metabolism as a nuclear process and reshape our understanding of metabolic regulation. It further defines the emerging hallmarks of nuclear metabolism and discusses how these insights open new avenues for cancer therapies.
    DOI:  https://doi.org/10.1038/s44324-025-00097-8
  9. Cell Metab. 2026 Feb 03. pii: S1550-4131(26)00002-1. [Epub ahead of print]38(2): 254-256
    Metastasis gets a little help from immune cell mitochondria.
    Michael V Berridge, Renata Zobalova, Jiri Neuzil.
      Although a role for mitochondrial transfer has been implicated in metastasis, the mechanisms are unclear. Using mouse metastatic models, Okwan-Duodu and colleagues1 report that mitochondrial transfer from non-cancer immune cells to cancer cells in the tumor facilitates lymph node metastasis via the cGAS/STING immune evasion pathway involving type I interferon.
    DOI:  https://doi.org/10.1016/j.cmet.2026.01.002
  10. Mol Metab. 2026 Feb 03. pii: S2212-8778(26)00009-8. [Epub ahead of print] 102325
    Dietary sulfur amino acid restriction improves glucose homeostasis through hepatic de novo serine synthesis.
    Andres F Ortega, Cha Mee Vang, Ferrol I Rome, Kaitlyn M Andreoni, Aiden M Phoebe, Alisa B Nelson, Peter A Crawford, James J Galligan, Stanley Ching-Cheng Huang, Curtis C Hughey.
      Dietary sulfur amino acid restriction (SAAR) improves whole-body glucose homeostasis, elevates liver insulin action, and lowers liver triglycerides. These adaptations are associated with an increased expression of hepatic de novo serine synthesis enzymes, phosphoglycerate dehydrogenase (PHGDH) and phosphoserine aminotransferase 1 (PSAT1). This study tested the hypothesis that enhanced hepatic serine synthesis is necessary for glucose and lipid adaptations to SAAR. Hepatocyte-specific PSAT1 knockout (KO) mice and wild type (WT) littermates were fed a high-fat control or SAAR diet. In WT mice, SAAR increased liver PSAT1 protein (∼70-fold), serine concentration (∼2-fold), and 13C-serine (∼20-fold) following an intravenous infusion of [U-13C]glucose. The elevated liver serine and partitioning of circulating glucose to liver serine by SAAR were attenuated in KO mice. This was accompanied by a blunted improvement in glucose tolerance in KO mice fed a SAAR diet. Interestingly, SAAR decreased liver lysine lactoylation, a SAA-supported post-translational modification known to inhibit PHGDH enzymatic activity. This suggests dietary SAAR may increase serine synthesis, in part, by lowering lysine lactoylation. Beyond glucose metabolism, dietary SAAR reduced body weight, adiposity, and liver triglycerides similarly in WT and KO mice. Collectively, these results demonstrate that hepatic PSAT1 is necessary for glucose, but not lipid, adaptations to SAAR.
    Keywords:  De novo serine synthesis; Glucose homeostasis; Liver intermediary metabolism; Sulfur amino acid restriction
    DOI:  https://doi.org/10.1016/j.molmet.2026.102325
  11. Nature. 2026 Feb 04.
    PtdIns(3,5)P2 is an endogenous ligand of STING in innate immune signalling.
    Jay Xiaojun Tan, Bo Lv, Jie Li, Tuo Li, Fenghe Du, Xiang Chen, Xuewu Zhang, Xiao-Chen Bai, Zhijian J Chen.
      Exposure to cytosolic DNA triggers innate immune responses through cyclic GMP-AMP (cGAMP) synthase (cGAS)1,2,3. After binding to DNA, cGAS produces cGAMP as a second messenger that binds to stimulator of interferon genes (STING), a signalling adaptor protein anchored to the endoplasmic reticulum (ER)3-5. STING then traffics from the ER through the Golgi to perinuclear vesicle clusters, which leads to activation of the kinases TBK1 and IKK and subsequent induction of interferons and other cytokines6-9. Here we show that phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2; also known as PI(3,5)P2) is an endogenous ligand of STING that functions together with cGAMP to induce STING activation. Proteomic analyses identified a constitutive interaction between STING and PIKFYVE, an enzyme that produces PtdIns(3,5)P2 in mammalian cells. Deletion of PIKFYVE blocked STING trafficking from the ER and TBK1 activation. In vitro reconstitution uncovered a strong and selective effect of PtdIns(3,5)P2 on STING activation by cGAMP. PtdIns(3,5)P2 bound directly to STING in fluorescence resonance energy transfer assays. Consistently, cryo-electron microscopy revealed that PtdIns(3,5)P2 promotes cGAMP-induced STING oligomerization10, functioning as a molecular glue. Similar to PIKFYVE depletion, mutation of the PtdIns(3,5)P2-binding residues in STING largely blocked its trafficking and downstream signalling. These findings reveal that PtdIns(3,5)P2 is a lipid ligand of STING with essential roles in innate immunity.
    DOI:  https://doi.org/10.1038/s41586-025-10084-0
  12. FEBS J. 2026 Feb 04.
    Proteostasis of organelles in aging and disease.
    Yara Nabawi, Cansu Doğan, Dunja Petrović, Gülce Perçin, Seda Koyuncu, David Vilchez.
      To maintain proteome integrity within distinct subcellular compartments, cells rely on tightly regulated proteostasis mechanisms, including protein synthesis, folding, trafficking, and degradation. Disruption of these processes leads to the accumulation of damaged proteins and structural changes that progressively compromise organelle function, contributing to aging and age-associated disorders, such as neurodegeneration, cancer, and metabolic dysfunction. Here, we discuss recent insights into how proteostasis influences the integrity and function of specific organelles, including the nucleus, mitochondria, endoplasmic reticulum, Golgi apparatus, and lysosomes, as well as membraneless organelles, such as stress granules, processing bodies, the nucleolus, and nuclear speckles. We further discuss how dysfunction in these systems contributes to different hallmarks of aging and disease progression, highlighting potential therapeutic strategies aimed at maintaining organelle homeostasis to promote healthy aging.
    Keywords:  aging; cellular stress responses; membraneless organelles; membrane‐bound organelles; neurodegenerative diseases; organelle dysfunction; protein aggregation; proteostasis; stress granules
    DOI:  https://doi.org/10.1111/febs.70439
  13. Cell Metab. 2026 Jan 29. pii: S1550-4131(26)00001-X. [Epub ahead of print]
    Dual targeting of SLC25A51 and succinate dehydrogenase selectively depletes mitochondrial NAD+ to eradicate KRAS-driven AML.
    Ang Jia, Xiaowen Zhang, Ji-Hao Zhou, Yongcan Ma, Jing Wang, Yongbo Gong, Wenjie Song, Hangcheng Hu, Yufei Yu, Haixia Yang, Youli Lu, Linzhang Huang, Xingrong Du, Chunmei Chang, Shanshan Pei, Peng Li, Craig T Jordan, Tong-Jin Zhao, Haobin Ye.
      Acute myeloid leukemia (AML) arises from diverse mutations, yet its most aggressive drivers remain elusive. Here, we show that Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations drive hyperproliferative and therapy-/glucose stress-resistant AML, whereas existing inhibitors lack sufficient cytotoxicity. Dual physiological/glucose-deprived screening identified compound 615 selectively eliminating KRAS-mutant cells through concurrently inhibiting succinate dehydrogenase (SDH) and the cytosol-to-mitochondrial NAD+ transporter SLC25A51. Mechanistically, KRAS-mutant cells exhibit reduced 2-oxoglutarate dehydrogenase complex-mediated SLC25A51 K264 succinylation, a mitochondrial NAD+-dependent modification promoting protein stability. This creates a synthetic lethal vulnerability: low-dose 615 triggers a cascade failure by acutely inhibiting SLC25A51, followed by its destabilization, causing complete transporter suppression. Together with concurrent SDH inhibition, this drives catastrophic mitochondrial NAD+ depletion. Conversely, KRAS-wild-type cells preserve NAD+ influx via sufficient baseline succinyl-SLC25A51, which stabilizes SLC25A51 and enables sufficient succinate accumulation to drive hypoxia inducible factor 1 subunit alpha (HIF1α)-mediated compensatory NAD+ production during treatment. Our work reveals a KRAS-specific metabolic vulnerability and proposes a dual-inhibition therapy for KRAS-driven AML.
    Keywords:  NAD(+); OGDH complex; SLC25A51; leukemia; metabolism
    DOI:  https://doi.org/10.1016/j.cmet.2026.01.001
  14. Nature. 2026 Feb 04.
    Activated ATF6α is a hepatic tumour driver restricting immunosurveillance.
    Xin Li, Cynthia Lebeaupin, Aikaterini Kadianaki, Clementine Druelle-Cedano, Niklas Vesper, Charlotte Rennert, Júlia Huguet-Pradell, Borja Gomez Ramos, Chaofan Fan, Robert Stefan Piecyk, Laimdota Zizmare, Pierluigi Ramadori, Luqing Li, Lukas Frick, Menjie Qiu, Cangang Zhang, Luiza Martins Nascentes Melo, Vikas Prakash Ranvir, Peng Shen, Johannes Hanselmann, Jan Kosla, Mirian Fernández-Vaquero, Mihael Vucur, Praveen Baskaran, Xuanwen Bao, Olivia I Coleman, Yingyue Tang, Miray Cetin, Zhouji Chen, Insook Jang, Stefania Del Prete, Mohammad Rahbari, Peng Zhang, Timothy V Pham, Yushan Hou, Aihua Sun, Li Gu, Laura C Kim, Ulrike Rothermel, Danijela Heide, Adnan Ali, Suchira Gallage, Nana Talvard-Balland, Marta Piqué-Gili, Albert Gris-Oliver, Alessio Bevilacqua, Lisa Schlicker, Alec Duffey, Kristian Unger, Marta Szydlowska, Jenny Hetzer, Duncan T Odom, Tim Machauer, Daniele Bucci, Pooja Sant, Jun-Hoe Lee, Jonas Rösler, Sven W Meckelmann, Johannes Schreck, Sue Murray, M Celeste Simon, Sven Nahnsen, Almut Schulze, Ping-Chih Ho, Manfred Jugold, Kai Breuhahn, Jan-Philipp Mallm, Peter Schirmacher, Susanne Roth, Nuh Rahbari, Darjus F Tschaharganeh, Stephanie Roessler, Benjamin Goeppert, Bertram Bengsch, Geoffroy Andrieux, Melanie Boerries, Nisar P Malek, Marco Prinz, Achim Weber, Robert Zeiser, Pablo Tamayo, Peter Bronsert, Konrad Kurowski, Robert Thimme, Detian Yuan, Rafael Carretero, Tom Luedde, Roser Pinyol, Felix J Hartmann, Michael Karin, Alpaslan Tasdogan, Christoph Trautwein, Moritz Mall, Maike Hofmann, Josep M Llovet, Dirk Haller, Randal J Kaufman, Mathias Heikenwälder.
      Hepatocellular carcinoma (HCC) is the fastest growing cause of cancer-related mortality and there are limited therapies1. Although endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) are implicated in HCC, the involvement of the UPR transducer ATF6α remains unclear2. Here we demonstrate the function of ATF6α as an ER-stress-inducing tumour driver and metabolic master regulator restricting cancer immunosurveillance for HCC, in contrast to its well-characterized role as an adaptive response to ER stress3. ATF6α activation in human HCC is significantly correlated with an aggressive tumour phenotype, characterized by reduced patient survival, enhanced tumour progression and local immunosuppression. Hepatocyte-specific ATF6α activation in mice induced progressive hepatitis with ER stress, immunosuppression and hepatocyte proliferation. Concomitantly, activated ATF6α increased glycolysis and directly repressed the gluconeogenic enzyme FBP1 by binding to gene regulatory elements. Restoring FBP1 expression limited ATF6α-activation-related pathologies. Prolonged ATF6α activation in hepatocytes triggered hepatocarcinogenesis, intratumoural T cell infiltration and nutrient-deprived immune exhaustion. Immune checkpoint blockade (ICB)4 restored immunosurveillance and reduced HCC. Consistently, patients with HCC who achieved a complete response to immunotherapy displayed significantly increased ATF6α activation compared with those with a weaker response. Targeting Atf6 through germline ablation, hepatocyte-specific ablation or therapeutic hepatocyte delivery of antisense oligonucleotides dampened HCC in preclinical liver cancer models. Thus, prolonged ATF6α activation drives ER stress, leading to glycolysis-dependent immunosuppression in liver cancer and sensitizing to ICB. Our findings suggest that persistently activated ATF6α is a tumour driver, a potential stratification marker for ICB response and a therapeutic target for HCC.
    DOI:  https://doi.org/10.1038/s41586-025-10036-8
  15. Nature. 2026 Feb 04.
    Tumour-brain crosstalk restrains cancer immunity via a sensory-sympathetic axis.
    Haohan K Wei, Chuyue D Yu, Bo Hu, Xing Zeng, Hiroshi Ichise, Liang Li, Yu Wang, Ruiqi L Wang, Ronald N Germain, Rui B Chang, Chengcheng Jin.
      Body-brain communication has emerged as a key regulator of tissue homeostasis1-5. Solid tumours are innervated by different branches of the peripheral nervous system and increased tumour innervation is associated with poor cancer outcomes6-8. However, it remains unclear how the brain senses and responds to tumours in peripheral organs, and how tumour-brain communication influences cancer immunity. Here we identify a tumour-brain axis that promotes oncogenesis by establishing an immune-suppressive tumour microenvironment. Combining genetically engineered mouse models with neural tracing, tissue imaging and single-cell transcriptomics, we demonstrate that lung adenocarcinoma induces innervation and functional engagement of vagal sensory neurons, a major interoceptive system connecting visceral organs to the brain. Mechanistically, Npy2r-expressing vagal sensory nerves transmit signals from lung tumours to brainstem nuclei, driving elevated sympathetic efferent activity in the tumour microenvironment. This, in turn, suppresses anti-tumour immunity via β2 adrenergic signalling in alveolar macrophages. Disruption of this sensory-to-sympathetic pathway through genetic, pharmacological or chemogenetic approaches significantly inhibited lung tumour growth by enhancing immune responses against cancer. Collectively, these results reveal a bidirectional tumour-brain communication involving vagal sensory input and sympathetic output that cooperatively regulate anti-cancer immunity; targeting this tumour-brain circuit may provide new treatments for visceral organ cancers.
    DOI:  https://doi.org/10.1038/s41586-025-10028-8
  16. Neurooncol Adv. 2026 Jan-Dec;8(1):8(1): vdaf223
    Metabolomic profiling and stable isotope tracing of human schwannomas: A novel perspective on tumor biology and radiation response.
    Mark C Dougherty, Hashim S Syed, Linjing Xu, S John Liu, David R Raleigh, Adam J Rauckhorst, Eric B Taylor, Marlan R Hansen.
       Background: Although schwannomas are common and benign, their growth patterns are often hard to predict. Currently, surgery and radiotherapy are the only standard treatments. Since metabolites are the end products of genes and proteins, metabolomics may reveal downstream tumor features in ways that other -omics cannot. Here, we use metabolomic profiling and stable isotope tracing to characterize primary human schwannomas and describe their changes following radiation in patient-derived xenografts.
    Methods: Schwannomas collected during surgical resection underwent metabolomic profiling with gas chromatography-mass spectrometry and liquid chromatography-mass spectrometry (N = 44) as well as DNA methylation profiling (N = 29). Large tumors were also implanted subcutaneously in athymic mice as patient-derived xenografts. Mice were randomized to radiation treatment or control 4-6 weeks post-implantation. Xenografts were harvested 72 h after radiation for metabolomic profiling (N = 53). Another group of xenografts (N = 33) was injected with U-13C-glutamine prior to tumor harvest for stable isotope tracing.
    Results: The schwannoma metabolome differs from that of Schwann cells, and metabolomics-based clustering of schwannomas resembles DNA methylation-based classification. In xenografts, radiation decreases cellular proliferation and produces small but detectable changes to the tricarboxylic acid (TCA) cycle and nucleotide metabolism. 13C-glutamine tracing shows that schwannomas can produce urea cycle intermediates, TCA cycle intermediates, cytosine monophosphate (CMP), and cytosine triphosphate from glutamine even after radiation. CMP was the only metabolite with altered 13C uptake following radiation.
    Conclusions: Schwannomas have distinct metabolic signatures compared to the Schwann cells from which they originate. Schwannoma xenograft metabolism is surprisingly robust to radiotherapy, and xenografts readily incorporate glutamine into the TCA cycle, urea cycle, and pyrimidine synthesis.
    Keywords:  NF2; metabolomics; radiation; schwannoma
    DOI:  https://doi.org/10.1093/noajnl/vdaf223
  17. Nat Metab. 2026 Feb 03.
    Mitochondrial superoxide regulates nuclear envelope integrity and ageing via redox-mediated lipid metabolism.
    Peng X Chen, Leyuan Zhang, Xueying Wu, Zhiqiang Liang, Xusheng Hao, Qingyuan Zhu, Ying Liu, Jinrou Zheng, Qian Zhang, Qinmeng Yang, Fan Zhou, Chunbao Zhou, Ye Tian.
      The nuclear envelope (NE) is essential for cellular homeostasis, yet its integrity declines with age, accelerating functional deterioration. Here we report a mitochondria-to-NE signalling pathway that safeguards NE integrity through redox-dependent lipid metabolism. In Caenorhabditis elegans, reducing mitochondrial ETC activity preserves NE morphology during ageing. This effect requires developmental mitochondrial superoxide, which downregulates SBP-1 (SREBP orthologue) and suppresses unsaturated fatty acid biosynthesis. The resulting reduction in unsaturated fatty acid levels limits lipid peroxidation, thereby preserving NE structure. Interventions targeting lipid peroxidation preserve NE integrity, extend lifespan in worms and ameliorate senescence-associated phenotypes in human fibroblasts and monkey cells mimicking Hutchinson-Gilford progeria syndrome disease. Our findings reveal a previously unrecognized role for mitochondrial superoxide as a protective developmental signal that programs long-term NE integrity. This work establishes lipid peroxidation control as a conserved strategy to delay nuclear ageing and highlights redox-lipid cross-talk as a therapeutic axis for healthy ageing.
    DOI:  https://doi.org/10.1038/s42255-026-01452-9
  18. bioRxiv. 2026 Jan 17. pii: 2026.01.16.699967. [Epub ahead of print]
    Distinct sensing of BCAAs by mTOR and c-Myc governs T cell proliferation, independent of catabolism.
    Kelly Rome, Elise Hall, Aaron Wu, Will Bailis.
      The branched chain amino acids (BCAAs: leucine, isoleucine, valine) are essential amino acids that function as catabolic substrates and signaling molecules via mTORC1. While individual BCAAs have unique roles in organismal and cellular physiology, the mechanisms underlying their individual effects remain poorly understood. We demonstrate that the three BCAAs have distinct roles in T cell biology. We find that isoleucine and valine are necessary and sufficient for quiescence exit and cell division, whereas leucine is dispensable. Mechanistically, these effects are independent of their diverging catabolic fates and instead due to differential sensing of leucine and isoleucine/valine by mTOR and c-Myc. While isoleucine and valine are necessary and sufficient for c-Myc expression, mTORC1 leucine-sensing represses c-Myc and proliferation during BCAA restriction. Together, we find that the discrete sensing of the BCAAs uncouples two major anabolic regulators, mTORC1 and c-Myc, in cell growth. This provides mechanistic insight into the distinct roles of the BCAAs in cell physiology, highlighting divergent BCAA sensing rather than catabolism, and offering a new lens to appreciate their impact on immunity and pathophysiology.
    DOI:  https://doi.org/10.64898/2026.01.16.699967
  19. bioRxiv. 2026 Jan 15. pii: 2026.01.14.699605. [Epub ahead of print]
    Ribosome-associated quality control of aberrant protein production during amino acid limitation.
    Alicia M Darnell, Christopher Chidley, Victoria Paradise, Danica S Cui, Kristian Davidsen, Sarah C Lincoln, Keene L Abbott, Ryan Elbashir, Campbell P Vander Heiden, Peter K Sorger, Lucas B Sullivan, Joseph H Davis, Matthew G Vander Heiden.
      Amino acids can become limiting for protein synthesis through depletion of charged tRNAs, leading to ribosome stalling and disruption of translation elongation at specific codons. To assess whether this is a mechanism by which amino acid availability can directly influence gene expression, we designed a reporter library to measure translation disruption across all sense codons in the context of amino acid limitations. We found that arginine limitation consistently impairs translation at the arginine codon AGA, resulting in synthesis of proteins from endogenous transcripts. In contrast, GCN2 pathway activation suppresses translation disruption following depletion of most other amino acids. Genome-wide screens revealed that the ribosome quality control trigger (RQC-T) and RQC pathways, which resolve ribosome collisions on defective mRNAs, catalyze ribosome splitting and premature fall-off in response to arginine depletion. Additionally, the E3 ubiquitin ligase RNF14, recently shown to clear ribosome A-site obstructions, promotes translation disruption through both ribosome fall-off and frameshifting during arginine limitation. Together, these data show that the RQC machinery is engaged by tRNA-limited ribosomes and identify a new role for RNF14 as a regulator of translation upon arginine limitation.
    DOI:  https://doi.org/10.64898/2026.01.14.699605
  20. Nat Cell Biol. 2026 Jan 30.
    A p53-controlled lysosomal recycling circuit fuels phospholipid synthesis.
      
    DOI:  https://doi.org/10.1038/s41556-025-01868-7
  21. Nature. 2026 Feb 04.
    Regulation of STING activation by phosphoinositide and cholesterol.
    Jie Li, Jay Xiaojun Tan, Zhijian J Chen, Xuewu Zhang, Xiao-Chen Bai.
      Stimulator of interferon genes (STING) is an essential adaptor in the cytosolic DNA-sensing innate immune pathway1. STING is activated by cyclic GMP-AMP (cGAMP) produced by the DNA sensor cGAMP synthase (cGAS)2-5. cGAMP-induced high-order oligomerization and translocation of STING from the endoplasmic reticulum to the Golgi and post-Golgi vesicles are critical for STING activation6-11. Other studies have shown that phosphatidylinositol phosphates (PtdInsPs) and cholesterol also have important roles in STING activation, but the underlying mechanisms remain unclear12-17. Here we demonstrate that cGAMP-induced high-order oligomerization of STING is enhanced strongly by phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2 and PtdIns(4,5)P2, and by PtdIns4P to a lesser extent. Our cryo-electron microscopy structures reveal that PtdInsPs together with cholesterol bind at the interface between STING dimers, directly promoting the high-order oligomerization. The structures also provide an explanation for the preference of the STING oligomer to different PtdInsPs. Mutational and biochemical analyses confirm the binding modes of PtdInsPs and cholesterol and their roles in STING activation. Our findings shed light on the regulatory mechanisms of STING mediated by specific lipids, which may underlie the role of intracellular trafficking in dictating STING signalling.
    DOI:  https://doi.org/10.1038/s41586-025-10076-0
  22. Aging Cell. 2026 Feb;25(2): e70405
    Lifespan and Fecundity Impacts of Reduced Insulin Signalling Can Be Directed by Mito-Nuclear Epistasis in Drosophila.
    Rita Ibrahim, Christin Froschauer, Susanne Broschk, David R Sannino, Adam J Dobson.
      The changing demography of human populations has motivated a search for interventions that promote healthy ageing, and especially for evolutionarily-conserved mechanisms that can be studied in lab systems to generate hypotheses about function in humans. Reduced Insulin/IGF signalling (IIS) is a leading example, which can extend healthy lifespan in a range of animals, but whether benefits and costs of reduced IIS vary genetically within species is under-studied. This information is critical for any putative translation. Here, in Drosophila, we test for genetic variation in lifespan response to a dominant-negative form of the insulin receptor, along with a metric of fecundity to evaluate corollary fitness costs/benefits. We also partition genetic variation between DNA variants in the nucleus (nDNA) and mitochondrial DNA (mtDNA), in a fully-factorial design that allows us to assess 'mito-nuclear' epistasis. We show that reduced IIS can have either beneficial or detrimental effects on lifespan, depending on the combination of mtDNA and nDNA. This suggests that, while insulin signalling has a conserved effect on ageing among species, intraspecific effects can vary genetically, and the combination of mtDNA and nDNA can act as a gatekeeper.
    DOI:  https://doi.org/10.1111/acel.70405
  23. Nat Metab. 2026 Jan 30.
    Glucose deprivation drives LIF-dependent lung cancer.
    Fedra Luciano-Mateo, Joaquim Moreno-Caceres, Miguel Hernández-Madrigal, Franziska Püschel, Lidia Collado-Rodriguez, Francesca Favaro, Sara Hijazo-Pechero, Mabel Cruz-Rodríguez, Felipe Jiménez-Hernández, Verónica Villagrasa-Araya, Nil Figueras-Duch, Jaime Redondo-Pedraza, Didac Palau-Gallinat, Silvia Plans-Marin, Agnés Figueras, Pedro Fuentes Varela, Lidia de Benito-Gómez, Antonio Gentilella, José Carlos Perales, Xavier Solé, Andrés Méndez-Lucas, Francesc Viñals, Ernest Nadal, Cristina Muñoz-Pinedo.
      Glucose deficiency promotes the secretion of cytokines and inflammatory factors to rewire the immune compartment and restore blood flow. Here we show that cancer cells subjected to glucose deprivation or hypoxia, but not to other metabolic stressors, secrete LIF, an interleukin-6 family cytokine implicated in the development of solid tumours. We find that mannose supplementation prevents LIF release by sustaining multiple metabolic pathways in the absence of glucose. Mechanistically, LIF release is associated with impairment of N-glycosylation and activation of PERK and MEK MAP kinases. In mouse models of non-small-cell lung cancer, reduction of LIF impairs angiogenesis and tumour growth, rewires the immune system toward an antitumour phenotype and inhibits tumour implantation in the lung. In individuals with non-small-cell lung cancer, LIF levels correlate with markers of hypoxia, glucose deprivation and angiogenesis. Overall, these findings identify LIF as a metabolic stress-induced cytokine that could be targeted to disrupt adaptive responses in cancer.
    DOI:  https://doi.org/10.1038/s42255-025-01437-0
  24. Brain. 2026 Feb 02. pii: awag037. [Epub ahead of print]
    Mitochondrial DNA release and inflammation in mitochondrial disease pathogenesis.
    Marton Szabo, Daniel Lagos, Emily Cross, Jack Collier, Rita Horvath.
      Primary mitochondrial diseases (PMDs) affect ∼1 in 4,300 individuals, yet mitochondrial dysfunction is also a hallmark of common inherited and acquired disorders. While advances in genomics now allow molecular diagnosis in 30-60% of mitochondrial diseases, treatment remains largely supportive, leading to progressive disability and early mortality. Despite progress in gene-modifying approaches, no approved therapies exist for the majority of mitochondrial diseases, and none of the recent trials have met their primary endpoints, underlining the urgent need for innovative therapeutic strategies. Patients with PMDs have very variable phenotypes, further complicated by increased susceptibility to infections, chronic inflammation and metabolic abnormalities. Recently, it has become evident that certain mitochondrial pathologies, including the loss of mitochondrial membrane integrity, impaired mtDNA maintenance, quality control defects, or respiratory chain defects, result in the release of mtDNA into the cytosol. Infections or metabolic changes also trigger the release of mtDNA, leading to the activation of a sterile innate immune response and interferon signalling. Free mtDNA acts as a pathogen-associated molecular pattern (PAMP), activating innate immune pathways such as the cGAS-STING axis, initiating a sterile inflammatory response. This can be followed by the extracellular release of mtDNA to convey the inflammatory response systemically to communicate between cells or across organs. However, it is unclear whether these pathways worsen the disease phenotype (hyperinflammatory reaction) or, in contrast, rescue the symptoms due to upregulation of compensatory pathways. In this review, we summarise recent advances in understanding the mechanism of mtDNA release and how it activates innate immune signalling in PMDs. We also discuss the implications for pathogenesis, clinical phenotypes, and therapeutic development. Defining the role of circulating mitochondrial material as a biomarker or therapeutic target is a critical step for precision medicine approaches in PMDs. These pathways may also have wider implications for common metabolic, inflammatory, and neurodegenerative disorders with mitochondrial dysfunction.
    Keywords:  mitochondria derived vesicles (MDVs); mtDNA; mtDNA release, primary mitochondrial diseases (PMD); pathogen-associated molecular patterns (PAMPs); sterile-inflammation
    DOI:  https://doi.org/10.1093/brain/awag037
  25. Curr Biol. 2026 Feb 03. pii: S0960-9822(26)00006-0. [Epub ahead of print]
    The mitochondrial intermembrane space nuclease Nuc1 (endonuclease G) prevents mitophagy-mediated mtDNA escape in yeast.
    Ryan R Cupo, Eunice Domínguez-Martín, Richard Youle.
      Mitochondria contain a genome (mtDNA) encoding a handful of proteins essential for cellular respiration. mtDNA can leak into the cytosol and drive fitness defects. The first genes associated with mtDNA escape were discovered in yeast and aptly named "yeast mitochondrial escape" (YME) genes. We identify the mechanism by which an intermembrane space nuclease, endonuclease G (human ENDOG; yeast Nuc1), prevents mtDNA escape to the cytosol in yeast. Nuc1 nuclease activity and mitochondrial localization are essential for preventing mtDNA escape and suggest a direct role of Nuc1 in degrading mtDNA bound for escape. We find that blocking autophagy via atg1 and atg8 mutants prevents mtDNA escape in the absence of Nuc1. We further demonstrate that blocking mitophagy via atg11 and atg32 mutants prevents mtDNA escape, whereas inducing mitophagy increases mtDNA escape in the absence of Nuc1. Finally, we demonstrate that Nuc1 degrades mtDNA bound for escape via the vacuole, as an atg15 mutant that prevents disassembly of autophagic bodies in the vacuole also prevents mtDNA escape. Overall, our results implicate vacuolar entry of mitochondria during mitophagy as an important mtDNA escape pathway in yeast, which is normally mitigated via the degradation of mtDNA by Nuc1.
    Keywords:  Atg1; Atg32; Drp1; NUMT; STING; autophagy; fission; lysosome; nucleoid; vacuole
    DOI:  https://doi.org/10.1016/j.cub.2026.01.006
  26. Amino Acids. 2026 Jan 31. 58(1): 7
    Polyamine metabolism as a regulator of cellular and organismal aging.
    Takeshi Uemura, Jun Takayama, Akihiro Oguro, Yusuke Terui.
      Polyamines - putrescine, spermidine, and spermine - are ubiquitous cationic molecules that are essential for cellular proliferation and homeostasis. Their intracellular concentrations decline with age, contributing to physiological and cognitive deterioration. Recent studies have revealed that spermidine supplementation extends lifespan and improves cognitive and cardiac function in various model organisms, suggesting that maintaining polyamine balance has anti-aging potential. Polyamine metabolism is tightly regulated through biosynthesis, degradation, and transport; however, age-associated upregulation of spermine oxidase (SMOX) and accumulation of its toxic byproduct acrolein promote oxidative damage and cellular senescence. Suppressing SMOX activity or polyamine degradation attenuates senescence markers and DNA damage, highlighting spermine catabolism as a therapeutic target. Polyamines also modulate epigenetic regulation, including DNA methylation and histone acetylation, thereby influencing gene expression and chromatin structure during aging. Moreover, polyamine-dependent hypusination of eIF5A sustains protein synthesis in senescent cells. These multifaceted actions indicate that polyamine metabolism integrates redox control, translational regulation, epigenetic maintenance and autophagy to determine cellular and organismal longevity. While animal studies demonstrate clear anti-aging effects of spermidine and spermine, human clinical evidence remains limited, with variable outcomes likely due to bioavailability and metabolic conversion. Future strategies combining dietary or probiotic polyamine enhancement, enzyme-targeted inhibitors, and personalized metabolic interventions hold promise for extending healthspan. Collectively, maintaining optimal polyamine homeostasis emerges as a key approach to counteract aging and age-related diseases.
    Keywords:  Aging; Autophagy; Epigenetic regulation; Polyamine metabolism; Senescence; Spermine oxidase; Translational regulation
    DOI:  https://doi.org/10.1007/s00726-026-03497-2
  27. bioRxiv. 2026 Jan 22. pii: 2026.01.19.699752. [Epub ahead of print]
    Dying oligodendrocytes persist without mitochondria.
    Xhoela Bame, S Zoela Gilani, Yasmine Kamen, Robert A Hill.
      Myelin is an insulating, multi-layered membrane that supports axonal integrity and neural communication. Different stressors impair myelinating oligodendrocytes, leading to demyelination, inflammation, and neurodegeneration. The intracellular processes underlying oligodendrocyte degeneration and death are unclear. Here, using optically targeted DNA damage that causes single-cell demyelination, we reveal that injured mature oligodendrocytes lose mitochondria within days and persist without them for weeks to months before cell death. This differs from other oligodendrocyte lineage cells, which exhibit acute mitochondrial changes followed by rapid cell death. Conditional deletion of the mitochondrial-related gene, Fis1 , in mature oligodendrocytes, similarly causes acute loss of mitochondria and prolonged cell death. The unique cell death is characterized by nuclear changes, intracellular stress, and markers of disease-associated oligodendrocytes. Thus, mitochondrial loss may be an early marker of oligodendrocyte pathology, and mitochondrial quality control is required for oligodendrocyte and myelin homeostasis.
    DOI:  https://doi.org/10.64898/2026.01.19.699752
  28. Nat Commun. 2026 Feb 04.
    Cytoplasmic NAD/H synthesis via NRK1 regulates inflammatory capacity and promotes survival of CD4+ T cells.
    Victoria Stavrou, Myah Ali, Nancy Gudgeon, Emma L Bishop, Taylor Fulton-Ward, Bethany Turley, Silke Heising, Sally H Mohamed, Sofia Hain, Lorna George, Minghao Deng, Jack McCowan, Lozan Sheriff, Scott P Davies, Bryan Marzullo, Daniel A Tennant, Craig L Doig, David A Bending, Ed W Roberts, Gareth G Lavery, Rebecca A Drummond, Sarah Dimeloe.
      T cell metabolism increases upon activation, underpinning immune effector functions. Nicotinamide adenine dinucleotide (NAD/H) is an essential redox cofactor for glycolysis and mitochondrial substrate oxidation. It's phosphorylation to NADP/H regulates reactive oxygen species (ROS) abundance. NAD/H levels increase upon T cell activation, but synthesis pathways and implications are not fully characterised. Here, we interrogate the role of the NAD/H-synthesis enzyme nicotinamide riboside kinase 1 (NRK1), the expression of which increases upon stimulation of both human and murine CD4+ T cells. Functionally, NRK1 activity restrains activation and cytokine production of CD4+ T cells while promoting survival. These activities are linked to increased NRK1 expression in the cytoplasm, where it locally raises NAD/H levels. This supports glycolysis, but more profoundly impacts cytoplasmic NADP/H generation, thereby controlling ROS abundance and nuclear NFAT translocation. During fungal and viral infection, T-cell-intrinsic NRK1 maintains effector CD4+ T cell abundance within affected tissues and draining lymph nodes, supporting infection control. Taken together, these data confirm that subcellular regulation of immune cell metabolism determines immune responses at the level of whole organism.
    DOI:  https://doi.org/10.1038/s41467-026-68863-w
  29. bioRxiv. 2026 Jan 17. pii: 2026.01.16.699897. [Epub ahead of print]
    A Recombinant Antibody Against Human DRP1 Serine 616 Phosphorylation Enables Detection of BRAF V600E -Associated Mitochondrial Division in Cancer.
    Shanon T Nizard, Yiyang Chen, Madhavika N Serasinghe, Ruben Fernandez-Rodriguez, Kamrin D Shultz, Jesminara Khatun, Anthony Mendoza, Juan F Henao-Martinez, Jesse D Gelles, Stella G Bayiokos, J Andrew Duty, Shane Meehan, Mihaela Skobe, Jerry Edward Chipuk.
      Mitochondria are dynamic organelles that continuously undergo balanced cycles of fusion and division to meet cellular demands. Mitochondrial division is mediated by Dynamin-Related Protein 1 (DRP1), a cytosolic large GTPase whose phosphorylation at serine 616 (DRP1-S616Ⓟ) promotes its translocation to the outer mitochondrial membrane and organelle division. Dysregulated, mitochondrial division disrupts cellular homeostasis and contributes to disease pathogenesis, including cancer. Our prior work demonstrated that the oncogene-induced mitogen-activated protein kinase (MAPK) pathway constitutively phosphorylates DRP1 at serine 616 (DRP1-S616Ⓟ), which is essential to cellular transformation and correlates with oncogene status in patient tissues. Similarly, DRP1-S616Ⓟ is subject to pharmacologic control by targeted therapies against oncogenic MAPK signaling. Building upon this foundation, we developed a human recombinant monoclonal antibody with high specificity for DRP1-S616Ⓟ, referred to as 3G11. Using diverse biochemical platforms, we demonstrate the robust utility of 3G11 to detect DRP1-S616Ⓟ in melanoma cell extracts and isolated organelles. Immunofluorescence revealed that pharmacologic inhibition of oncogenic MAPK signaling reduces DRP1-S616Ⓟ levels which correlates with mitochondrial hyperfusion; while immunohistochemistry showed that elevated DRP1-S616Ⓟ expression in human tissues correlates with BRAF V600E disease. Together, these findings establish 3G11 as a specific, versatile, renewable, and cost-effective tool for studying mitochondrial division, with strong potential for clinical applications.
    DOI:  https://doi.org/10.64898/2026.01.16.699897
  30. bioRxiv. 2026 Jan 22. pii: 2026.01.19.700325. [Epub ahead of print]
    BCLAF1 links RNA splicing to ATF4-dependent metabolic adaptation in acute myeloid leukemia.
    Laura López-Hernández, Stephanie J Crowley, Sara Cea-Sánchez, Ricardo de Arellano, Neetij Krishnan, Patrick Toolan-Kerr, Lynn White, Domenico Ignoti, Emily Soto-Hidalgo, Stefano Gustincich, Román González-Prieto, Luca Pandolfini, Isaia Barbieri, Patricia Altea-Manzano, Jeffrey A Magee, Jeffrey J Bednarski, Gonzalo Millán-Zambrano.
      Acute myeloid leukemia (AML) is driven by a combination of genetic alterations and non-mutational mechanisms that disrupt normal hematopoiesis and support leukemic cell survival. While the mutational landscape of AML is well characterized, the non-genetic processes that sustain leukemic maintenance remain comparatively less understood. Using human AML cell lines and murine models of AML, we identify BCL2-associated transcription factor 1 (BCLAF1) as a key regulator of leukemic progression through control of mRNA processing. BCLAF1 physically associates with core spliceosome components and regulates alternative splicing, with a predominant effect on intron retention. We demonstrate that BCLAF1 is required for the productive splicing of activating transcription factor 4 (ATF4) mRNA, thereby sustaining ATF4 protein expression. Loss of BCLAF1 reduces ATF4 protein levels, leading to downregulation of metabolic target genes and disruption of de novo amino acid biosynthesis. Furthermore, depletion of BCLAF1 sensitizes AML cells to venetoclax, a clinically relevant BCL-2 inhibitor. Together, these findings uncover a previously unrecognized role for BCLAF1 in coordinating mRNA splicing and metabolic adaptation in AML, highlighting its potential as a therapeutic target.
    Statement of significance: Aberrant RNA splicing and metabolic reprogramming are hallmarks of cancer, yet how these processes are mechanistically linked remains unclear. This study identifies BCLAF1 as a key regulator connecting splicing control to amino acid metabolism in acute myeloid leukemia, revealing a previously unrecognized functional vulnerability at the intersection of these pathways.
    DOI:  https://doi.org/10.64898/2026.01.19.700325
  31. bioRxiv. 2026 Jan 12. pii: 2026.01.12.699091. [Epub ahead of print]
    Rhythmic Nuclear Import Mediated by Importins Regulates the Neurospora Circadian Clock.
    Ziyan Wang, Bin Wang, Bradley M Bartholomai, Jennifer J Loros, Jay C Dunlap.
      Circadian clocks in eukaryotes rely on precisely regulated negative feedback loops to generate daily rhythms. However, the delay mechanisms that extend this structurally simple feedback loop to ∼24 hours are not yet fully understood. In the filamentous fungal model organism Neurospora crassa , the negative arm complex, centered by FREQUENCY (FRQ), must enter the nucleus to repress the White Collar Complex (WCC) and close the feedback loop, but the mechanisms and dynamics of its nuclear transport have remained unresolved. Using long-term live-cell imaging and fluorescence recovery after photobleaching (FRAP), we demonstrate that FRQ nuclear import is an active circadian-regulated process that is fastest early in the subjective day and progressively decreases as nuclear FRQ approaches peak levels, corresponding to altered direct binding between FRQ and Importin α. We further establish that Importin α is required for the spatial regulation of FRQ and WC-1 and the correct timing of Neurospora circadian clock. Analysis of the three Neurospora Importin β homologs reveals that each of them contributes differently to the circadian clock through pathways beyond FRQ or WCC nuclear import. More specifically, we find a genetic interaction between Impβ3 and the phosphatase PP-4. Together, these findings indicate that nuclear import is a selective, dynamic, and rate-limiting regulatory step in the fungal circadian clock and reveal both conserved and fungal-specific mechanisms by which importins tune circadian timing.
    DOI:  https://doi.org/10.64898/2026.01.12.699091
  32. J Clin Invest. 2026 Feb 02. pii: e195725. [Epub ahead of print]136(3):
    Cell-free DNA epigenomic profiling enables noninvasive detection and monitoring of translocation renal cell carcinoma.
    Simon Garinet, Karl Semaan, Jiao Li, Ze Zhang, Prathyusha Konda, Ananthan Sadagopan, John Canniff, Noa Phillips, Kelly Klega, Medha Pandey, Hunter Savignano, Matthew P Davidsohn, Kevin Lyons, Alessandro Medda, Prateek Khanna, Mingkee Achom, Brad J Fortunato, Rashad Nawfal, Razane El Hajj Chehade, Jillian O'Toole, Jack Horst, Dory Freeman, Rachel Trowbridge, Cindy H Chau, William D Figg, Jacob E Berchuck, Brian D Crompton, Ji-Heui Seo, Toni K Choueiri, Matthew L Freedman, Sylvan C Baca, Srinivas R Viswanathan.
      TFE3 translocation renal cell carcinoma (tRCC), an aggressive kidney cancer driven by TFE3 gene fusions, is frequently misdiagnosed owing to morphologic overlap with other kidney cancer subtypes. Conventional liquid biopsy assays that detect tumor DNA via somatic mutations or copy number alterations are unsuitable for tRCC since it often lacks recurrent genetic alterations and because fusion breakpoints are highly variable between patients. We reasoned that epigenomic profiling could more effectively detect tRCC because the driver fusion constitutes an oncogenic transcription factor that alters gene regulation. By defining a TFE3-driven epigenomic signature in tRCC cell lines and detecting it in patient plasma using ChIP-seq, we distinguished tRCC from clear-cell RCC (AUC = 0.86) and samples of individuals without evidence of cancer (AUC = 0.92) at low tumor fractions (<1%). This work establishes a framework for noninvasive epigenomic detection, diagnosis, and monitoring of tRCC, with implications for other mutationally quiet, fusion-driven cancers.
    Keywords:  Biomarkers; Cancer; Clinical Research; Molecular diagnosis; Oncology
    DOI:  https://doi.org/10.1172/JCI195725
  33. bioRxiv. 2026 Jan 17. pii: 2026.01.16.699963. [Epub ahead of print]
    Glucose availability tunes latent CD8+ T cell expansion potential through a mitogen-independent, mTOR-dependent regulatory switch.
    Tran Ngoc Van Le, Krittin Trihemasava, Lucien Turner, Kelly Rome, Aaron Wu, Will Bailis.
      Mitogenic signals are understood to license cell cycle progression and the metabolic reprogramming required for cell division, with acquired nutrients serving as permissive substrates. Here, we show that nutrient availability instead functions as a mitogen-independent regulatory input that dynamically controls CD8+ T cell proliferative potential. Activating stimuli have been shown to set T cell expansion capacity through their control of c-Myc expression, with the rate of c-Myc decay functioning as a division timer. We demonstrate that nutrient availability is sufficient to control c-Myc expression dynamics and dictates how division potential is stored and later actualized. Glucose-restricted T cells sustain proliferative potential and exhibit high AKT and ERK phosphorylation, despite limited growth. Upon glucose restoration, these cells rapidly increase c-Myc expression, accelerate through the cell cycle, and return to the expansion potential of glucose-replete controls, even after days of enforced restriction. Glucose restriction thus maintains a latent metabolic and mitogenic signaling state that is rapidly realized upon recovery. Mechanistically, mTOR signaling is required for this glucose recovery-driven proliferation, despite c-Myc and pERK remaining elevated following mTOR inhibition, indicating that glucose and mitogen signals operate through parallel rather than hierarchical control points. Altogether, these findings reveal that nutrient availability is not merely rate-limiting for proliferation but dictates the kinetics at which mitogenic signals are dissipated and realized. While mitogenic and nutrient cues converge on a shared anabolic network, they operate through distinct regulatory arms to coordinate the tempo and magnitude of clonal expansion, with implications for protective immunity and immunotherapy.
    Significance Statement: CD8+ T cells rapidly proliferate to fight infections and cancer, often in variable nutrient environments. Activation signals are understood to control T cell expansion potential by setting c-Myc expression and its subsequent decay, with nutrients providing fuel. Here we find that glucose availability functions as an independent regulatory switch. Glucose-restricted T cells remain proliferatively poised for days, keeping pro-growth signaling and metabolic capacity primed. Upon glucose restoration, cells undergo a proliferative burst and catch up to glucose-replete counterparts. Although c-Myc expression rises upon glucose restoration, accelerated division kinetics instead require mTOR activity. These findings reveal that nutrient availability operates in parallel with mitogenic signaling, tuning the rate at which T cells store and realize their expansion potential.
    DOI:  https://doi.org/10.64898/2026.01.16.699963
  34. Nat Commun. 2026 Feb 06.
    Zebrafish macrophages convert physical wound signals into rapid vascular permeabilization.
    Zaza Gelashvili, Zhouyang Shen, Yanan Ma, Mark Jelcic, Philipp Niethammer.
      Blood vessels near injury sites rapidly dilate, become permeable, and release serum and leukocytes into the wounded tissue to support healing and regeneration. How the vasculature senses distant homeostatic tissue perturbations within seconds-to-minutes remains incompletely understood. Using high-speed imaging of live zebrafish larvae, we monitor two hallmark vascular responses to injury: vessel dilation and serum exudation. By genetic, pharmacologic, and osmotic perturbation along with leukocyte depletion, we show that the cPla2 nuclear membrane mechanotransduction pathway converts a ~ 50 μm/s osmotic wound signal into rapid vessel-permeabilization via perivascular macrophages, 5-lipoxygenase (Alox5a), and leukotriene A4 hydrolase (Lta4h). By revealing a previously undescribed physiological function of nuclear membrane mechanotransduction, we provide real-time insights into the long-range communication of wounds and blood vessels in intact tissue.
    DOI:  https://doi.org/10.1038/s41467-026-68520-2
  35. Nat Aging. 2026 Feb 03.
    Aging clocks delineate neuron types vulnerable or resilient to neurodegeneration and identify neuroprotective interventions.
    Christian Gallrein, David H Meyer, Yvonne Woitzat, Valeria Ramirez-Ramirez, Thanh Vuong-Brender, Janine Kirstein, Björn Schumacher.
      Different neuron types show distinct susceptibility to age-dependent degeneration, yet the underlying mechanisms are poorly understood. Here we applied aging clocks to single neuron types in Caenorhabditis elegans and found that distinct neurons differ in their biological age. Ciliated sensory neurons with high neuropeptide and protein biosynthesis gene expression show accelerated aging and degeneration, correlating with loss of function, which could be prevented by pharmacological inhibition of translation. We show that the C. elegans neuronal aging transcriptomes correlate with human brain aging patterns and anticorrelate with geroprotective interventions. We performed an in silico drug screen to identify potentially neuroprotective small molecules. We show that the natural occurring plant metabolite syringic acid and the piperazine derivative vanoxerine delay neuronal degeneration, and propose these compounds as neuroprotective interventions. Furthermore, we identify neurotoxins that accelerate neurodegeneration, indicating that distinguishing aging trajectories between neuron types can inform on protective interventions as well as risk factors.
    DOI:  https://doi.org/10.1038/s43587-026-01067-5
  36. Nat Commun. 2026 Jan 30.
    The biological role of local and global fMRI BOLD signal variability in multiscale human brain organization.
    Giulia Baracchini, Yigu Zhou, Jason da Silva Castanheira, Justine Y Hansen, Can Fenerci, Roni Setton, Jenny R Rieck, Gary R Turner, Cheryl L Grady, Bratislav Misic, Jason S Nomi, Lucina Q Uddin, R Nathan Spreng.
      Variability drives the organization and behavior of complex systems, including the human brain. Understanding the variability of brain signals is thus necessary to broaden our window into brain function and behavior. Few empirical investigations of macroscale brain signal variability have been undertaken, given the difficulty in separating biological sources of variance from artefactual noise. Here, we characterize the temporal variability of the most predominant macroscale brain signal, the fMRI BOLD signal, and systematically investigate its statistical, topographical, and neurobiological properties. We contrast fMRI acquisition protocols, and integrate across histology, microstructure, transcriptomics, neurotransmitter receptor and metabolic data, fMRI static connectivity, and empirical and simulated magnetoencephalography data. We show that BOLD signal variability represents a spatially heterogeneous, central property of multi-scale multi-modal brain organization, distinct from noise. Our work establishes the biological relevance of BOLD signal variability and provides a lens on brain stochasticity across spatial and temporal scales.
    DOI:  https://doi.org/10.1038/s41467-026-68700-0
  37. Cell Death Dis. 2026 Feb 02. 17(1): 195
    Reversible arginine methylation regulates mitochondrial IDH2 activity: coordinated control by CARM1 and KDM3A/4A.
    Yena Cho, Jessica Winarto, Dae-Geun Song, Dong Hee Na, Kyo Bin Kang, Su-Nam Kim, Yong Kee Kim.
      Mitochondria are essential for cellular homeostasis, supplying key metabolites and energy. While post-translational modifications regulate mitochondrial enzymes, their roles remain less explored compared to those in the nucleus and cytoplasm. Here, we demonstrate that reversible arginine methylation governs the activity of several mitochondrial enzymes, with a particular focus on isocitrate dehydrogenase 2 (IDH2). We identify coactivator-associated arginine methyltransferase 1 (CARM1) as a mitochondrial enzyme that asymmetrically dimethylates IDH2 at R188, leading to enzymatic inhibition while enhancing protein stability. This modification is dynamically reversed by the lysine demethylases KDM3A and KDM4A, which restore IDH2 activity. Notably, despite its reduced stability, demethylated IDH2 promotes α-ketoglutarate production, enhancing mitochondrial membrane potential and oxygen consumption. These findings highlight the critical role of reversible arginine methylation in fine-tuning mitochondrial enzyme function and maintaining mitochondrial homeostasis.
    DOI:  https://doi.org/10.1038/s41419-026-08444-3
  38. iScience. 2026 Feb 20. 29(2): 114608
    The loss of peroxiredoxin 2 in mice disrupts the biochemical aging phenotype in erythrocytes.
    Neema Jamshidi, Katharina von Löhneysen, Katrin Soldau, Jeffrey S Friedman.
      Biochemical aging involves progressive declines in energy metabolism and redox maintenance. The peroxiredoxin enzyme family is critical for maintenance of cellular redox states. In mice, enucleate mature red blood cells (RBCs) persist for roughly 50 days, providing an ideal system for tracking cellular aging in vivo. To define the impact of impaired redox function, we analyzed the RBC metabolome across defined cellular ages using biotin labeling to isolate populations at approximately 1, 2, and 3 weeks. A total of 183 metabolites were quantified by mass spectrometry. Overall metabolic trajectories were similar between wild-type and Prdx2-deficient RBCs, with age-associated shifts involving ATP-generating pathways, redox maintenance processes, and membrane-structure-related reactions. However, these metabolic changes were consistently more pronounced in Prdx2 knockout RBCs, indicating accelerated disruption of pathways linked to energy production and redox balance. These findings indicate that Prdx2 is essential for maintaining metabolic homeostasis during RBC aging.
    Keywords:  Biochemistry
    DOI:  https://doi.org/10.1016/j.isci.2025.114608
  39. Res Sq. 2026 Jan 12. pii: rs.3.rs-8349343. [Epub ahead of print]
    Senescent cells secrete chromatin components via senescence-associated extracellular particles.
    Peter Adams, Sviatlana Zaretski, Jose L Nieto Torres, Xue Lei, John Nolan, Malene Hansen.
      Senescent cells influence their surroundings through the senescence-associated secretory phenotype (SASP), an assortment of secreted molecules and macromolecular complexes. Among SASP's intracellular drivers are cytoplasmic chromatin fragments (CCFs), nuclear-derived DNA that activates the pro-inflammatory cGAS/STING pathway. While autophagy contributes to CCFs degradation, the full repertoire of CCF fates and signaling functions remains unclear. Here, we show that senescent cells release CCF components, ɣH2AX and double-stranded DNA (dsDNA), into the extracellular space via an ESCRT-independent multivesicular body pathway. Secreted CCF components localize to extracellular particles exhibiting an unusual "popcorn"-like morphology, distinct from canonical small extracellular vesicles. Notably, inhibition of autophagy enhances secretion of CCF components and particles, suggesting an inverse relationship between intracellular clearance and extracellular release. A fraction of CCF-containing extracellular particles activates cGAS-STING signaling in non-senescent proliferating cells and is enriched in the circulation of aged mice, pointing to a previously unrecognized mode of extracellular signaling by senescent cells.
    DOI:  https://doi.org/10.21203/rs.3.rs-8349343/v1
  40. Biophys J. 2026 Jan 31. pii: S0006-3495(26)00084-6. [Epub ahead of print]
    Condensates and Cell States: A New Paradigm for Understanding Tumor Biology.
    Ruth Nussinov, Hyunbum Jang.
      Traditionally, cells have been classified by their type. Identifying cell types was deemed vital for understanding biological processes. More recently, cell type classification has been recognized as not good enough. Cells have many transient states that depend on their spatial environment and vary over time. The current cell states description recognizes that a cell is dynamic, varying over developmental time, location, senescence, and disease. While cell states refer to the functional behavior of the cells, biomacromolecular condensates are now recognized as the membraneless structures within them, which by concentrating functionally related proteins, make the function happen. Here, we (i) clarify the molecular basis of the current separation between cell types and states and point to the merit of the "cell states", which make the classical "cell types" distinction expendable; (ii) discuss how fundamental physical principles evolved the functionally specific, conformationally biased biomacromolecular condensates; and (iii) consider the pharmacology of cell states and condensates. Recent reports highlighted condensates as drug targets. However, drugs designed to dismantle condensates can be toxic due to lack of specificity-unlike cell states, which are controlled by targetable specific epigenetics players. Especially (iv), we consider transitioning primary cancer cells, linking cell states and condensates to tumor proliferation. We suggest that original cancer cells transitioning to other tissues are primarily influenced by cell states,supported by their multi-condensates structuring. The high genetic homogeneity of untreated cancers-within primary tumors and metastases-underscores the significance of the transient nature of cell states.
    Keywords:  allosteric; allostery; cell types; drugs; epigenetics; metastases; spatial microenvironment; tumor proliferation
    DOI:  https://doi.org/10.1016/j.bpj.2026.01.052
  41. Genes Dev. 2026 Feb 04.
    Multiomic analysis of clonal development reveals new regulators of leukemic cell growth.
    Gracia Bonilla, Alexander Morris, Sharmistha Kundu, Anthony DuCasse, Grace Kirkpatrick, Jelena Milosevic, Nathan E Jeffries, Kashish Chetal, Emma E Yvanovich, Ting Zhao, Jun Xia, Rana Barghout, David Scadden, Michael K Mansour, Robert E Kingston, David B Sykes, Francois E Mercier, Ruslan I Sadreyev.
      Mechanisms driving the increase in cell growth in developing leukemia are not fully understood. We focused on epigenomic regulation of this process by analyzing the changes of chromatin marks and gene expression in leukemic cell clones as they progressed toward increased proliferation in a mouse model of acute myeloid leukemia (AML). This progression was characterized by gradual modulation of chromatin states and gene expression across the genome, with a surprising preferential trend of reversing the prior changes associated with the origins of leukemia. Our analyses of this modulation in independently developing clones predicted a small set of potential growth regulators whose transcriptomic and epigenomic progression was consistent between clones and maintained both in vivo and ex vivo. We selected three of these genes as candidates (Irx5 and Plag1 as growth suppressors and Smad1 as a driver) and successfully validated their causal growth effects by overexpression in mouse leukemic cells. Overexpression of the IRX5 gene in human MOLM13 leukemic cells suppressed cell growth both in vitro and in mouse xenografts. Public patient data confirmed expression levels of PLAG1 and SMAD1 as markers of AML status and survival, suggesting that multiomic analysis of evolving clones in a mouse model is a valuable predictive approach relevant to human AML.
    Keywords:  Polycomb group proteins; acute myeloid leukemia; cell growth regulation; chromatin modifications; clonal evolution; epigenetic factors; epigenome dynamics
    DOI:  https://doi.org/10.1101/gad.353186.125
  42. Nat Aging. 2026 Feb 03.
    Treatment resistance to platinum-based chemotherapy in lung and ovarian cancer is driven by a targetable TGFβ senescent secretome.
    Estela González-Gualda, Marika A V Reinius, David Macias, Samir Morsli, Jianfeng Ge, Ioana Olan, José Ezequiel Martín, Hui-Ling Ou, Muhamad Hartono, María Pilar Puerto-Camacho, Mary Denholm, Rosalind Kieran, Reuben Hoffmann, Mark Dane, Dimitris Veroutis, Guillermo Medrano, Francisca Mulero, Mercedes Jimenez-Linan, Ljiljana Fruk, Carla P Martins, Mariano Barbacid, Vassilis Gorgoulis, James E Korkola, Doris M Rassl, Gary J Doherty, Robert C Rintoul, Masashi Narita, James D Brenton, Daniel Muñoz-Espín.
      Platinum-based chemotherapy is commonly used for non-small cell lung cancer (NSCLC) and high-grade serous ovarian cancer (HGSOC) treatments, yet clinical outcomes remain poor. Cellular senescence and its associated secretory phenotype (SASP) can have multiple tumor-promoting activities, but both are largely unexplored in these cancers. In this study, using xenograft, orthotopic and KrasG12V-driven murine NSCLC models, we demonstrate that cisplatin-induced senescence strongly promotes malignant phenotypes and tumor progression, which is stimulated by aging. Mechanistically, we found that a transforming growth factor-beta (TGFβ)-enriched SASP drives pro-proliferative effects through TGFBR1 and AKT/mTOR. TGFBR1 inhibition with galunisertib or senolytic treatment reduces tumor progression driven by cisplatin-induced senescence, and concomitant use of TGFBR1 inhibitors with platinum-based chemotherapy reduces tumor burden and improves survival. Finally, we validate the translational relevance of tumor-promoting TGFβ-enriched SASP using clinical NSCLC and HGSOC samples from patients who received neoadjuvant platinum-based chemotherapy. Together, our findings identify a potential cancer therapy resistance mechanism and provide preclinical proof of concept for future trials.
    DOI:  https://doi.org/10.1038/s43587-025-01054-2
  43. J Biol Chem. 2026 Jan 28. pii: S0021-9258(26)00083-9. [Epub ahead of print] 111213
    Mannose metabolic pathway senses glucose supply and regulates cell fate decisions.
    Ziwei Wang, Yasuhide Miyamoto, Takehiro Suzuki, Miki Tanaka-Okamoto, Yu Mizote, Naoshi Dohmae, Hideaki Tahara, Naoyuki Taniguchi, Yoichiro Harada.
      Mammalian cells exploit diverse metabolic pathways to regulate cell fates during glucose deprivation. We previously reported that glucose deprivation lowers the metabolic activity of mannose pathway that is interconnected with glycolysis, leading to biosynthetic arrest and degradation of the glycan precursors for asparagine-linked glycosylation (N-glycosylation) in the endoplasmic reticulum (ER). However, the cellular role of this sequential metabolic response remains unknown, largely due to metabolic complications caused by glucose deprivation. Here, we genetically engineered cells to separate mannose pathway from glycolysis, allowing precise control of mannose pathway activity by adjusting mannose supply levels instead of changing glucose supply. Moderate decrease in mannose supply severely suppressed N-glycosylation, leading to activation of pro-survival PERK-eIF2 signals. Although further decrease in mannose supply to the minimal levels did not compromise cell survival, it depleted luminal protective glycocalyx of lysosomes and increased a risk of cell death by impairing lysosome integrity. These results indicate that low metabolic flux of glucose into mannose pathway initiates alterations in homeostasis of the ER and lysosomes, at least in part through N-glycosylation defects, leading to cell fate decisions.
    Keywords:  Cell fate decision; N-glycosylation; endoplasmic reticulum; glucose deprivation; lysosomes
    DOI:  https://doi.org/10.1016/j.jbc.2026.111213
  44. bioRxiv. 2026 Jan 15. pii: 2026.01.14.699555. [Epub ahead of print]
    LONP-1 deficiency causes dysregulated protein synthesis within mitochondria that is restored by mitoribosomal mutations.
    Levi Ali, Avijit Mallick, Yunguang Du, Rui Li, Lihua Julie Zhu, Kuang Shen, Cole M Haynes.
      Mitochondrial homeostasis is maintained by multiple molecular chaperones and proteases located within the organelle. The mitochondrial matrix-localized protease LONP-1 degrades oxidatively damaged or misfolded proteins. Importantly, LONP-1 also regulates mitochondrial DNA replication. Here, we show that mutations in C. elegans that impair LONP-1 function cause dysregulation of mitochondrial DNA replication, mitochondrial RNA transcription and protein synthesis within the mitochondrial matrix. LONP-1 deficient worms had reduced levels of oxidative phosphorylation proteins despite increased mtDNA-encoded protein synthesis. Via a forward genetic screen, we identified three mutations that restored mitochondrial function and the rate of development in lonp-1 mutants to levels comparable to those in wildtype worms. Interestingly, all three suppressor mutations were found in genes encoding mitochondrial ribosome proteins. A point mutation in the mitochondrial ribosome protein MRPS-38 restored oxidative phosphorylation in lonp-1 mutant worms. Combined, our results suggest that LONP-1 regulates mitochondrial protein synthesis and that the suppressor mutations within MRPS-38 or MRPS-15 enhance oxidative phosphorylation complex assembly by slowing translation.
    DOI:  https://doi.org/10.64898/2026.01.14.699555
  45. bioRxiv. 2026 Jan 20. pii: 2026.01.20.700435. [Epub ahead of print]
    Acetyl-CoA availability regulates neuronal metabolism, growth, and synaptic activity.
    Eric R McGregor, Cassandra J McGill, Nicholas L Arp, Josef P Clark, Dominique A Baldwin, Di Kuang, Gonzalo Fernandez-Fuente, Yun Hwa Choi, Keenan S Pearson, Jason K Nagorski, Judith A Simcox, Jing Fan, Luigi Puglielli, Rozalyn M Anderson.
      The metabolite acetyl-CoA plays a central role in cellular metabolic homeostasis. As part of the secretory pathway, acetyl-CoA is imported into the endoplasmic reticulum (ER) by a membrane-bound transporter AT-1 (SLC33A1). AT-1 has been linked to peripheral neuropathy (heterozygous mutations), developmental delay with premature death (homozygous mutations) and intellectual disability with progeria (duplication). These phenotypes can be reproduced in the mouse. Here, we show that AT-1 overexpression in primary neurons impacts diverse phenotypes related to neuronal function and plasticity. At the gene level, AT-1 induces brain aging signatures, and key differences in ribosomal and synaptic processes were identified in both the transcriptome and the proteome. Changes in mitochondria-associated pathways were reflected in an increase in expression of mitochondrial master regulator PGC-1α and its target genes. Functionally, marked differences in mitochondrial membrane potential, architecture, and respiration were detected. Tracing experiments indicated altered glucose utilization in glycogen storage and nucleotide production. Shifts in redox metabolism were linked to differences in levels of NAD-dependent SIRT1 and CtBP2, with consequences for acetylated lysine modification. Depletion of lipid stores was associated with greater plasticity in fuel substrate utilization and a major shift in cellular lipid composition. These broad-scale changes in metabolism were coincident with reduced expression of synaptic proteins and reduced activity among synaptic networks, indicating that neuronal electrophysiology and network communication are coordinated at least in part through neuronal acetyl-CoA metabolism.
    DOI:  https://doi.org/10.64898/2026.01.20.700435
  46. Sci Immunol. 2026 Feb 06. 11(116): eaef9196
    Aldehyde and seek: Toxic aldehydes drive exhaustion in tumor-infiltrating T cells.
    Cait A McAlindon, Rachael A Clark.
      Aldehydes accumulating in response to reduced fatty acid oxidation in tumor-infiltrating lymphocytes damage mitochondria and drive T cell exhaustion.
    DOI:  https://doi.org/10.1126/sciimmunol.aef9196
  47. ACS Chem Biol. 2026 Jan 30.
    Multiple Adenylate-Forming Enzymes Contribute to Biosynthesis of the DPO Quorum-Sensing Autoinducer.
    Delaney M Lacey, Gabriel D D'Agostino, Emilee E Shine, Bonnie L Bassler.
      Bacteria use a process of chemical communication called quorum sensing to regulate group behaviors. Quorum sensing relies on the synthesis, release, and detection of signal molecules called autoinducers that accumulate with increasing cell density. The pathogen Vibrio cholerae makes and detects three autoinducers which together, regulate genes required for group behaviors including virulence and biofilm formation. Two autoinducers are produced by dedicated autoinducer synthases that employ S-adenosyl methionine as a substrate. The third autoinducer, 3,5-dimethylpyrazin-2-ol (DPO), is produced from threonine and alanine. The threonine dehydrogenase (Tdh) enzyme oxidizes l-threonine to 2-amino-3-ketobutyric acid, which spontaneously decarboxylates to aminoacetone. Here, we define the steps required to convert aminoacetone and alanine into DPO. We show that diverse adenylate-forming enzymes can condense ATP and d- or l-alanine to form alanyl-adenylate, the necessary intermediate in DPO biosynthesis. Upon release, alanyl-adenylate spontaneously condenses with aminoacetone to form N-alanyl-aminoacetone, which cyclizes to form DPO. We propose that DPO is distinct from other autoinducers in that there is apparently no dedicated synthase. Rather, a collection of enzymes contribute to the production of this quorum-sensing autoinducer.
    DOI:  https://doi.org/10.1021/acschembio.5c00932
  48. Cell Death Differ. 2026 Feb 03.
    The second mitochondrial activator of caspases (SMAC) regulates growth, inflammation and mitochondrial integrity in cancer cells.
    Tarek N Amer, Aladin Haimovici, Susanne Kirschnek, Juliane Vier, Abdul Moeed, Uzochukwu Ukachukwu, Daniela Neugebauer, Philip Neubert, Martin Helmstädter, Severine Kayser, Rupert Öllinger, Roland Rad, Olaf Groß, Jochen Holzschuh, Wolfgang Driever, Arnim Weber, Mohamed Tarek Badr, Georg Häcker.
      SMAC is a mitochondrial intermembrane space protein, which is released during apoptosis and whose known function is antagonism of inhibitor of apoptosis proteins in the cytosol, to facilitate caspase activation. Recent data suggest that SMAC can also be released by sub-lethal signals in the apoptosis pathway, in the absence of cell death. We here explored potential functions of SMAC in non-apoptotic cells. We found that a portion of SMAC is spontaneously released into the cytosol in the absence of apoptosis, regulated by the BCL-2-family proteins BAX and BAK and the fission GTPase DRP1. In cancer cell lines, SMAC was required for the activation of caspases in lethal and non-lethal conditions, while this contribution to caspase-activation was much smaller in non-malignant fibroblast lines. In cells with high levels of cytosolic SMAC, SMAC deficiency reduced in vitro migration, invasion and anchorage-independent growth as well as metastasis in a xenograft model in zebrafish. SMAC-deficient cells further showed a reduced activity in interferon signaling, associated with reduced cytosolic presence of mitochondrial DNA and activation of the stimulator of interferon genes (STING), and SMAC expression levels correlated with interferon-induced genes in cancer data sets. We further found that SMAC can regulate mitochondrial morphology and integrity. Finally, high gene-expression of SMAC was associated with poor prognosis in patients of several cancer types. These results identify SMAC as a regulator of inflammation and growth behavior of cancer cells. They further report a mitochondrial function of SMAC and demonstrate a role of SMAC in human cancer biology across several cancer entities.
    DOI:  https://doi.org/10.1038/s41418-026-01667-z
  49. Sci Transl Med. 2026 Feb 04. 18(835): eadq6647
    Kras G12C- and G12D-driven lung cancers differ in oncogenic potency, immunogenicity, and relapse after Kras inhibition in mouse models.
    Hai-Cheng Huang, Qing Deng, Lei Guo, Teresa Gorria, Federica Pecci, Daniella Yang, Scott Rodig, Luis De Las Casas, Jill Hallin, James G Christensen, Mark M Awad, Lin Xu, Biagio Ricciuti, Esra A Akbay.
      The development of allele-specific KRAS inhibitors underscores the importance of understanding the distinct tumor biology associated with common KRAS mutations, G12D and G12C, in genetically engineered mouse models (GEMMs) of non-small cell lung cancer (NSCLC) and patient samples. Lung tumors driven by the most common KRAS mutation, G12C, show delayed onset and slower progression compared with those driven by KRAS G12D in patients and mice. G12C tumors display lower proliferation and increased immune cell engagement, the latter of which is consistent with observations in patient tumors. Allele-specific KRAS G12C/D inhibitors effectively suppress the growth of respective autochthonous lung tumors. However, G12D-driven tumors relapse more rapidly than G12C-driven tumors in autochthonous models, reflecting greater intrinsic aggressiveness. Given this aggressive clinical behavior, we focused on elucidating the mechanism of action and strategies to potentiate KRASG12D inhibition in nonimmunogenic and immunogenic lung cancer models. G12D inhibition enhances tumor antigen presentation, activates T cells, and enables antigen-specific cytotoxicity, leading to efficacy with immune checkpoint blockade combination. This combination induces durable immune memory in immunogenic models but not in nonimmunogenic settings. Our findings underscore key differences between KRAS G12D and G12C mutations in shaping lung cancer biology, reveal distinct resistance dynamics under long-term targeted therapy, and uncover immune-mediated mechanisms specific to KRASG12D inhibition with direct clinical and translational relevance.
    DOI:  https://doi.org/10.1126/scitranslmed.adq6647
  50. Cell Rep. 2026 Feb 03. pii: S2211-1247(25)01680-8. [Epub ahead of print]45(2): 116908
    Brief pulses of high-level fluid shear stress enhance metastatic potential and rapidly alter the metabolism of cancer cells.
    Amanda N Pope, Devon L Moose, Guy O Hudson, Hank R Weresh, Marion R Dykstra, Aabha Y Joshi, Patrick Breheny, Eric B Taylor, Michael D Henry.
      Circulating tumor cells (CTCs) face challenges to their survival, including mechanical and oxidative stresses that are different from cancer cells in solid primary and metastatic tumors. The impact of adaptations to the fluid microenvironment of the circulation on the outcome of the metastatic cascade is not well understood. Here, we find that cancer cells exposed to brief pulses of high-level fluid shear stress (FSS) exhibit enhanced invasiveness and anchorage-independent proliferation in vitro and enhanced metastatic colonization/tumor formation in vivo. Cancer cells exposed to FSS rapidly alter their metabolism in a manner that promotes survival by providing energy for cytoskeletal remodeling and contractility as well as reducing equivalents to counter oxidative stress associated with cell detachment. Thus, exposure to FSS may provide CTCs with an unexpected survival benefit that promotes metastatic colonization.
    Keywords:  CP: cancer; CP: cell biology; circulating tumor cells; fluid shear stress; metabolism; metastasis; oxidative stress
    DOI:  https://doi.org/10.1016/j.celrep.2025.116908
  51. Sci Adv. 2026 Feb 06. 12(6): eaea0405
    Fungal infection drives metabolic reprogramming in epithelial cells via aerobic glycolysis and an alternative TCA cycle shunt.
    Aize Pellon, Shervin Dokht Sadeghi Nasab, Gholamreza Bidkhori, James S Griffiths, Stefania Vaga, Neelu Begum, Mariana Blagojevic, Nitesh Kumar Sigh, Natalia K Kotowicz, Ifeanyi Uzochukwu, Adrien Le Guennec, Rhonda Henley-Smith, Harry Gregson-Williams, Frederick Clasen, Miranda Pryce, Nadia Karimpour, Richard Cook, Juan Anguita, Jonathan P Richardson, Selvam Thavaraj, Julian R Naglik, Saeed Shoaie, David L Moyes.
      Candida albicans-induced immunometabolic changes drive complex responses in immune cells. However, whether and how C. albicans causes remodeling of oral epithelial cell (OEC) metabolism is unclear. Here, we use in vitro experiments and patient biopsies to demonstrate that OECs undergo metabolic reprogramming when infected by C. albicans independently of candidalysin secretion, increasing glycolysis and decreasing tricarboxylic acid (TCA) cycle activity. Glycolysis and glucose transport inhibition show that these pathways support OEC cytokine release, highlighting the partial control of antifungal epithelial immunity by cellular metabolism. However, glucose supplementation disrupts OEC responses both in vitro and in vivo, suggesting that the fungus benefits from these metabolic shifts and that increased aerobic glycolysis in OECs is detrimental. Genome-scale metabolic modeling predicted a shutdown of the TCA cycle and a previously unidentified role for glutamic-oxaloacetic transaminase 1 (GOT1) in response to C. albicans, which was subsequently shown to be important for OEC survival during infection. This study reveals a fundamental role for hexose metabolism and identifies a GOT1-mediated TCA cycle shunt in regulating OEC survival and immune responses during mucosal fungal infections.
    DOI:  https://doi.org/10.1126/sciadv.aea0405
  52. J Cell Sci. 2026 Feb 01. pii: jcs264300. [Epub ahead of print]139(3):
    Adaptive regulation of glycerophospholipid metabolism.
    Tong Zhang, Yuan Wang, Cunqi Ye.
      Lipid membranes form the essential barriers that compartmentalize life, separating intracellular processes from the external environment. To maintain cellular function and viability, both the plasma membrane and internal organelle membranes undergo continuous compositional and functional remodeling in response to environmental fluctuations. Traditionally, glycerophospholipids have been primarily considered structural components of these membranes. However, their dynamic synthesis plays a crucial role in modulating membrane functions and, consequently, cellular adaptability. This Review discusses how cells orchestrate complex glycerophospholipid metabolism to adapt to diverse environmental challenges. By examining membrane adaptation to various changes, including temperature shifts, pH imbalances and nutrient availability, we propose that responsive alterations in glycerophospholipid synthesis act as a central metabolic hub. This hub influences overall cellular metabolism and regulatory networks. This Review highlights an often overlooked aspect of lipid biology: the pivotal role of glycerophospholipid metabolism in modulating cellular adaptability and resilience.
    Keywords:  Cellular adaptability; Glycerophospholipid; Lipid membranes; Metabolic regulation; Metabolism; Phospholipid synthesis
    DOI:  https://doi.org/10.1242/jcs.264300
  53. Am J Hum Genet. 2026 Feb 05. pii: S0002-9297(25)00484-7. [Epub ahead of print]113(2): 309-323
    Mendelian randomization linking metabolites with enzymes reveals pathway regulation and therapeutic avenues.
    Adriaan van der Graaf, Sadegh Rizi, Chiara Auwerx, Zoltán Kutalik.
      Reactions between metabolites are catalyzed by enzymes. These biochemical reactions form complex metabolic networks, which are only partially characterized in humans and whose regulation remains poorly understood. Here, we assess human biochemical reactions and regulation using Mendelian randomization (MR), a genetic observational causal inference technique, to understand the methods' strengths and weaknesses in identifying metabolic reactions and regulation. We combine four metabolite and two protein quantitative trait locus (QTL) studies to determine how well MR recovers 945 curated canonical enzyme-substrate/product relationships. Using genetic variants from an enzyme's transcribed (cis) region as instrumental variables, MR-inferred estimates have high precision (35%-47%) but low recall (3.2%-4.6%) for identifying the substrates and products of an enzyme. Testing reverse causality from metabolites to enzymes using genome-wide instruments yields lower precision (1.8%-8.5%) and recall (1.0%-1.9%) due to an increased multiple-testing burden. Literature review of 106 Bonferroni-significant results identifies 45 links (43%) confirmed by different degrees of evidence, including bidirectional links between linoleate and cytochrome P450 3A4 (CYP3A4) levels (p = 8.6 × 10-32). Eleven enzymes in the 106 links involve drug targets, allowing for an interpretation between N-acetyl putrescine and IL1RAP (p = 2.7 × 10-7), as IL1RAP is a target of the psoriasis drug spesolimab, and putrescine levels are elevated in psoriatic tissues. This work highlights how MR can be leveraged to explore human metabolic regulation and identify both canonical reactions and previously unknown regulation.
    Keywords:  Mendelian randomization; enzymes; metabolic regulation; metabolism; proteomics
    DOI:  https://doi.org/10.1016/j.ajhg.2025.12.013
  54. NPJ Aging. 2026 Jan 30. 12(1): 23
    The human pathome shows sex and tissue specific aging patterns.
    Michael Ben Ezra, Jonas Bach Garbrecht, Nasya Rasmussen, Marta Cortés Mediavilla, Indra Heckenbach, Michael A Petr, Daniela Bakula, Laust Mortensen, Morten Scheibye-Knudsen.
      Little is known about tissue-specific changes that occur with aging in humans. Using the description of 33 million histological samples we extract thousands of age- and mortality-associated features from text narratives that we call The Human Pathome (pathoage.com). Notably, we can broadly determine when post-development aging starts at the organism and tissue level, indicating a sexual dimorphism with females aging earlier but slower and males aging later but faster. We employ unsupervised topic-modeling to identify terms and themes that predict age and mortality. As a proof of principle, we cross-reference these terms in PubMed to identify nintedanib as a potential aging intervention and show that nintedanib reduces markers of cellular senescence, reduces pro-fibrotic gene pathways in senescent cells and extends the lifespan of fruit flies. Our findings pave the way for expanded exploitation of population text datasets towards discovery of novel aging interventions.
    DOI:  https://doi.org/10.1038/s41514-025-00307-z
  55. Cell Chem Biol. 2026 Feb 04. pii: S2451-9456(26)00023-1. [Epub ahead of print]
    Aerobic glycolysis promotes NLRP3 inflammasome activation via NLRP3 lactylation.
    Wei Liu, Tianyi Zhang, Bohong Wang, Hang Yin.
      Bacteria-infected macrophages undergo pyroptosis to release inflammatory cytokines, which contributes to host defense. It has been known that activated macrophages involve metabolic reprogramming. However, the metabolic changes and the role of metabolites in pyroptotic macrophages are not fully understood. Here, we revealed that aerobic glycolysis product, lactate, could promote NLRP3 inflammasome activation induced pyroptosis. We found that endogenous lactate facilitates ASC recruitment to NLRP3 cores on the organelle membrane, thus inducing NLRP3 inflammasome complex formation. Mechanistically, we identified NLRP3 as a target protein modified by lactate, which is lactylated by AARS2. We confirmed lactylated sites on NLRP3 by LC-MS/MS analysis and verified that lactylation at K24 and K565 of NLRP3 facilitates inflammasome activation in macrophage. In vivo, inhibition of lactate production alleviates inflammatory responses in polymicrobial sepsis. Overall, our results indicate the role of lactate in regulating macrophage pyroptosis and the crosstalk between metabolism and innate immunity.
    Keywords:  NLRP3 inflammasome; lactylation; pyroptosis
    DOI:  https://doi.org/10.1016/j.chembiol.2026.01.003
  56. Elife. 2026 Feb 06. pii: RP108742. [Epub ahead of print]14
    Suppression of interferon signaling via small-molecule modulation of TFAM.
    Dionisia Sideris, Husan Lee, Lyndsay Olson, Kalyan Nallaparaju, Keiichiro Okuyama, Jeffrey Ciavarri, Robert Lafyatis, Mads Larsen, Bo Lin, Irene Alfaras, Jason Kennerdell, Toren Finkel, Yuan Liu, Bill Chen, Lin Lyu.
      The mitochondrial transcription factor A (TFAM) is essential for mitochondrial genome maintenance. It binds to mitochondrial DNA (mtDNA) and determines the abundance, packaging, and stability of the mitochondrial genome. Because its function is tightly associated with mtDNA, TFAM has a protective role in mitochondrial diseases, and supportive studies demonstrate reversal of disease phenotypes by TFAM overexpression. In addition, TFAM deficiency has been shown to cause release of mtDNA into the cytosol and activation of the cGAS/STING innate immune response pathway. As such, TFAM presents as a unique target for therapeutic intervention, but limited efforts for activators have been reported. Herein, we disclose novel TFAM small-molecule modulators with sub-micromolar activity. Our results demonstrate that these compounds result in an increase of TFAM protein levels and mtDNA copy number. This results in inhibition of a mtDNA stress-mediated inflammatory response by preventing mtDNA escape into the cytosol. Furthermore, we see beneficial effects in cellular disease models in which boosting TFAM activity has been advanced as a disease-modifying strategy including improved energetics in MELAS cybrid cells and a decrease of fibrotic markers in systemic sclerosis fibroblasts. These results highlight the therapeutic potential of using small-molecule TFAM activators in indications characterized by mitochondrial dysfunction.
    Keywords:  TFAM; cGAS-STING pathway; cell biology; human; interferon sinaling; mitochondria; mitochondrial DNA; small molecule
    DOI:  https://doi.org/10.7554/eLife.108742
  57. PLoS Biol. 2026 Jan;24(1): e3003619
    Five energy metabolism pathways show distinct regional distributions and lifespan trajectories in the human brain.
    Moohebat Pourmajidian, Justine Y Hansen, Golia Shafiei, Bratislav Misic, Alain Dagher.
      Energy metabolism involves a series of biochemical reactions that generate ATP, utilizing substrates such as glucose and oxygen supplied via cerebral blood flow. Energy substrates are metabolized in multiple interrelated pathways that are cell- and organelle-specific. These pathways not only generate energy but are also fundamental to the production of essential biomolecules required for neuronal function and survival. How these complex biochemical processes are spatially distributed across the cortex is integral to understanding the structure and function of the brain. Here, using curated gene sets and whole-brain transcriptomics, we generate maps of five fundamental energy metabolic pathways: glycolysis, pentose phosphate pathway, tricarboxylic acid cycle, oxidative phosphorylation and lactate metabolism. We find consistent divergence between primarily energy-producing and anabolic pathways, particularly in unimodal sensory cortices. We then explore the spatial alignment of these maps with multi-scale structural and functional attributes, including metabolic uptake, neurophysiological oscillations, cell type composition, laminar organization and macro-scale connectivity. We find that energy pathways exhibit unique relationships with the cellular and laminar organization of the cortex, pointing to the higher energy demands of large pyramidal cells and efferent projections. Finally, we show that metabolic pathways exhibit distinct developmental trajectories from the fetal stage to adulthood. The primary energy-producing pathways peak in childhood, while the anabolic pentose phosphate pathway shows greater prenatal expression and declines throughout life. Together, these results highlight the rich biochemical complexity of energy metabolism organization in the brain.
    DOI:  https://doi.org/10.1371/journal.pbio.3003619
  58. ACS Sens. 2026 Feb 02. XXX
    An mTurquoise2-Based Glucose Biosensor.
    Dennis Botman, Annemoon Tielman, Joachim Goedhart, Bas Teusink.
      Glucose is an important substrate for organisms to acquire energy needed for cellular growth. Despite the importance of this metabolite, single-cell information at a fast time-scale about the dynamics of intracellular glucose levels is difficult to obtain as the current available sensors have drawbacks in terms of pH sensitivity or unmatched glucose affinity. To address this, we developed a convenient method to create and screen biosensor libraries using yeast as a workhorse. This resulted in TINGL (Turquoise INdicator for GLucose), a robust and specific biosensor with an affinity that is compatible with intracellular glucose detection. We show that the sensor can be calibrated in vivo (i.e., intracellular) through equilibration of internal and external glucose in a yeast mutant unable to phosphorylate glucose. Using this method, we estimated dynamic glucose levels in budding yeast during transitions to glucose. We found that glucose concentrations reached levels up to approximately 1 mM as previously determined biochemically. Furthermore, the sensor showed that intracellular glucose dynamics differ based on whether cells are glucose-repressed or not. Finally, the human codon-optimized version (THINGL, Turquoise Human INdicator for GLucose) also showed a robust response after glucose addition to starved human cells, showing the versatility of the sensors. We believe that this sensor can aid researchers interested in cellular carbohydrate metabolism.
    Keywords:  budding yeast; fluorescent biosensors; glucose; lifetime imaging; microscopy
    DOI:  https://doi.org/10.1021/acssensors.5c03325
  59. FASEB J. 2026 Feb 15. 40(3): e71504
    Timing of NAD Deficiency During Organogenesis Dictates Defect Type and Penetrance.
    Kayleigh Bozon, Hartmut Cuny, Nana Sunn, Ella M M A Martin, Delicia Z Sheng, Gavin Chapman, Sally L Dunwoodie.
      Major congenital malformations are common, and most cases have no known etiology because of complex interactions between genetic and environmental factors and variable phenotypic outcomes. Congenital NAD Deficiency Disorder (CNDD), a cause of multiple congenital malformations and embryo loss, exemplifies this variability in phenotypic presentation, even between siblings with the same underlying genetic variants. Mouse models show that CNDD is caused by embryonic nicotinamide adenine dinucleotide (NAD) deficiency because of the embryos' genetic inability to synthesize NAD and/or insufficient maternal provision of NAD precursors to embryos. But it is unknown when during pregnancy embryos become susceptible to developing malformations and what drives the malformation variability. Here, we induced CNDD in wild-type mice via the maternal diet and longitudinally tracked affected and unaffected embryos in utero. We compared 3-day interval measurements of the maternal blood NAD metabolome with embryo phenotype using Fast Spin Echo Magnetic Resonance Imaging, mass spectrometry, and micro-computed tomography. Malformations varied between litters, but they correlated with different embryo growth dynamics. Mice with lower maternal NAD Salvage Pathway metabolite levels and minimal levels of derived excretion metabolites from embryonic day 6.5 onward had smaller embryos with more malformations. This showed that altered embryo growth and reduced maternal NAD precursor availability during organogenesis resulted in CNDD. Variability in the timing of maternal metabolic perturbation corresponded to variability in organ and tissue defect types between litters. As embryo phenotypes are directly linked to maternal NAD precursor availability prior to and during organogenesis, this suggests NAD-derived metabolites are potential biomarkers predicting CNDD.
    Keywords:  NAD; congenital malformation; embryonic development; magnetic resonance imaging; metabolism
    DOI:  https://doi.org/10.1096/fj.202502824RRR
  60. PLoS One. 2026 ;21(2): e0340957
    Quantitative and temporal analysis of autophagy: Differential Response to amino acid and glucose starvation.
    Katie R Martin, Stephanie L Celano, Jessica D Guillaume, Ryan D Sheldon, Russell G Jones, Jeffrey P MacKeigan.
      Autophagy is a highly conserved, intracellular recycling process by which cytoplasmic contents are degraded in the lysosome. This process occurs at a low level constitutively; however, it is induced robustly in response to stressors, in particular, starvation of critical nutrients such as amino acids and glucose. That said, the relative contribution of these inputs is ambiguous, and many starvation medias are poorly defined or devoid of multiple nutrients. Here, we set out to create a quantitative dataset of autophagy across multiple stages in single, living cells, measured under normal growth conditions and during nutrient starvation of amino acids or glucose. We found that autophagy is induced by starvation of amino acids, but not glucose, in U2OS cells, and that MTORC1-mediated ULK1 regulation and autophagy are tightly linked to amino acid levels. While autophagy is engaged immediately during amino acid starvation, a heightened response occurs during a period marked by transcriptional upregulation of autophagy genes during sustained starvation. Finally, we demonstrated that cells immediately return to their initial, low-autophagy state when nutrients are restored, highlighting the dynamic relationship between autophagy and environmental conditions.
    DOI:  https://doi.org/10.1371/journal.pone.0340957
  61. Nucleic Acids Res. 2026 Jan 22. pii: gkag071. [Epub ahead of print]54(3):
    Functional characterisation of tumour suppressor PDCD4 reveals previously undisclosed role in the control of cell adhesion.
    Veronica Dezi, Robert F Harvey, Tom Smith, Cameron H Cole, Mariavittoria Pizzinga, Mark Stoneley, Gavin D Garland, Emilie Horvilleur, Lajos Kalmar, Ritwick Sawarkar, Kathryn S Lilley, Anne E Willis.
      PDCD4 is a multifunctional RNA-binding protein that has tumour suppressor function. To more fully understand how dysregulation of this protein contributes to carcinogenesis, we have carried out a comprehensive analysis of the role of PDCD4 in RNA metabolism in untransformed epithelial cells. We show that PDCD4 predominantly localises in the nucleus, where it interacts with proteins involved in a range of different RNA metabolic processes. We find that PDCD4 knockdown is associated with significant changes in either the expression or splicing of a number of transcripts, although it appears to have an indirect role in splicing. We identified the RNA targets of PDCD4 using iCLIP and observed an enrichment in binding to transcripts encoding cell adhesion and structural proteins. Consistent with these data, we show that PDCD4 acts as a general regulator of cell adhesion, which in a tumour setting would increase the metastatic potential of cells, and demonstrate that the nuclear localisation of PDCD4 is crucial in this process. Overall, the information obtained in untransformed cells provides a new perspective for the role of PDCD4 as a tumour suppressor.
    DOI:  https://doi.org/10.1093/nar/gkag071
  62. Cell Rep. 2026 Jan 28. pii: S2211-1247(25)01684-5. [Epub ahead of print]45(2): 116912
    Early-life NAD+ deficiency programs skeletal muscle aging by sustained suppression of hyaluronic acid synthesis beginning in childhood.
    Mariam Karim, Keisuke Yaku, Jun-Dal Kim, Akira Okekawa, Tsutomu Wada, Hitoshi Uchida, Amane Mizutani, Tran Canh Tung Nguyen, Yoshiharu Kawaguchi, Yoshimi Nakagawa, Toshiyasu Sasaoka, Yasuhito Yahara, Takashi Nakagawa.
      Nicotinamide adenine dinucleotide (NAD+) levels decline with age, which has been associated with the development of aging-associated diseases. However, it remains unknown whether low NAD+ levels in early life affect aging. This study demonstrates that deficiency of NAD synthetase (NADS), a critical enzyme of the deamidated NAD+ biosynthesis pathway, drastically reduced NAD+ levels in skeletal muscle and impaired muscle function at a young age. Intriguingly, NAD+ levels were restored to normal in middle-aged NADS-knockout mice, whereas muscle function remained compromised. Gene expression analysis showed that hyaluronic acid synthase 2 (Has2) was downregulated in both young NADS-knockout mice and aged wild-type mice. We also found that the α-ketoglutarate-JMJD3 axis downregulates Has2 expression. Then, impaired hyaluronic acid signaling dampened muscle stem cells, leading to decreased locomotor activity. These results suggest that maintaining NAD+ levels during early life is important for promoting healthy aging in skeletal muscle.
    Keywords:  CP: metabolism; DOHaD theory; NAD(+); aging; histone methylation; hyaluronic acid; skeletal muscle
    DOI:  https://doi.org/10.1016/j.celrep.2025.116912
  63. bioRxiv. 2026 Jan 16. pii: 2026.01.15.699810. [Epub ahead of print]
    Illuminating spatial dynamics of glutamine metabolism with a sensitive genetically encoded biosensor.
    Jack M Scully, Michael J Sun, Siddharth Das, Nataly J Arias, Edmund D Kapelczak, Tiffany D Robinson, Katie G Vineall, Teagan S Dean, Tara TeSlaa, Ajit S Divakaruni, Danielle L Schmitt.
      Glutamine is the most abundant amino acid in serum, used as a key nutrient by cells for protein synthesis, energy production, carbon and nitrogen metabolism, and cellular redox balance. The use of glutamine in the cell is highly compartmentalized, but the dynamics of glutamine metabolism across organelles and individual cells are not fully understood. To illuminate subcellular glutamine dynamics, we developed an intracellular glutamine optical reporter, iGlo. We find iGlo is sensitive and specific for glutamine and can be used to measure glutamine uptake, production, and consumption with high spatiotemporal resolution in multiple cell types. Furthermore, multiplexed imaging of iGlo with a lactate biosensor in single cells reveals temporal crosstalk between glucose and glutamine metabolism to maintain energy homeostasis. Thus, iGlo enables the sensitive and precise study of compartmentalized glutamine dynamics and represents a new and enhanced tool for studying the spatiotemporal dynamics and regulation of metabolism.
    DOI:  https://doi.org/10.64898/2026.01.15.699810
  64. EMBO J. 2026 Feb 05.
    Cellular quiescence uncouples the proteome from the transcriptome in neural stem cells.
    Alice Rossi, Antoine Coum, Manon Madelenat, Lachlan Harris, Stephanie Strohbuecker, Andrea Chai, Hania Fiaz, Rita Chaouni, Peter Faull, Neve Costello Heaven, William Grey, Dominique Bonnet, Fursham Hamid, Eugene V Makeyev, Ambrosius P Snijders, Gavin Kelly, François Guillemot, Rita Sousa-Nunes.
      Quiescence is a cellular state defined by reversible cell-cycle arrest and diminished biosynthesis, particularly of nucleic acids and proteins. These features protect stem cells from proliferation-induced mutations, self-renewal exhaustion, and environmental insults. Despite relevance to development, tissue homeostasis and cancer, we lack understanding about many aspects of quiescence regulation and unique molecular markers for this state. Here, we employ Drosophila and mammalian neural stem cells to reveal that a mechanism for inhibiting translation in quiescence is selective nuclear enrichment of transcripts from more than 2000 genes, resulting in uncoupling between transcriptome and proteome. Three-quarters of these transcripts become increasingly nuclear as quiescence deepens, and nuclear bias predicts protein downregulation for the large majority of targets. We find that a large fraction of nuclear-biased transcripts present GA-rich multivalency and relocalise to nuclear speckles with increased SR-protein enrichment, which we propose promotes their nuclear retention. Finally, our evidence for differing degrees of transcript processing in steady-state quiescence suggests regulated sequential deployment of factors towards cell-cycle reentry. In brief, we present a previously unappreciated layer of post-transcriptional control of quiescence.
    Keywords:  Neural Stem Cells; Nucleocytoplasmic Partitioning; Nucleoporins; Quiescence; RNA Localisation
    DOI:  https://doi.org/10.1038/s44318-026-00693-4
  65. Sci Immunol. 2026 Jan 30. 11(115): eadv7615
    B cells drive CD4 T cell immunosenescence and age-associated health decline.
    Saad Khan, Mainak Chakraborty, Fei Wu, Nan Chen, Tao Wang, Yi Tao Chan, Azin Sayad, Max Kotlyar, Faisal J Alibhai, Minna Woo, Ren-Ke Li, Mansoor Husain, Igor Jurisica, Adam J Gehring, Pamela S Ohashi, David Furman, Sue Tsai, Shawn Winer, Daniel A Winer.
      Dysregulation of the adaptive immune system is a key feature of aging and is associated with age-related chronic diseases and mortality. Here, we find that T cell aging, especially in the CD4 subset, is controlled by B cells. B cells contributed to the age-related reduction of naive CD4 T cells, their differentiation toward immunosenescent T cell subsets, and age-associated T cell receptor clonal restriction. Concurrently, mice lacking B cells displayed improvements in health span and life span. We uncovered a role for B cell-intrinsic insulin receptor signaling in influencing age-related B cell phenotypes that in turn induces CD4 T cell dysfunction, a process that is in part driven by major histocompatibility complex class II. These results identify B cells as critical mediators driving age-associated adaptive immune dysfunction and health-span outcomes and suggest previously unrecognized modalities to manage aging and related health decline.
    DOI:  https://doi.org/10.1126/sciimmunol.adv7615
  66. J Biol Chem. 2026 Feb 02. pii: S0021-9258(26)00090-6. [Epub ahead of print] 111220
    AHCY: A Metabolic Gatekeeper at the Interface of Methylation, Redox Balance, and Cellular Stress Response.
    Sarah C Stanhope, Vikki M Weake.
      S-Adenosylhomocysteinase (AHCY, also known as SAHH) is a highly conserved enzyme that catalyzes the reversible hydrolysis of S-adenosylhomocysteine (SAH) into adenosine and homocysteine. As the sole enzyme capable of catalyzing this reaction, AHCY modulates cellular methylation potential required for DNA, RNA, and protein methyltransferase activity. Recent discoveries, however, expand its role well beyond this canonical function, positioning AHCY as a metabolic gatekeeper that integrates one-carbon metabolism with epigenetic regulation, RNA processing, nucleotide balance, and redox signaling. This review brings together mechanistic, structural, and regulatory insights into AHCY while critically evaluating diverse biochemical and biophysical methods for assaying its activity. Comparative structural analyses uncover conserved tetrameric organization alongside species-specific adaptations in oligomeric state, NAD+ pocket accessibility, and C-terminal dynamics that shape enzyme catalytic efficiency and regulation. AHCY function is further fine-tuned through a wide spectrum of post-translational modifications and small-molecule interactions, linking it to transcriptional control, stress adaptation, and viral infection. By linking SAH turnover to methylation capacity and adenosine/homocysteine flux, AHCY coordinates metabolism with chromatin regulation and stress responses. These cross-cutting roles highlight how a single metabolic enzyme bridges catalysis, regulation, and disease. In doing so, AHCY exemplifies the broader principle that metabolic enzymes can have a central role as regulators of metabolic flux and cellular regulation, offering both mechanistic depth and translational promise as a therapeutic target.
    Keywords:  S-Adenosylhomocysteinase (AHCY); S-Adenosylhomocysteinase Hydrolase (SAHH); enzymatic regulation; methylation potential; one-carbon metabolism; redox homeostasis
    DOI:  https://doi.org/10.1016/j.jbc.2026.111220
  67. bioRxiv. 2026 Jan 14. pii: 2026.01.13.699287. [Epub ahead of print]
    Butyrate extends health and lifespan in mice with mitochondrial deficiency.
    Enrique Gabandé-Rodríguez, Manuel M Gómez de Las Heras, Pablo Ramírez-Ruiz de Erenchun, Carolina Simó, Virginia García-Cañas, Naohiro Inohara, Inés Berenguer-López, Violeta Enríquez-Zarralanga, Álvaro Fernández-Almeida, Jorge Oller, Gonzalo Soto-Heredero, Elisa Carrasco, Sandra Delgado-Pulido, José Ignacio Escrig-Larena, Isaac Francos-Quijorna, Raquel Justo-Méndez, Juan Francisco Aranda, Joanna Poulton, Ana Victoria Lechuga-Vieco, José Antonio Enríquez, Gabriel Núñez, María Mittelbrunn.
      Mitochondrial diseases progressively lead to multisystemic failure with treatment options remaining extremely limited. To investigate novel strategies that alleviate mitochondrial dysfunction, we have generated an ubiquitous and tamoxifen-inducible knockout mouse model of mitochondrial transcription factor A (TFAM), a nuclear-encoded protein involved in mitochondrial DNA (mtDNA) maintenance - Tfam fl/fl Ub Cre-ERT2 (iTfamKO) mice. Systemic TFAM deficiency triggers mitochondrial decline in a myriad of tissues in adult mice. Consequently, iTfamKO mice manifest multiorgan dysfunction including lipodystrophy, sarcopenia, metabolic alterations, kidney failure, neurodegeneration, and locomotor dysregulation, which result in the premature death of these mice. Interestingly, iTfamKO mice display intestinal barrier disruption and gut dysbiosis, with diminished levels of microbiota-derived short-fatty acids (SCFAs), such as butyrate. Mice with a deficient proof-reading version of the mtDNA polymerase gamma (mtDNA-mutator mice) phenocopy the dysfunction of the intestinal barrier and bacterial dysbiosis with reduced levels of butyrate, suggesting that different mouse models of mitochondrial dysfunction share deficient generation of butyrate. Transfer of microbiota from healthy control mice or administration of tributyrin, a butyrate precursor, delay multiple signs of multimorbidity extending lifespan in iTfamKO mice. Mechanistically, butyrate supplementation recovers epigenetic histone acylation marks that are lost in the intestine of Tfam deficient mice. Overall, our findings highlight the relevance of preserving host-microbiota symbiosis in disorders related to mitochondrial dysfunction.
    DOI:  https://doi.org/10.64898/2026.01.13.699287
  68. Cancer Cell. 2026 Feb 05. pii: S1535-6108(26)00045-0. [Epub ahead of print]
    CCL3 is produced by aged neutrophils across cancers and promotes tumor growth.
    Evangelia Bolli, Pratyaksha Wirapati, Mehdi Hicham, Yuxuan Xie, Marie Siwicki, Florent Duval, Anne-Gaëlle Goubet, Máté Kiss, Béatrice Zitti, Thomas Zwahlen, Sheri Mcdowell, Ruben Bill, Simona Angerani, Camilla Engblom, Seth Anderson, Aiping Jiang, Oliver Hartley, David B Sykes, Maja Jankovic, Nadine Fournier, Matthias Gunzer, David Tarussio, Stéphanie Tissot, Peter M Sadow, William C Faquin, Moshe Sade-Feldman, Ralph Weissleder, Sara Pai, François Mercier, Robert Manguso, Mikaël J Pittet.
      Tumor-associated neutrophils (TANs) are abundant across cancers, yet their phenotypic diversity and functional states remain poorly defined. Here, we introduce a cell-type probability classifier that recovers low-transcript neutrophils from scRNAseq datasets, enabling pan-cancer analyses of TAN heterogeneity. Across >190 human and murine tumors, we identify a conserved differentiation trajectory that culminates in a terminal CCL3hi state. This state exhibits pro-tumor transcriptional programs, including those involved in hypoxic adaptation and senescence. Consistently, CCL3hi TANs are enriched in hypoxic tumor niches in both humans and mice. Through mechanistic perturbations of neutrophil-derived CCL3 in mice, we show that it sustains TAN survival in hypoxic tumor regions via CCR1-dependent signaling. These findings establish CCL3 as a conserved marker and functional driver of pro-tumor neutrophils in growing tumors, and provide a scalable framework for dissecting neutrophil biology across cancer types.
    Keywords:  CCL3-CCR1 signaling; CRISPR perturbation; hypoxia; neutrophil aging; neutrophil differentiation; neutrophil heterogeneity; pan-cancer analysis; single-cell RNA sequencing; tumor microenvironment; tumor-promoting neutrophils
    DOI:  https://doi.org/10.1016/j.ccell.2026.01.006
  69. Cell. 2026 Jan 29. pii: S0092-8674(25)01498-9. [Epub ahead of print]
    Hallmarks of cancer-Then and now, and beyond.
    Douglas Hanahan.
      Cancer presents a remarkably instructive perturbation of mechanisms manifesting in our biology that have gone awry, eliciting a malady that is inexorably increasing in incidence and societal burden concomitant with healthier aging. The wealth of knowledge and data forthcoming from decades of cancer research can be organized into conceptually distinct but interconnected parametric dimensions that define the mechanistic foundation of the disease: aberrantly acquired functional capabilities (the hallmarks of cancer), enabling phenotypic characteristics, hallmark-conveying cells populating cancer microenvironments, and systemic interactions. Collectively, they provide a logical framework with which to illuminate the operating systems of these outlaw organs, from inception through multistage tumorigenesis to adaptive evolution. This review presents a concise synthesis of the hallmark conceptualization as it has been refined during the past 25 years, including a corollary hypothesis that mechanism-guided hallmark co-targeting could offer impactful new therapeutic strategies for treating human cancers.
    DOI:  https://doi.org/10.1016/j.cell.2025.12.049
  70. Proc Natl Acad Sci U S A. 2026 Feb 10. 123(6): e2529243123
    Metabolite control of enzyme activity links stress to biosynthetic regulation.
    Wilhelmina van de Ven, Manhoi Hur, María Fernanda Gómez-Méndez, Jingzhe Guo, Haiyan Ke, Raisul Awal Mahmood, Sunghwan Kim, Thomas D Sharkey, Katayoon Dehesh.
      Cells must continuously adjust metabolic output to maintain homeostasis under changing environmental conditions, yet the mechanisms that enable rapid and reversible control of pathway activity remain largely unknown. The methylerythritol phosphate (MEP) pathway, of bacterial origin and conserved in plastid-bearing eukaryotes, including plants and apicomplexan parasites, produces isoprenoid precursors essential for growth and stress adaptation. Here, we identify methylerythritol cyclodiphosphate (MEcPP) as a dual-function metabolite that serves both as a biosynthetic intermediate and a direct modulator of enzyme activity. Genetic perturbations and high light stress revealed step-specific MEcPP accumulation independent of transcriptional regulation. Biochemical and protease-protection assays showed that MEcPP destabilizes and inhibits methylerythritol cytidylyltransferase (MCT) while modestly stabilizing hydroxymethylbutenyl diphosphate synthase (HDS). Molecular docking analyses indicate that MEcPP interacts directly with the MCT catalytic site, displacing the natural substrate and thereby attenuating enzyme activity, suggesting a competitive, feedback-like mechanism of metabolic control. These results define MEcPP as a metabolic feedback signal that translates stress-induced changes into targeted enzymatic control. This mechanism illustrates how pathway intermediates dynamically coordinate biosynthetic activity with environmental cues, representing a broadly conserved strategy for metabolite-driven control of cellular metabolism.
    Keywords:  MEP pathway; MEcPP; isoprenoid biosynthesis; metabolic feedback regulation; plastidial stress response
    DOI:  https://doi.org/10.1073/pnas.2529243123
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