bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2026–10–18
forty-nine papers selected by
Christian Frezza, Universität zu Köln
  1. Genetic modulation of NAD(P)H homeostasis reveals distinct redox-coupled metabolic vulnerabilities.
  2. SPRIZ (CCDC127) protein conserved in deuterostome animals is a rigid OMM-IMM tether that locally sets mitochondrial IMS volume.
  3. Regulation of PDH via cysteine oxidation on DLAT.
  4. PINK1-mediated mitophagy supports lung cancer initiation and limits the efficacy of KRAS-targeted therapy.
  5. Mitochondria strike two hits to drive the SASP.
  6. Mitochondrial Psychobiology.
  7. STING engages PKR to drive lysosomal cell death in lung ischemia-reperfusion injury.
  8. Glucose-6-Phosphate Dehydrogenase Deficiency Reprograms Macrophage Metabolism in Hyperlipidemia.
  9. A multi-fluid exercise proteomic atlas reveals regulators of health and disease.
  10. Lactate dehydrogenase A-dependent redox control of selective mRNA translation directs monocyte fate commitment.
  11. Pharmacological inhibition of MCL-1 disrupts mitochondrial cristae and depletes the human neural progenitor cell pool.
  12. Micronuclear ecDNA constrains tumor cell fitness and is associated with favorable patient survival.
  13. Combined Loss of VHL and TSC1 Drives Clear Cell Renal Cell Carcinoma with Metabolic and Redox Reprogramming that Creates an NRF2 Dependency.
  14. Mitochondrial Genetic Background Shapes Baseline Retinal Function, Age-Related Bioenergetic Remodeling, and Microglial STING Phenotypes.
  15. Nuclear acetyl-CoA accumulation drives reversible RBP hyperacetylation and transcriptome-wide splicing shifts in age-equivalent Alzheimer's disease neurons.
  16. A systemic circadian nicotinic acid riboside (NaR) signal engages the unfolded protein response and adipogenesis via the prefoldin complex.
  17. Dynamic protein phosphorylation shapes mitochondrial catalysis, import, and architecture.
  18. Mitochondrial Supercomplex-Associated Proximity Increases in Malignant Glioma Tissue.
  19. Simulated microgravity induces aging phenotypes in human organoids.
  20. Transcriptomic reprogramming screen identifies SRSF1 as a regulator of aging.
  21. Inherent electrochemical activity of extrachromosomal DNA hub shapes spatial redox environment in nucleus.
  22. Warburg redefined: Metabolites, mitochondria and macrophages in immune regulation.
  23. Proteasomal surveillance of exposed cysteines.
  24. Unprecedented atlas explores mitochondria across the tree of life.
  25. The malonyl-CoA synthetase ACSF3 is required for metabolic editing downstream of biotin carboxylation.
  26. ATAD-3 couples plasma membrane injury to mitochondrial Ca2+ signaling.
  27. Selenium-associated BHMT2 and DMGDH loci connect one-carbon metabolism, selenoprotein biology, and red blood cell fragility.
  28. Mitochondria-targeted tetraoxanes initiate lipid peroxidation to drive ferroptosis and tumor suppression.
  29. The COX2-PGE2-PKA axis suppresses antiviral immunity by inhibiting mtDNA-dependent STING activation.
  30. Electrostatic control of chromatin compaction safeguards against apoptotic DNA release.
  31. A context-dependent framework for targeting NAD metabolism in cancer.
  32. Cellular self-organization orchestrates ferroptosis propagation.
  33. RMND1 dysfunction causes OXPHOS deficiency and alters mitoribosomal protein homeostasis in vivo.
  34. A health-system-scale, episode-resolved multimodal atlas of cancer cachexia.
  35. Clonal heterogeneity in human pancreatic ductal adenocarcinoma and its impact on tumor progression.
  36. MCT6 is an intestinal Lac-Phe exporter required for metformin-associated weight loss.
  37. Mitochondrial stress induces transcription of cytosolic and mitochondrial protein synthesis components via NHR-180.
  38. SQOR regulates H2S detoxification and lipid metabolism to maintain glioblastoma metabolic fitness.
  39. The p53-p21-Cyclin D2 regulatory axis drives metabolic reprogramming and a distinct senescent macrophage senotype during aging and MASLD.
  40. A CK2-β-TrCP kinase-E3 ubiquitin ligase cascade is a metabolic sensor regulating tryptophan 2,3-dioxygenase stability.
  41. An NAD+-responsive adipose signal coordinates inter-organ defense against muscle atrophy.
  42. Deoxythymidylate Kinase (DTYMK)-Driven Pyrimidine Hypermetabolism Is Associated with a Folate-Dependent Macrophage Programme in Triple-Negative Breast Cancer.
  43. The molecular heterogeneity and clinical impact of genomic driver alterations in prostate cancer.
  44. PTEN-loss confers dependence on the guanylate synthesis enzyme IMPDH in T-cell acute lymphoblastic leukemia.
  45. METTL10 trimethylation of eEF1A at K318 enhances protein synthesis and tumorigenesis.
  46. Systemic proteomic dynamics of acute exercise reveal genetic links to health and disease.
  47. Compartment-specific PPARδ activity controls the outcome of cancer-immune cell competition and immunotherapy efficacy.
  48. Neoplastic and non-neoplastic astrocyte states converge on mesenchymal and injury-response programs during glioblastoma recurrence.
  49. WNK1 links ionic signals to microtubule dynamics to control pyrin inflammasome assembly.
  1. Nat Metab. 2026 Oct 14.
    Genetic modulation of NAD(P)H homeostasis reveals distinct redox-coupled metabolic vulnerabilities.
    Xingxiu Pan, Austin L Zuckerman, Karl N Miller, Marcos G Teneche, Subrata Munan, Andrew Pon, Niklas B Thompson, Rasangi M Perera, Roya AminiTabrizi, Adarsh Rajesh, Sara Violante, Jiwu Wang, Justin R Cross, Peter D Adams, Hardik Shah, Valentin Cracan.
      An elevated NADH/NAD+ ratio (NADH-reductive stress) is a hallmark of mitochondrial dysfunction, yet how it drives pathologies ranging from primary mitochondrial disorders to ageing remains poorly understood1,2. Here, we show that mitochondrial respiratory chain inhibition in primary human fibroblasts induces NADH-reductive stress that coexists with profound NADPH depletion. Using the Escherichia coli soluble transhydrogenase (EcSTH)3 to model this redox coupling in cells with intact mitochondria, we demonstrate that perturbation of both NAD(H) and NADP(H) redox pairs elicits metabolomic and transcriptomic reprogramming, culminating in proliferation arrest with senescence features. Notably, normalizing the NADH/NAD+ ratio alone while NADPH depletion persists fails to rescue proliferation in EcSTH-expressing primary human cells, unlike in transformed HeLa cells. Stable isotope tracing reveals that primary fibroblasts rely more on NADPH-driven reductive carboxylation than HeLa cells, explaining why NADH/NAD+ normalization alone is insufficient for rescue. To test this NADPH dependency, we develop a constitutively active Staphylococcus aureus NAD kinase (SaNADK) that expands the mammalian NADP(H) pool. In fibroblasts, SaNADK restores reductive carboxylation and de novo pyrimidine biosynthesis, and reverses proliferation arrest and senescence features. Furthermore, hepatic SaNADK expression in aged male mice partially alleviates transcriptional signatures of inflammation and metabolic dysregulation. Together, these findings establish EcSTH and SaNADK as xenotopic tools for dissecting NAD(P)H redox coupling and provide a framework for counteracting ageing-associated metabolic decline.
    DOI:  https://doi.org/10.1038/s42255-026-01640-7
  2. Sci Adv. 2026 Oct 16. 12(42): eaef3522
    SPRIZ (CCDC127) protein conserved in deuterostome animals is a rigid OMM-IMM tether that locally sets mitochondrial IMS volume.
    Raman Shulinski, Roman Loban, Danny Farhat, Benjamín Cartes-Saavedra, Matthew J Magda, Pavel Kotchetkov, Victoria Caminiti, Linda David, Yuri I Wolf, Conor O'Dwyer, Morgan Fullerton, Yan Burelle, Jyh-Yeuan Eric Lee, Andrea Raimondi, Eugene V Koonin, György Hajnóczky, Mary-Ellen Harper, Luca Pellegrini.
      The double-membrane nature of mitochondria generates an intermembrane volume through which ions, reactive oxygen species, and metabolites must flux to reach the matrix or cytosol, but whether this volume is a genetically specified structure remains unknown. We identify SPRIZ (spatial regulator of the intermembrane zone), the product of Ccdc127, a gene conserved across deuterostome animals. SPRIZ assembles into an ∼18-nanometer homodimeric tether anchored in the outer mitochondrial membrane (OMM) and inserted into the inner mitochondrial membrane (IMM) through vertebrate-specific hydrophobic loops, physically spacing the two membranes and setting local intermembrane volume. Cryo-electron tomography of native mitochondria revealed rod-like densities spanning the intermembrane space (IMS), consistent with SPRIZ's predicted rigid coiled-coil architecture and membrane-spanning topology. In mouse liver, two-dimensional morphometry measured ∼3-fold expansion of IMS area with SPRIZ and ∼5.5-fold with lengthened mitochondrial artificial increaser of the IMS (MARTINI); 3D electron tomography confirmed MARTINI's greater OMM-IMM separation and normalized IMS volume. This expansion was functionally validated by increased 14C-mannitol accessibility to the IMS and by impaired mitochondrial Ca2+ uptake. Constitutive Ccdc127/SPRIZ knockout produced viable mice and, in liver mitochondria, preserved overall ultrastructure but caused modest IMS expansion, consistent with loss of local OMM-IMM constraints that stabilize membrane geometry at discrete sites. We therefore identify IMS volume as a genetically encoded and tunable architectural parameter of vertebrate mitochondria. In this model, SPRIZ is a molecular spacing system that locally sets OMM-IMM separation, shaping the environment through which metabolites, ions, and signals diffuse and establishing local gradients within the IMS.
    DOI:  https://doi.org/10.1126/sciadv.aef3522
  3. Nat Commun. 2026 Oct 14. pii: 10784. [Epub ahead of print]17(1):
    Regulation of PDH via cysteine oxidation on DLAT.
    Fabiola Garcia-Cortizo, Tobias Weber, Hana Nůsková, Daniel Pfaff, Michael Büttner, Angela Wirth, Elisabeth Kliemank, Gernot Poschet, Marc Freichel, Thomas Fleming, Alba Sulaj, Peter Paul Nawroth, Julia Szendroedi, Aurelio A Teleman.
      Pyruvate dehydrogenase (PDH) complex is a key regulator of metabolism, controlling flux from glycolysis into the tricarboxylic acid (TCA) cycle. PDH is often dysregulated in metabolic diseases and cancer. We discover here that in addition to its well characterized regulation by phosphorylation, PDH activity is also regulated via inhibitory oxidation of three cysteines of the DLAT subunit - Cys488, Cys586 and Cys618. Oxidation of these cysteines increases under oxidative stress, and is highly prevalent in mouse and human tissues. This mechanism enables cells to efficiently fight oxidative stress. Under oxidative stress, cells execute a metabolic shift, blocking glycolytic flux into the TCA cycle to shunt glycolytic carbons toward the pentose phosphate pathway. This generates NADPH which cells use to detoxify H2O2 and to reduce oxidized cysteines. We find that DLAT oxidation is required for cells to mount an effective antioxidant response. Mutations preventing DLAT oxidation render PDH resistant to oxidative inhibition, impair NADPH generation, reduce peroxide detoxification, and sensitize cells to oxidative damage and death. DLAT oxidation also drives a Warburg-like metabolic phenotype of increased glucose uptake, elevated lactate secretion, and reduced TCA cycle activity. Thus DLAT oxidation is a redox-sensing mechanism that regulates PDH activity and central carbon metabolism.
    DOI:  https://doi.org/10.1038/s41467-026-78266-6
  4. Sci Adv. 2026 Oct 16. 12(42): eaef8820
    PINK1-mediated mitophagy supports lung cancer initiation and limits the efficacy of KRAS-targeted therapy.
    Diogo Gonçalves, Emma Guilbaud, Léa Di Mascio, Camille Guerrier, Linda Mejri, Sonia Núñez-Vázquez, Lucie Levasseur, Rachel Paul, Corinne Menigot, Christophe Bontoux, Guylène Rignol, Véronique Hofman, Paul Hofman, Marin Truchi, Bernard Mari, Laurent Yvan-Charvet, Johanna Chiche, Sandrine Marchetti, Jean-Ehrland Ricci.
      Mitophagy, the selective degradation of mitochondria by lysosomes, is a major mitochondrial quality-control pathway, yet its role in lung cancer initiation and therapeutic response remains poorly understood. We investigated PINK1-dependent mitophagy in human lung adenocarcinoma and directly monitored mitophagy in vivo using mito-QC reporter mice during lung tumor development. We found that PINK1 activity and mitophagy are increased in human tumors and are activated from the earliest stages of tumorigenesis. Genetic inhibition of PINK1 impaired oncogenic transformation but had little impact once tumor cells were established, identifying mitophagy as a critical early adaptation during lung cancer initiation. PINK1 deficiency markedly enhanced the efficacy of KRAS-targeted therapy in vitro and in vivo. Together, our findings identify PINK1-dependent mitophagy as an early vulnerability in KRAS-driven lung cancer and provide a rationale for targeting mitophagy to improve the efficacy of KRAS-targeted therapies.
    DOI:  https://doi.org/10.1126/sciadv.aef8820
  5. Dev Cell. 2026 Oct 14. pii: S1534-5807(26)00358-8. [Epub ahead of print]61(10): 1945-1946
    Mitochondria strike two hits to drive the SASP.
    Jun Bum Park, Zhixun Dou.
      Senescent cells develop a persistent inflammatory signature with broad consequences for tissue function and disease. Martini et al.1 show that mitochondrial citrate metabolism drives inflammation through a pathway that acts independently of mitochondrial DNA-driven immune signaling yet cooperates with it to amplify the inflammatory response.
    DOI:  https://doi.org/10.1016/j.devcel.2026.09.010
  6. Neurosci Biobehav Rev. 2026 Oct 13. pii: S0149-7634(26)00494-X. [Epub ahead of print] 107036
    Mitochondrial Psychobiology.
    Ana C Andreazza, Alexander Behnke, Juan P Bolanos, Jaime de Juan-Sanz, Elissa Epel, Michele K Evans, Lisa Feldman Barrett, Lauren E Gyllenhammer, Yusuke Hirabayashi, Michio Hirano, Fiona Hollis, D Parker Kelly, Christopher Kempes, Iris-Tatjana Kolassa, Nick Lane, Mary Kay Lobo, Lilianne R Mujica-Parodi, Aoife O'Donovan, Dost Ongur, Martin Picard, Sarah D Pressman, Carmen Sandi, Orian Shirihai, Caroline Trumpff, Lukas Van Oudenhove, Tor D Wager.
      A field that uses mitochondria to unify biological and psychological sciences and to better understand the basis of health has emerged-Mitochondrial Psychobiology. Mitochondria are the body's cellular hubs for energy transformation and signaling. Mitochondria regulate functions as diverse as metabolism, gene expression, and stress adaptation; consequently, their dysregulation is linked to most chronic illnesses and aging. Here, we propose that mitochondria provide a mechanistic bridge between body and the measurable functions of the mind, including perception, cognition, emotion, and behavior. From this perspective, mitochondria provide a scientifically tractable interface through which bioenergetic processes relate to subjective experiences and behaviors. We outline foundational principles for Mitochondrial Psychobiology, discuss the key gaps that the field needs to address to advance our understanding of mind-mitochondria relationships across the lifecourse, and review emerging approaches to probe the mind-mitochondria connection across levels. This stimulating scientific challenge is a unique opportunity to train the next generation of interdisciplinary scientists, resolve conceptual and technical challenges spanning temporal and spatial scales, and develop a more accurate, holistic model of health. Rooted in general energetic principles, mitochondrial psychobiology is poised to productively steer biomedicine over the coming decades.
    Keywords:  bioenergetics; brain; environment; evolution; mitochondria; modeling; psychopathology; regulation; resilience; robustness; stress; transdisciplinary
    DOI:  https://doi.org/10.1016/j.neubiorev.2026.107036
  7. Mol Cell. 2026 Oct 14. pii: S1097-2765(26)00667-2. [Epub ahead of print]
    STING engages PKR to drive lysosomal cell death in lung ischemia-reperfusion injury.
    Peigen Gao, Tao Wang, Yingjian Liu, Fenghui Zhuang, Chongwu Li, Guodong Wu, Yifang Dang, Huikang Xie, Chenyang Dai, Mengmeng Zhao, Deping Zhao, Xiangyang Wu, Chang Chen, Haipeng Liu, Junqi Wu.
      Stimulator of interferon genes (STING) has been implicated in multiple forms of cell death. However, the effector kinases that couple STING to these death programs remain poorly defined. Here, we show that during lung ischemia-reperfusion injury, mitochondrial DNA release engages the cyclic GMP-AMP synthase (cGAS)-STING pathway to trigger lysosomal cell death (LCD) in mouse and rat models. In human lung epithelial cells, STING oligomerization at the endoplasmic reticulum drives autophosphorylation of double-stranded RNA-dependent protein kinase (PKR) at serine 33. This phosphorylation of PKR activates IκB kinase-NF-κB signaling independently of the canonical STING-TBK1 and PKR-eIF2α pathways. In turn, NF-κB induces LAMP3 transcription, promoting lysosomal membrane permeabilization and LCD. STING-PKR signaling is also observed in patient-derived lung epithelial cells and alveolar organoids. These findings identify PKR as a non-canonical STING effector and show that blockade of STING-PKR signaling attenuates epithelial LCD and lung injury.
    Keywords:  LAMP3; PKR; STING; lung ischemia-reperfusion injury; lysosomal cell death
    DOI:  https://doi.org/10.1016/j.molcel.2026.09.024
  8. Blood Red Cells Iron. 2026 Dec;pii: 100119. [Epub ahead of print]2(4):
    Glucose-6-Phosphate Dehydrogenase Deficiency Reprograms Macrophage Metabolism in Hyperlipidemia.
    Christopher M Clements, Megan Mazzei, Sydney Blimbaum, Ariel M Hay, Francesca I Cendali, Monika Dzieciatkowska, Sotirios P Fortis, Julie A Reisz, Brett P Ransegnola, Coleen A McNamara, James C Zimring, Angelo D'Alessandro.
      Macrophages regulate inflammatory responses in hyperlipidemia and dysmetabolic states while performing a critical homeostatic function by clearing damaged or senescent red blood cells (RBCs) through erythrophagocytosis. This process delivers heme and iron that must be detoxified and recycled through NADPH-dependent pathways. Glucose-6-phosphate dehydrogenase deficiency (G6PDd), affecting ~6% of the global population, limits NADPH generation and predisposes RBCs to oxidative damage and hemolysis. Whether G6PD deficiency alters macrophage metabolic responses to RBC clearance in hyperlipidemic environments remains unknown. Humanized mouse models expressing canonical (hG6PDND), African (hG6PDA-), or Mediterranean (hG6PDMed-) G6PD variants were exposed to Western diet-induced hyperlipidemia. RBCs, plasma, and splenic macrophages were analyzed using metabolomics, lipidomics/oxylipin profiling, and quantitative proteomics. Hyperlipidemia increased circulating lipid species and altered RBC metabolism, while G6PD deficiency selectively reduced pentose phosphate pathway intermediates. Plasma metabolomics revealed signatures consistent with increased hemolysis in hyperlipidemic G6PD-deficient mice. Splenic macrophages from G6PDd animals showed biochemical evidence of erythrophagocytosis, glutathione depletion, and remodeling of central carbon metabolism. Variant-specific alterations included increased glycolytic flux, disrupted TCA cycle activity, and elevated succinate/fumarate ratios consistent with mitochondrial dysfunction. Proteomics revealed extensive mitochondrial and proteasomal remodeling. G6PD deficiency and hyperlipidemia converge to reprogram macrophage metabolism through NADPH limitation, redox imbalance, and impaired handling of RBC-derived metabolites. These findings identify an NADPH-dependent metabolic vulnerability linking RBC fragility, erythrophagocytosis, and inflammatory macrophage reprogramming.
    Keywords:  Erythrophagocytosis; G6PD; Hemolysis; Lipid; Multi-Omics analysis
    DOI:  https://doi.org/10.1016/j.brci.2026.100119
  9. Nat Metab. 2026 Oct 12.
    A multi-fluid exercise proteomic atlas reveals regulators of health and disease.
      
    DOI:  https://doi.org/10.1038/s42255-026-01642-5
  10. Immunity. 2026 Oct 15. pii: S1074-7613(26)00397-3. [Epub ahead of print]
    Lactate dehydrogenase A-dependent redox control of selective mRNA translation directs monocyte fate commitment.
    Ning Yang, Huixia He, Xin Liu.
      Monocyte-to-macrophage differentiation is a central process that shapes immune responses across diverse contexts, yet how inflammatory cues engage metabolism to instruct monocyte fate commitment remains unclear. Here, using a CRISPR-based metabolic screen combined with monocyte-specific perturbations in bacterial lung infection, we identified lactate dehydrogenase A (LDHA) as a key metabolic regulator of monocyte commitment to the nitric oxide synthase 2 (NOS2)+ macrophage fate in vivo. LDHA-dependent cytosolic nicotinamide adenine dinucleotide (NAD+) regeneration enabled selective hypoxia-inducible factor 1-alpha (HIF1α) translation through its 5' untranslated region (UTR) and is associated with structural remodeling of this region. HIF1α then functioned as a downstream effector that promoted the NOS2+ macrophage fate. Granulocyte-macrophage colony-stimulating factor (GM-CSF) further acted as an upstream metabolic priming signal that enhanced LDHA-dependent HIF1α regulation and supported this differentiation process. Together, these findings suggest that metabolic redox state regulates monocyte fate commitment through selective mRNA translation coupled to RNA structural remodeling.
    Keywords:  GM-CSF; HIF1α; LDHA; RNA structural remodeling; cytosolic NAD(+) regeneration; monocyte fate commitment; redox metabolism; selective mRNA translation
    DOI:  https://doi.org/10.1016/j.immuni.2026.09.022
  11. J Cell Sci. 2026 Oct 01. pii: jcs265172. [Epub ahead of print]139(19):
    Pharmacological inhibition of MCL-1 disrupts mitochondrial cristae and depletes the human neural progenitor cell pool.
    Marina R Hanna, James Costanzo, Madison Yarbrough, Melanie Gil, Matthew Murrow, Vivian Gama.
      Myeloid cell leukemia 1 (MCL-1) is a canonical anti-apoptotic protein crucial for early neurodevelopment. Loss of MCL-1 results in embryonic-lethal neurodevelopmental defects that cannot be rescued by other anti-apoptotic proteins of the B cell lymphoma 2 (BCL-2) family. Here, we pharmacologically inhibit MCL-1 in human neural progenitor cells and find non-apoptotic roles for MCL-1 in sustaining mitochondrial cristae integrity, fatty acid oxidation and neural progenitor identity. MCL-1 inhibition disrupts mitochondrial ultrastructure, leading to a swollen network with disorganized cristae and destabilized OPA1-MICOS machinery that fails to maintain inner mitochondrial membrane architecture. These structural defects are accompanied by displacement of ACSL1 from the outer mitochondrial membrane, impaired fatty acid oxidation, lipid droplet accumulation and reduced mitochondrial oxygen consumption, revealing a tight link between cristae architecture and metabolic competence. Mechanistically, MCL-1 acts through two coordinated functions: maintaining cristae integrity at the inner mitochondrial membrane and retaining ACSL1 at the outer mitochondrial membrane, both independently of caspase activation. Functionally, MCL-1 inhibition selectively depletes intermediate progenitor cells without affecting proliferation, indicating a direct role in lineage progression. Together, our findings position MCL-1 upstream of OPA1, MICOS and ACSL1, and identify it as a critical coordinator of cristae organization, lipid metabolism and neural progenitor fate. This establishes mitochondrial inner membrane architecture as an instructive determinant of human neurogenesis and highlights non-canonical MCL-1 functions as critical regulators of human brain development.
    Keywords:  ACSL1; Cristae; Intermediate progenitors; MCL-1; MICOS; Mitochondria; Neural progenitor cells; OPA1
    DOI:  https://doi.org/10.1242/jcs.265172
  12. Nat Genet. 2026 Oct 12.
    Micronuclear ecDNA constrains tumor cell fitness and is associated with favorable patient survival.
    Lotte Brückner, Robin Xu, Jun Tang, Aditi Gnanasekar, Alexander Herrmann, Ivy Tsz-Lo Wong, Shu Zhang, Fengyu Tu, Madison Pilon, Alexander Kukalev, Katharina Pardon, Olga Sidorova, Joshua Atta, Qinghao Yu, Giulia Montuori, Davide Pradella, Mila Ilić, Kentaro Suina, Marco Novais-Cruz, Sarah Kaltenbach, Denise Treue, Mădălina Giurgiu-Kraljič, Sergej Herzog, Ann-Sophie Hollinger, Nadine Wittstruck, Martina Fernandez, Nicole Wolozyn, Finnja Becker, Varvara-Rigina Louma, Xiaowei Yan, Rachel Schmargon, Jan R Dörr, David Gamlin, Annika Lehmann, Dennis Gürgen, Matthias Richter, Frank Dubois, Fabrizio Simeoni, Betheney R Pennycook, Alastair Hamilton, Ralph K Lindemann, Courtney Dawes, Gabriel Balmus, Barbara Hero, Matthias Fischer, Vineet Bafna, Roel Verhaak, Geoffrey Wahl, Yang Liu, Richard P Koche, Stamatis Papathanasiou, René Medema, Bastiaan Spanjaard, Andrea Ventura, Ana Pombo, Weini Huang, Monika Scheer, Benjamin Werner, Howard Y Chang, Paul S Mischel, Anton G Henssen.
      Extrachromosomal DNA (ecDNA) contributes to cancer genome instability by enabling high-copy oncogene amplification and genetic intratumoral heterogeneity. Micronuclei (MNs) are common in chromosomally unstable cancers, yet their role in ecDNA-driven tumors remains unclear. Here we investigate how ecDNA damage, mitotic segregation and MN formation are linked. We find that ecDNAs are a major source of MNs following their damage, particularly under replication stress. Replication stress promotes mitotic ecDNA clustering, asymmetric inheritance, mis-segregation into MNs and reduced transcriptional output. Single-MN sequencing reveals that multiple distinct ecDNA species coalesce within individual MNs. Cells inheriting ecDNA+ MNs display impaired proliferative capacity and are more likely to undergo cell death. In patients with MYCN-amplified neuroblastoma, higher frequencies of ecDNA+ MNs at diagnosis are associated with improved overall survival. Together, these findings identify ecDNA mis-segregation as a mechanism that limits tumor fitness, highlighting mitotic ecDNA retention as a potential therapeutic vulnerability.
    DOI:  https://doi.org/10.1038/s41588-026-02782-w
  13. bioRxiv. 2026 Sep 28. pii: 2026.09.24.754188. [Epub ahead of print]
    Combined Loss of VHL and TSC1 Drives Clear Cell Renal Cell Carcinoma with Metabolic and Redox Reprogramming that Creates an NRF2 Dependency.
    Jianing Xu, Xiaoqing Cheng, Omran A Aboud, Yingbei Chen, Ann Bialik, Ed Reznik, Toshinao Oyama, Satish Tickoo, Robert H Weiss, Emily H Cheng, James J Hsieh.
      Cancer genomics studies have implicated combined loss of VHL and TSC1 as sufficient to initiate clear cell renal cell carcinoma (ccRCC) in humans. Here, we engineered a mouse model with kidney-specific deletion of Vhl and Tsc1. VhlF/FTsc1F/FKsp-Cre+ mice developed multifocal renal cell carcinomas starting at 7 weeks of age with 100% penetrance, and the resulting Vhl-/-Tsc1-/- tumors recapitulated the histopathology of human VHL-/-TSC1-/- ccRCC. Integrated transcriptomic and metabolomic analyses of 4-week-old preneoplastic renal cortices deficient for Vhl and Tsc1 demonstrated heightened HIF and mTORC1 signaling and unexpectedly revealed activation of an antioxidant response regulated by NRF2 (NFE2L2). Biochemical, cell biological, multi-omic, and xenograft studies identified an NRF2 dependency in human VHL-/-TSC1-/- ccRCC cells. Altogether, we report a mouse model that recapitulates human VHL-/-TSC1-/- ccRCC, delineate metabolic and redox reprogramming driven by unrestrained HIF and mTORC1 activation in the renal cortex, and identify NRF2 as a potential therapeutic vulnerability.
    DOI:  https://doi.org/10.64898/2026.09.24.754188
  14. Aging Cell. 2026 Oct;25(10): e70771
    Mitochondrial Genetic Background Shapes Baseline Retinal Function, Age-Related Bioenergetic Remodeling, and Microglial STING Phenotypes.
    McKenna M Somerville, Sydney S Lin, Scott W Ballinger, Alecia K Gross.
      Mitochondria are central regulators of retinal bioenergetics and innate immune signaling, yet how mitochondrial genetic background and aging jointly influence immunometabolic responses in the retina remains poorly defined. Here, we investigated the effects of mitochondrial DNA (mtDNA) variation on retinal function and the combined effects of mtDNA variation and age on bioenergetic composition, mtDNA damage, and the microglial expression and intracellular localization of stimulator of interferon genes (STING) protein. Using mitochondrial-nuclear eXchange (MNX) mice harboring identical C57BL/6J nuclear genomes but distinct C57 or C3H mtDNA haplotypes, we assessed oxidative phosphorylation complex composition, electrophysiological function, mtDNA damage, and microglial STING dynamics across the lifespan and following acute intraocular pressure (IOP) elevation. Aging was associated with increased mtDNA damage and remodeling of oxidative phosphorylation complex composition, characterized by reduced Complex III and V abundance and increased Complex IV. Despite these age-associated changes, photoreceptor- and retinal ganglion cell-associated retinal responses were preserved at early ages, whereas bipolar cell-associated responses differed by mtDNA background. Microglial STING expression increased with age. Acute IOP elevation was associated with differential microglial STING dynamics and STING association with lysosomal compartments decreased with age. Together, these findings demonstrate that mitochondrial genetic background and aging influence retinal bioenergetics and neuroimmune protein expression and identify mtDNA variation as a modifier of age-associated microglial STING expression in the retina.
    Keywords:  metabolism; microglia; neuroinflammation; retina
    DOI:  https://doi.org/10.1111/acel.70771
  15. bioRxiv. 2026 Oct 01. pii: 2026.09.26.754222. [Epub ahead of print]
    Nuclear acetyl-CoA accumulation drives reversible RBP hyperacetylation and transcriptome-wide splicing shifts in age-equivalent Alzheimer's disease neurons.
    Larissa Traxler, Oliver Borgogno, Kylie Champion, Joseph R Herdy, Monika Dzieciatkowska, Julie A Reisz, Ayk Petrosyan, Cat Siler, Colin C Anderson, Elisa Gorostieta-Salas, Raffaella Lucciola, Douglas Galasko, Fred H Gage, Angelo D'Alessandro, Jerome Mertens.
      Metabolic alterations and dysregulated alternative RNA splicing are central layers of Alzheimer's disease (AD) pathogenesis, yet whether and to what extent these changes are mechanistically linked in adult human neurons in the aging brain remains unclear. To assess this, we generated induced neurons (iNs) by direct conversion of fibroblasts from sporadic AD patients and age-matched control donors. Fibroblast-derived iNs retaining donor-specific aging signatures have been shown to display several AD-related phenotypes. Metabolomic analysis revealed that AD iNs divert citrate toward ATP-citrate lyase (ACLY)-dependent citrate-to-acetyl-CoA flux, which drives increased nuclear levels of the high-energy metabolite acetyl-CoA. Acetyl-proteomics showed that acetyl-CoA accumulation leads to widespread hyperacetylation of RNA-binding proteins (RBPs) and splice regulators, suggestive of a direct mechanistic link between a metabolic shift and RNA processing. Indeed, single-cell long-read RNA sequencing identifies splicing alterations in AD-relevant transcripts whose isoform usage mirrors changes observed in post-mortem AD cortex samples. Subcellular acetyl-CoA imaging reveals that inhibition of ACLY enzymatic activity selectively reduces nuclear acetyl-CoA levels, and further improves citrate metabolic flux, normalizes RBP acetylation, and re-establishes a normal neuronal splicing landscape in AD iNs. Together, these findings reveal a nuclear acetyl-CoA-RNA processing axis that links age- and disease-related metabolic alterations to alternative splicing dysregulation in AD, and identify neuronal nuclear acetyl-CoA production as a causal and reversible node for restoring metabolic and RNA homeostasis in aging human AD neurons.
    Highlights: Sporadic Alzheimer's disease (AD) patient-derived directly induced neurons (iNs) shift metabolism toward nuclear acetyl-CoA production via ATP-citrate lyase (ACLY).Elevated nuclear acetyl-CoA causes hyperacetylation of RNA-binding proteins (RBPs).Patient iNs show pathogenic RNA splicing patterns similar to post-mortem AD brains.Inhibition of ACLY normalizes neuronal acetyl-CoA metabolism and restores RNA splicing homeostasis.
    DOI:  https://doi.org/10.64898/2026.09.26.754222
  16. Cell Rep. 2026 Oct 13. pii: S2211-1247(26)01215-5. [Epub ahead of print]45(10): 118136
    A systemic circadian nicotinic acid riboside (NaR) signal engages the unfolded protein response and adipogenesis via the prefoldin complex.
    Ivan Vlassakev, Christina Savva, Liying Zhou, Danilo Ritz, Alexander Schmidt, Cholsoon Jang, Amir Ata Saei, Paul Petrus.
      Daily light-dark cycles impose environmental fluctuations that require coordinated regulation of physiology. This coordination is mediated by the circadian clock, which operates as a network of tissue oscillators; however, the signals that convey circadian information between organs remain incompletely defined. We identify nicotinic acid riboside (NaR) as a circulating metabolite whose rhythmicity depends on the liver clock. In adipocytes and neuronal cells, NaR engages the unfolded protein response (UPR). Proteome-wide stability profiling implicates the prefoldin complex as a target of NaR, linking NaR exposure to altered proteostasis. In adipocytes, NaR-induced UPR signaling converges on the transcription factor CCAAT/enhancer-binding protein alpha (CEBPA). Sustained NaR exposure suppresses adipocyte lipid deposition, whereas temporally restricted NaR stimulation enhances adipogenesis. Together, these findings identify NaR as a liver clock-controlled circulating metabolite that couples systemic circadian metabolism to proteostasis and tissue remodeling, revealing a mechanism by which temporal metabolic signals shape tissue-specific physiological outcomes.
    Keywords:  CP: metabolism; CP: molecular biology; adipocyte; circadian rhythms; metabolism; organ communication; systems biology; unfolded protein response
    DOI:  https://doi.org/10.1016/j.celrep.2026.118136
  17. bioRxiv. 2026 Sep 29. pii: 2026.09.28.755151. [Epub ahead of print]
    Dynamic protein phosphorylation shapes mitochondrial catalysis, import, and architecture.
    Andrew J Smith, Patrick Forny, Sean W Rogers, Merima Forny, David J Pagliarini.
      Phosphorylation is a pervasive mitochondrial protein post-translational modification, yet the extent of its influence over mitochondrial functions remains unclear. To identify dynamic mitochondrial phosphoisoforms, we profiled the phosphoproteome of AML12 cells following individual genetic perturbations of 10 resident mitochondrial phosphatases. Guided by these results, we investigated the functional implications of phosphorylation on mitochondrial processes related to catalysis, import, and morphology. We find that phosphorylation of adenylate kinase 2 suppresses its nucleotide binding and catalytic activity. Elevated phosphorylation proximal to the mitochondrial targeting sequence of branched chain ketoacid dehydrogenase kinase disrupts its import and processing, resulting in enhanced catabolism of branched chain amino acids. Most notably, we discover extensive phosphorylation on proteins involved in mitochondrial cristae architecture, including multiple members of the MICOS complex and ATP synthase, upon silencing the phosphatase PGAM5. Collectively, our work connects reversible phosphorylation and resident phosphatases to the regulation of diverse mitochondrial processes.
    HIGHLIGHTS: Perturbation of 10 mitochondrial resident phosphatases maps dynamic phosphosites.AK2 S151 phosphorylation tunes catalysis by augmenting adenine nucleotide binding.MTS-proximal BCKDK phosphorylation impairs protein import and gates BCAA catabolism.MIC19 and ATP5I phosphorylation remodels cristae and modulates bioenergetics.
    DOI:  https://doi.org/10.64898/2026.09.28.755151
  18. FASEB J. 2026 Oct 31. 40(20): e72363
    Mitochondrial Supercomplex-Associated Proximity Increases in Malignant Glioma Tissue.
    Minou Tsujishita, Haesoo Bae, Anwaar Ali, Shanmuganathan Balakrishnan, Amina Abulimiti, Nelofer Syed, Kambiz N Alavian.
      In rapidly growing tumors, including gliomas, heterogeneous microenvironments with fluctuating oxygen and nutrient availability impose strong selective pressure for metabolic adaptation. For over a century, mitochondria have been recognized as central to the reprogramming of cancer metabolism. However, it remains unclear whether and how remodeling of oxidative phosphorylation (OXPHOS), including organization of electron transport chain (ETC) complexes, contributes to the proliferation of cancer cells. Recent reports suggest that mitochondrial supercomplexes (SCs), higher-order assemblies of ETC complexes, are enriched in tumor cells and may support proliferation by increasing respiratory efficiency and stabilizing electron transfer. Here, we evaluated respiratory SC formation across glioma grades by quantifying ETC complex proximity within mitochondria in patient tissue using proximity ligation assay (PLA). We observed increased PLA signal between ETC complexes I and IV, consistent with increased respirasome assembly, that was associated with malignant glioma (Grades III and IV), and increased proximity between ETC Complexes III and IV that was most prominent in proliferating glioblastoma (Grade IV) cells. Although the precise functions of SCs remain debated, these increases in high-grade glioma relative to Grade II and control tissue suggest that SC remodeling may be a feature of malignant glioma metabolic remodeling.
    DOI:  https://doi.org/10.1096/fj.202600937RR
  19. bioRxiv. 2026 Oct 01. pii: 2026.09.30.755771. [Epub ahead of print]
    Simulated microgravity induces aging phenotypes in human organoids.
    Wei-Chieh Mu, Jordan Baechle, Kevin Schneider, Matias Fuentealba, Fei Wu, Max Manwaring-Mueller, Nathan Bracey, Alexander Chebykin, Abhayjit Saini, Jiwoon Park, JangKeun Kim, Daniel A Winer, Alan I Gale, Christopher E Mason, Mark M Davis, David Furman.
      Simulated microgravity provides a controlled perturbation for testing how loss of mechanical load affects human tissues. After 24 hours in rotating-wall vessels, neural, cardiac and tonsil organoids developed tissue-specific transcriptional responses that overlapped published spaceflight datasets, accompanied by higher transcriptomic-age estimates in neural and cardiac models, altered cardiac-organoid contraction dynamics and modified tonsil-organoid antiviral gene-expression signatures. These findings establish a multi-organoid framework for studying acute responses to gravitational unloading.
    DOI:  https://doi.org/10.64898/2026.09.30.755771
  20. Nat Aging. 2026 Oct;6(10): 2057-2073
    Transcriptomic reprogramming screen identifies SRSF1 as a regulator of aging.
    Alexandru M Plesa, Sascha Jung, Helen H Wang, Fawad Omar, Michael Shadpour, David Choy Buentello, Maria C Perez-Matos, Naftali Horwitz, George Cai, Zhen Kai Ngian, Carol Magalhaes, Amy J Wagers, William B Mair, Antonio Del Sol, George M Church.
      Aging is characterized by progressive functional decline accompanied by distinct transcriptomic and epigenetic alterations. Although partial reprogramming via Yamanaka factors can reverse these signatures and improve cell function, toxicity and efficacy concerns limit their in vivo application, necessitating alternative geroprotective interventions. Here we develop an interpretable transcriptomic age predictor in human fibroblasts and perform a cDNA overexpression screen to identify factors that reprogram aged transcriptomes toward youthful states. This screen identifies the RNA-processing and splicing factor SRSF1 as a regulator of cellular aging that produces robust youthful transcriptional signatures without loss of cellular identity. In vitro, SRSF1 induction restores youthful phenotypes by reducing senescence, proteostatic stress and inflammatory signaling. In aged mice, inducible SRSF1 expression reduces frailty progression by 44% and is associated with a 14% extension of median lifespan (n = 9-10 per group). Our findings establish SRSF1 as a conserved regulator of aging and a promising geroprotective target.
    DOI:  https://doi.org/10.1038/s43587-026-01234-8
  21. Mol Cell. 2026 Oct 15. pii: S1097-2765(26)00661-1. [Epub ahead of print]
    Inherent electrochemical activity of extrachromosomal DNA hub shapes spatial redox environment in nucleus.
    Luning Qin, Ting Wu, Shuai Qiao, Shaoting Zheng, Jieshi Zhou, Bijia Cui, Xueting Zhen, Michael W Chen, Yifan Dai, Heng Zhang, Tao Sun.
      Extrachromosomal DNA (ecDNA) is a key element driving the malignant progression of tumors. Since ecDNA lacks canonical high-order chromatin compaction, how it maintains structural and functional stability in highly oxidizing tumor environments remains unclear. Using metabolomics, biochemistry, and imaging assays in human cancer cells and mouse models, we herein show that ecDNA hub establishes an active electrochemical environment, which drives the reduction of oxidized glutathione (GSSG) to reduced glutathione (GSH) through a non-enzymatic mechanism. GSH forms a protective "cloud" around ecDNA hubs, shielding ecDNA from damage and sustaining oncogene expression. Lastly, using spermidine, which disrupts the interfacial environment of ecDNA hubs, we found that affecting the redox balance of ecDNA hubs drives tumor death. This study uncovers a non-enzymatic function of ecDNA hubs that establishes a self-reinforcing maintenance loop to regulate spatial redox environments, revealing an electrochemical environment-dependent redox-regulation strategy in cancer biology.
    Keywords:  GSH/GSSG; ecDNA hub; non-enzymatic electrochemical activity; redox; spermidine
    DOI:  https://doi.org/10.1016/j.molcel.2026.09.018
  22. J Physiol. 2026 Oct 16.
    Warburg redefined: Metabolites, mitochondria and macrophages in immune regulation.
    Yukun Min, Órlaith C Henry, Luke A J O'Neill.
      Nearly 100 years ago, Otto Warburg observed that cancer cells preferentially use glycolysis even in the presence of oxygen, supporting rapid cell growth. Since then, the concept of the Warburg effect has expanded far beyond tumour bioenergetics and is now recognised as a key feature of immune cell activation. A notable example is in macrophages, which, following pro-inflammatory stimulation, undergo Warburg-like metabolic reprogramming, characterised by increased glycolysis. Recent studies have shown that accumulated metabolites such as lactate have a range of immunoregulatory functions that shape macrophage inflammatory responses. In addition, glycolytic enzymes have been found to exert non-canonical functions that directly regulate macrophage immune signalling. Mitochondria, once considered suppressed during Warburg reprogramming, also undergo profound changes, with the electron transport chain generating reactive oxygen species and metabolites such as succinate, fumarate and itaconate playing complex immunoregulatory roles, and mitochondrial dynamics actively shaping metabolism and immune responses. Together, these findings redefine the Warburg effect in macrophages as a coordinated metabolic and signalling process that integrates glycolysis, mitochondrial function and immunometabolite signalling to optimise context-dependent immune responses.
    Keywords:  ETC; TCA cycle; Warburg metabolism; glycolysis; itaconate; lactate; macrophage; mitochondria
    DOI:  https://doi.org/10.1113/JP291073
  23. bioRxiv. 2026 Sep 30. pii: 2026.09.29.755535. [Epub ahead of print]
    Proteasomal surveillance of exposed cysteines.
    Elijah L Mena, Ken C Dong, Anthony Kairouz, Katherine A Donovan, Mostafa A Soliman, Hai-Tsang Huang, Bercin Yildiran, Eric S Fischer, Richard I Sherwood, Richard T Timms, Andreas Martin, Stephen J Elledge.
      Cysteine residues are critical for both the catalytic activity and structural stability of many proteins, yet their high chemical reactivity threatens proteome integrity. Whether cells have specialized mechanisms to recognize and eliminate proteins with aberrant or exposed cysteines is unknown. By systematically analyzing the stability of thousands of cysteine-containing peptides, here we identify two complementary surveillance mechanisms targeting proteins with exposed cysteine residues. First, a set of E3 ubiquitin ligases - including AMBRA1, TRPC4AP, FBXO3, and FBXO21 - detects double cysteines and targets proteins for ubiquitin-dependent proteasomal degradation. Second, the PSMD14/Rpn11 subunit of the 26S proteasome recognizes exposed cysteines in a ubiquitin-independent manner. Both pathways function in quality control to clear misfolded proteins exposing cysteine residues, including zinc finger-containing proteins. Mutational escape from the ubiquitin-independent pathway through dysregulation of ornithine decarboxylase or FOS levels is responsible for two human diseases, Bachmann-Bupp Syndrome and osteoblastoma, respectively. Our findings reveal conserved mechanisms for degrading proteins with exposed cysteines and uncover an alternative mode of substrate recognition by the 26S proteasome.
    Keywords:  26S proteasome; FOS; UPS; cysteine; ornithine decarboxylase (ODC); proteostasis; ubiquitin-independent degradation; zinc
    DOI:  https://doi.org/10.64898/2026.09.29.755535
  24. Nature. 2026 Oct 16.
    Unprecedented atlas explores mitochondria across the tree of life.
    Miryam Naddaf.
      
    Keywords:  Cell biology; Drug discovery
    DOI:  https://doi.org/10.1038/d41586-026-03195-9
  25. J Biol Chem. 2026 Oct 14. pii: S0021-9258(26)02520-2. [Epub ahead of print] 113648
    The malonyl-CoA synthetase ACSF3 is required for metabolic editing downstream of biotin carboxylation.
    Joseph Choi, Jasmine Encarnacion, Daria Kurganova, Susanna Scafidi, Michael J Wolfgang.
      Acsf3, a mitochondrial malonyl-CoA synthetase, is mutated in the human inborn error Combined Malonic and Methylmalonic Aciduria. To clarify its role in mammalian metabolism, we generated Acsf3 knockout mice. We show that the loss of Acsf3 results in high concentrations of malonate and methylmalonate and exhibit expected defects in mitochondrial metabolism, but the KO mice are largely healthy similar to the human inborn error. Acsf3 KO mice exhibit redundancy in malonyl-CoA synthetase activity suggesting a genetic modifier of disease severity. Malonate and methylmalonate are metabolic poisons generated as a by-product of biotin dependent carboxylation that require metabolic editing. Indeed, the liver-specific loss of the biotin ligase, Holocarboxylase Synthetase (hlcs), inhibits all biotin dependent carboxylation and results in broad changes in liver mRNA, protein, posttranslational and metabolic regulation. Loss of Hlcs suppresses the metabolic deficits in Acsf3KO liver due to the inhibition of malonate and methylmalonate generation. Mice with a double knockout of Acsf3 and Hlcs maintained mitochondrial lipoylation demonstrating the highly redundant generation of mitochondrial malonyl-CoA. These data define the role of Acsf3 in metabolic editing of malonate and methylmalonate to maintain mitochondrial metabolism in the face of endogenously produced anti-metabolites.
    Keywords:  biotin; metabolic disease; metabolomics; mitochondrial metabolism; proteomics; tricarboxylic acid cycle
    DOI:  https://doi.org/10.1016/j.jbc.2026.113648
  26. Nat Commun. 2026 09 10. pii: 10690. [Epub ahead of print]17(1):
    ATAD-3 couples plasma membrane injury to mitochondrial Ca2+ signaling.
    Shiqi Xu, Yi Peng, Hengda Zhou, Xuecong Ren, Xin Wang, Zhenguang Ying, Meijiao Li, Yujie Sun, Bing Yang, Mao Zhang, Chonglin Yang, Weirui Ma, Suhong Xu.
      Mitochondrial Ca2+ uptake couples cellular Ca2+ signals to mitochondrial metabolism and stress responses and is primarily mediated by the mitochondrial Ca2+ uniporter (MCU). Here, we identify an ATAD-3-dependent mechanism that promotes mitochondrial Ca2+ uptake following plasma membrane injury in C. elegans. Living imaging reveals robust, albeit delayed, mitochondrial Ca2+ influx following injury in mcu-1 mutants, indicating the existence of a compensatory Ca2+ uptake mechanism. RNAi screen identifies the conserved AAA+ ATPase ATAD-3 as an essential regulator of this pathway, whereas MICU-3 acts as a negative regulator. Wounding induces ATAD-3 oligomerization and mitochondrial enrichment, which are enhanced in mcu-1 mutants. Disrupting ATAD-3 oligomerization or expression of disease-associated ATAD-3 variants abolishes wounding-induced mitochondrial Ca2+ uptake. Structure modeling predicts that oligomeric ATAD-3 adopts a channel-like architecture. These findings uncover ATAD-3 as a context-dependent regulator of mitochondrial Ca2+ homeostasis during cellular stress and provide insight into how this process may be disrupted in disease.
    DOI:  https://doi.org/10.1038/s41467-026-77690-y
  27. Blood Red Cells Iron. 2026 Sep 07. pii: 100132. [Epub ahead of print]
    Selenium-associated BHMT2 and DMGDH loci connect one-carbon metabolism, selenoprotein biology, and red blood cell fragility.
    Daniel Stephenson, Gregory R Keele, Julie A Reisz, Travis Nemkov, Amy Argabright, Mars Stone, Steve Kleinman, Michael P Busch, Philip J Norris, Grier P Page, Angelo D'Alessandro.
      Storage of red blood cells (RBCs) in the blood bank promotes the accumulation of lesions, including metabolic decline, oxidative injury, membrane remodeling, vesiculation, and hemolysis. Genetic and multi-omic studies implicate iron-dependent lipid peroxidation and ferroptosis-like biology in poor RBC storage quality and post-transfusion recovery, highlighting GPX4, a selenium-dependent antioxidant enzyme, as a candidate modifier of stored RBC fragility. Although the genetic and omic determinants of GPX4 heterogeneity in donated RBCs have been explored, inter-donor variability in RBC selenium levels remains untested. To bridge this gap, selenium was measured by inductively coupled plasma mass spectrometry in 637 blood donors and integrated with stored RBC metabolomics, lipidomics, proteomics, extracellular vesicle and mitochondrial DNA markers, hemolysis phenotypes, and genotypes. Selenium showed broad inter-donor variation but minimal association with age, sex, or BMI. Selenium correlated with day-42 RBC multi-omic features, including iron, zinc, metabolites, lipids, proteins, and EV/mtDNA markers, and showed modest associations with osmotic hemolysis and complete blood count hemoglobin levels. Comparison of high- versus low-selenium donors identified differences in selected selenoprotein trajectories, strongest for GPX1. GWAS of selenium identified chromosome 5 loci near BHMT2 and DMGDH, including an intronic BHMT2-region variant and a DMGDH S279P missense variant. In approximately 13,000 donors from the REDS RBC-Omics index cohort, these loci associated with one-carbon metabolites, selenium-related proteins, detectable RBC selenoproteins, and osmotic hemolysis. These data identify selenium as a genetically anchored axis of RBC storage biology linking one-carbon metabolism, selenoprotein/redox pathways, and selected features of erythrocyte fragility.
    Keywords:  GPX4; Selenium; ferroptosis; one-carbon metabolism; red blood cells; selenoproteins; storage lesion; transfusion medicine
    DOI:  https://doi.org/10.1016/j.brci.2026.100132
  28. Cell. 2026 Oct 15. pii: S0092-8674(26)01141-4. [Epub ahead of print]
    Mitochondria-targeted tetraoxanes initiate lipid peroxidation to drive ferroptosis and tumor suppression.
    Zijian Pan, Ming-Kwan Wong, Yang Lu, Jingxuan Mao, Fengxiang Wang, Xin Gu, Kaiyin Huang, Taotao Shi, Tianshu William Wu, Yuxuan Zhu, Yuan Zhang, En Chen, Jingrong Regina Han, Yunfei Qiu, Lei Zhou, Yinxin Li, Peng Lin, Zhibin Li, Shan Deng, Yingshan Fang, Qi Xie, Jian Cao, Nathchar Naowarojna, Dan Yang, Yilong Zou.
      Ferroptosis is implicated as a vulnerability in multiple cancers, yet approaches for effectively inducing ferroptosis in vivo are limited. Bypassing conventional strategies targeting the antiferroptotic glutathione peroxidase 4 (GPX4) and ferroptosis suppressor protein 1 (FSP1) proteins, we designed metabolic initiators of lipid peroxidation (MILPOs) and developed the compounds WMK-1/2, which contain tetraoxane radical-generating and mitochondria-targeting groups, as de novo ferroptosis inducers. WMK-1 localizes primarily to mitochondria, induces local lipid peroxidation, and impairs oxidative phosphorylation. WMK-1 induces a "mito-ferroptosis" sub-pathway that skips GPX4 inhibition as a prerequisite, can be rescued by lipophilic radical-trapping antioxidants, yet is minimally sensitive to acyl-coenzyme A synthetase long-chain family member 4 (ACSL4) perturbation and long-chain polyunsaturated fatty acid (PUFA) supplementation, and evades retinol-mediated protection. Instead, WMK-1-induced cell death requires labile Fe2+ and can be selectively suppressed by ɑ-lipoic acid, an endogenous, mitochondria-resident antioxidant. WMK-1/2 are bioavailable and exhibit significant efficacy in tumor suppression by eliciting ferroptosis in multiple cancer models and augmenting the antitumor effects of immune-checkpoint blockers. Our work provides a protein-targeting-independent metabolic ferroptosis induction strategy for potential cancer therapy.
    Keywords:  cancer and metastasis; ferroptosis induction; iron metabolism; metabolic initiator of lipid peroxidation; mito-ferroptosis; mitochondria; tetraoxanes
    DOI:  https://doi.org/10.1016/j.cell.2026.09.040
  29. Cell Rep. 2026 Oct 16. pii: S2211-1247(26)01233-7. [Epub ahead of print]45(10): 118154
    The COX2-PGE2-PKA axis suppresses antiviral immunity by inhibiting mtDNA-dependent STING activation.
    Pham Thuy Tien Vo, Julien Cicero, Zichen Wang, Hiroyuki Hakozaki, Thomas S Hoang, Sendi Rafael Adame-Garcia, Dana J Ramms, Kuniaki Sato, Erica Stevenson, Yuan Zhou, Katie Fan, Juliette A Bokor, Vasiliya Kril, Cara Schiavon, Scott B Biering, Danielle L Swaney, Nevan J Krogan, Johannes Schöneberg, Uri Manor, J Silvio Gutkind.
      The stimulator of interferon genes (STING) pathway is essential for mounting robust innate immunity, yet its chronic activation can drive detrimental inflammation. Although multiple cell-autonomous mechanisms that restrain STING signaling have been reported, whether inflammatory mediators within the tissue microenvironment regulate STING activation remains elusive. Using herpes simplex virus type 1 infection as a model of STING activation, we revealed that the COX2-PGE2-PKA axis functions as a critical negative regulator of STING-mediated antiviral innate immunity. Mechanistically, PGE2 acts through the EP4-PKA cascade to induce PTEN-induced kinase 1 (PINK1)-mediated mitophagy by phosphorylating STOML2 at Ser29. This pathway facilitates the clearance of damaged mitochondria that serve as a source of immunostimulatory cytosolic mitochondrial DNA, thereby attenuating downstream STING activation and type I interferons while promoting viral replication. Together, these findings establish mitochondrial quality control as the mechanistic link between PGE2 signaling and mtDNA-dependent STING activation and identify the COX2-PGE2-PKA pathway as a druggable therapeutic target to enhance STING-mediated innate immunity.
    Keywords:  CP: immunology; EP4; STING signaling; antiviral innate immunity; cyclooxygenase-2; herpes simplex virus type 1; mitochondrial DNA; mitophagy; prostaglandin E2; protein kinase A; type I interferons
    DOI:  https://doi.org/10.1016/j.celrep.2026.118154
  30. EMBO J. 2026 Oct 16.
    Electrostatic control of chromatin compaction safeguards against apoptotic DNA release.
    Maximilian F D Spicer, Sanne Wijma, Nikki Schütte, Jan Huertas, M Julia Maristany, José Ignacio Pérez López, Lifeng Chen, Mustafa Alaabo, Michael K Rosen, Rosana Collepardo-Guevara, Daniel W Gerlich.
      Apoptosis involves extensive intracellular reorganisation to facilitate the clearance of dying cells. A key step in this process is the destruction of the genome through fragmentation by caspase-activated DNase (CAD). Rather than dispersing after CAD-mediated cleavage, DNA fragments are compacted into a dense chromatin compartment, but the underlying mechanism and biological relevance of this compaction remain unknown. Here we show that global deacetylation of histone tails promotes chromatin compaction during apoptosis, preventing DNA release into apoptotic extracellular vesicles. Using synthetic effectors that modulate nucleosome electrostatics independently of histone modifications, we demonstrate that electrostatic attraction alone is sufficient to compact and sequester fragmented chromatin. These findings reveal a mechanism by which global reprogramming of histone modifications coordinates genome fragmentation with its physical sequestration during apoptosis. Our synthetic approach further provides a tool to probe how physical forces contribute to genome organisation across diverse biological contexts.
    DOI:  https://doi.org/10.1038/s44318-026-00932-8
  31. Cell Metab. 2026 Oct 15. pii: S1550-4131(26)00390-6. [Epub ahead of print]
    A context-dependent framework for targeting NAD metabolism in cancer.
    Leire Arrizabalaga, Laura Santambrogio, Guido Kroemer, Lorenzo Galluzzi, Aitziber Buqué.
      Nicotinamide adenine dinucleotide (NAD) occupies a privileged position at the intersection of cellular bioenergetics, redox homeostasis, and signal transduction. Beyond its canonical role in ATP synthesis, NAD serves as an obligate cofactor for enzymes including poly(ADP-ribose) polymerases (PARPs), sirtuins, and CD38, thereby regulating DNA repair, epigenetic remodeling, and inflammatory signaling. Thus, NAD metabolism supports the preservation of cellular homeostasis against oncogenic insults. Malignant transformation, however, imposes substantial biosynthetic and genotoxic stress, often driving metabolic adaptations that amplify NAD production via nicotinamide phosphoribosyltransferase (NAMPT). This endows cancer cells with enhanced proliferative capacity, stress tolerance, and immunoevasive features. Importantly, the dependence of malignant cells on sustained NAD availability constitutes a therapeutically exploitable vulnerability. Accordingly, NAMPT inhibitors, PARP inhibitors, and strategies targeting NAD-consuming ectoenzymes have shown preclinical and, in select settings, clinical efficacy. Here, we critically review the rewiring of NAD metabolism in cancer, associated therapeutic opportunities, and barriers to their clinical exploitation.
    Keywords:  IDO1; OXPHOS; clinical trials; immune checkpoint inhibitors; tumor microenvironment; tumor–infiltrating lymphocytes
    DOI:  https://doi.org/10.1016/j.cmet.2026.09.015
  32. Cell. 2026 Oct 15. pii: S0092-8674(26)01142-6. [Epub ahead of print]
    Cellular self-organization orchestrates ferroptosis propagation.
    Jen-Hao Cheng, Hannah K C Co, Hao-Kuen Lin, Chia-Chou Wu, Sheng-Hong Chen.
      Self-organization generates cellular patterns that guide morphogenesis, but how it regulates collective cell fate remains underexplored. We show that cellular self-organization constrains the propagation of ferroptosis, an iron-dependent form of oxidative cell death that can otherwise spread as unbounded trigger waves. The spatial patterning of cell density and alignment encodes transcriptional programs, priming cells toward ferroptosis-sensitive or -resistant fates. Low-density, misaligned regions with elevated YAP/TEAD1 activity are sensitive, whereas high-density, aligned regions with increased NRF2 expression form propagation-resistant boundaries. Cell elongation establishes a polarized distribution of oxidizable lipids, creating peroxidation hotspots at the cell poles that promote propagation along cell alignment. In silico and pharmacological perturbations reveal that pattern-dependent susceptibility and polarized lipid organization act together to constrain isotropic waves into spatially confined, anisotropic propagation. These findings identify self-organization as a systems-level mechanism governing collective homeostasis, providing a paradigm to explore how tissue-scale organization regulates cell death in development and disease.
    Keywords:  active nematics; cellular patterns; ferroptosis; self-organization; topological defects; trigger waves
    DOI:  https://doi.org/10.1016/j.cell.2026.09.039
  33. EMBO Mol Med. 2026 Oct 14.
    RMND1 dysfunction causes OXPHOS deficiency and alters mitoribosomal protein homeostasis in vivo.
    Alba Pesini, Maria J Sanchez-Quintero, Carlos Lopez-Gomez, Eliana Barriocanal-Casado, Agustin Hidalgo-Gutierrez, Eva Nyvltova, Joanna Rorbach, Giulio Kleiner, May T Ting, Christian Garcia, Lucia Dec-Prat, Kurenai Tanji, Christopher B Damoci, Robert McFarland, Robert W Taylor, Michal Minczuk, Antoni Barrientos, Catarina M Quinzii.
      Pathogenic, bi-allelic variants in RMND1 typically manifest as an early-onset multisystemic mitochondrial disease, yet the consequences of RMND1 dysfunction in vivo remain poorly understood. To answer this question, we generated and characterized the first in vivo model of RMND1-related disease, carrying the recurrent p.(Asn238Ser) variant. Homozygous Rmnd1N238S mice exhibit growth defect, premature mortality, and a multisystem phenotype marked by widespread tissue-dependent defects in oxidative phosphorylation assembly and activity. Quantitative proteomic analysis of Rmnd1N238S heart revealed extensive metabolic remodeling, with significant alterations in the abundance of mitoribosomal proteins and factors associated with mitoribosome maturation. Selected changes in mitoribosomal protein abundance were also observed in Rmnd1N238S liver, and RMND1 mutant and depleted human cells. Despite these changes, sucrose-gradient sedimentation did not reveal a gross alteration in mtSSU, mtLSU, or 55S distribution, suggesting that RMND1 dysfunction perturbs mitoribosomal protein homeostasis that could affect late-assembly stages of the mitochondrial ribosome large subunit. Together, our findings establish Rmnd1N238S mice as a robust in vivo model of RMND1-related disease and provide a framework for understanding how RMND1 supports mitochondrial gene expression.
    DOI:  https://doi.org/10.1038/s44321-026-00534-1
  34. Nat Med. 2026 Oct 12.
    A health-system-scale, episode-resolved multimodal atlas of cancer cachexia.
    Venise Jan Castillon, Amy X Xie, Sonia Boscenco, Ethan Tse, Neil Ruthen, Jamie Wang, Ziad Bakouny, Michele Waters, Chenlian Fu, Christopher Fong, Mustafa Saleh, Tarek Baroud, Wungki Park, Urvi A Shah, A Ari Hakimi, Puneeth Iyengar, Justin Jee, Eileen White, Alexander Gusev, Tobias Janowitz, Marcus D Goncalves, Ed Reznik.
      Cancer cachexia is a wasting syndrome with outsized impact on morbidity and mortality, yet its drivers and systemic consequences remain poorly defined. In this study, we repurposed longitudinal clinicogenomic data from 52,236 patients with cancer profiled by MSK-IMPACT (2010-2024) at Memorial Sloan Kettering Cancer Center to define episode-resolved trajectories of consensus-defined cachectic weight loss and linked these events to outcomes, serology and tumor genotypes. Cachectic episodes clustered near periods of disease progression and were associated with inferior outcomes in nearly all cancer types. Across diverse malignancies, cachectic weight loss episodes exhibited a consistent serologic signature characterized by lower albumin and hemoglobin and higher levels of liver enzymes. Numerous somatic tumor genotypes, including TP53 mutation across several diseases, were also associated with more frequent onset of cachectic episodes. Motivated by these observations, we developed a multivariate model to predict impending risk of cachectic weight loss in patients with lung, colorectal and prostate cancer, validated in an independent, external cohort from Dana-Farber Cancer Institute (n = 5,785). Routine clinicogenomic data are, therefore, a scalable resource for discovery in cancer cachexia.
    DOI:  https://doi.org/10.1038/s41591-026-04689-9
  35. Nat Genet. 2026 Oct 13.
    Clonal heterogeneity in human pancreatic ductal adenocarcinoma and its impact on tumor progression.
    Despoina Kalfakakou, Daniel C Cameron, Emily A Kawaler, Motoyuki Tsuda, Lidong Wang, Qi Su, Sungsik Kim, Elektra Manolakos, Xiaohong Jing, Cristina Hajdu, Dylan L Tamayo, Yoona Shim, Amanda Ackermann, Daniel Weissinger, Hayley Zimny, Rosmel Hernandez, Matthew Beier, Dacia Dimartino, Peter Meyn, Kalina Rice, Shanmugapriya Selvaraj, Cynthia Loomis, Adriana Heguy, Amanda W Lund, Hannah Carter, Rosalie C Sears, Theodore H Welling, Igor Dolgalev, Aristotelis Tsirigos, Diane M Simeone.
      Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer characterized by profound desmoplasia and cellular heterogeneity, which cannot be fully resolved using traditional bulk sequencing approaches. To understand how this heterogeneity contributes to PDAC biology, we analyzed a large cohort of primary tumors (n = 62) profiled using single-cell RNA sequencing (443,451 single cells), including a subset of 11 tumors with matched spatial transcriptomics (53,236 spots), to map clonal, transcriptional and spatial diversity. Moreover, our sample set includes a unique cohort of matched samples from six tumors collected before and after treatment with chemotherapy. Our analysis revealed notable intratumoral heterogeneity, with multiple genetically distinct neoplastic clones coexisting within individual tumors. We observed clone-specific ligand-receptor programs that are modulated by genomic dosage: amplifications of ligands or receptors enriched corresponding interactions, while deletions suppressed them, with genetically encoded differences supported by spatial transcriptomics and multiplex immunofluorescence. Phylogenetic integration identified focal 8q24 (MYC) amplification as recurrently associated with classical-to-basal transitions occurring within tumor lineages at a frequency above chance; these transitions were accompanied by coordinated depletion of immune-response programs. Functional perturbation experiments in murine and primary human models showed that MYC knockdown reactivates classical transcriptional programs and restores immune-response pathways, supporting a role for MYC in maintaining a basal, immune-depleted state. Spatial analyses further revealed dispersed clones enriched for epithelial-to-mesenchymal transition activity and immune suppression, correlating with metastatic potential and colonization of lymph node niches. These dispersed clones shifted toward a basal phenotype, contributing to disease progression. Our findings highlight the critical role of clonal diversity, transcriptional plasticity and tumor microenvironment interactions in shaping human PDAC biology. This work provides a detailed view of the molecular and spatial heterogeneity of PDAC and offers potential avenues for therapeutic intervention targeting clonal evolution and the mechanisms driving metastasis.
    DOI:  https://doi.org/10.1038/s41588-026-02779-5
  36. bioRxiv. 2026 Sep 28. pii: 2026.09.22.753556. [Epub ahead of print]
    MCT6 is an intestinal Lac-Phe exporter required for metformin-associated weight loss.
    Shuke Xiao, Alan Sheng-Hwa Tung, Jan Spaas, Sipei Fu, Xudong Chen, Tuan Kiet Trinh, Maria Dolores Moya-Garzon, Veronica L Li, Hannah T Cessna, Kentaro Ito, Saranya C Reghupathy, Chao Lin, Xuchao Lyu, Steffen H Raun, Miles D W Tyner, Arthur Germakovski, Jacob Tondreau, Megan Yeckley, Wei Wei, Michael R Howitt, Mark D Parker, Jason A Sprowl, Stephen M Hinshaw, Jonathan Z Long.
      Metabolites are increasingly recognized as circulating molecules that regulate physiology, yet the mechanisms that couple intracellular production to organism-wide action remain poorly defined. Using the anorexigenic metabolite Lac-Phe as a tractable system, we identify the orphan transporter MCT6 (SLC16A5) as a physiologic intestinal Lac-Phe exporter. This mechanism controls the extent to which intracellularly synthesized Lac-Phe acquires systemic activity. MCT6 transports Lac-Phe, mediates its cellular efflux, and is required for maintaining its blood levels in mice following strong glycolytic stimuli. Both global and intestinal epithelial-specific deletion of MCT6 confers resistance to metformin-associated weight loss on a high-fat diet. Bypassing the transport defect with exogenous Lac-Phe normalizes the body weight phenotype of MCT6-KO mice. Together, these data connect MCT6 to metformin pharmacology and intestinal lactate metabolism, and more generally underscore the importance of transporter-mediated release in the conversion of an intracellular metabolic state into a circulating metabolite effector.
    DOI:  https://doi.org/10.64898/2026.09.22.753556
  37. Cell Rep. 2026 Oct 14. pii: S2211-1247(26)01240-4. [Epub ahead of print]45(10): 118161
    Mitochondrial stress induces transcription of cytosolic and mitochondrial protein synthesis components via NHR-180.
    Avijit Mallick, Theresa Ramalho, Levi Ali, Yunguang Du, Duy Hoang, Rui Li, Pooja Rai, Sookyung Kim, Rakeyah Ahsan, Ala M Shaqra, Andreas Bergmann, Celia A Schiffer, Lihua Julie Zhu, Brian Kelch, Kuang Shen, Cole M Haynes.
      The mitochondrial unfolded protein response (UPRmt), which promotes mitochondrial biogenesis and proteostasis, is regulated by the transcription factor ATFS-1. In C. elegans, impaired atfs-1 expression perturbs mitochondrial function and slows development. Here, using an RNAi suppressor screen, we find that inhibition of the nuclear hormone receptor NHR-180 increases mitochondrial function and developmental rate in atfs-1(null) worms. NHR-180 levels increase and become more nuclear-localized during mitochondrial dysfunction, inducing transcription of genes required for protein synthesis on cytosolic and mitochondrial ribosomes. The NHR-180 ligand-binding domain interacts with AMP, suggesting that NHR-180 may link cellular energy status to protein synthesis during mitochondrial stress. However, NHR-180-dependent activity is associated with exacerbated mitochondrial dysfunction. Consistent with these findings, inhibition of the S6 kinase homolog RSKS-1 increases mitochondrial function in atfs-1(null) worms. S6 kinase inhibition also increases respiration and mitochondrial DNA (mtDNA) content in mammalian ATF5-knockout cells and oxidative phosphorylation (OXPHOS)-deficient models.
    Keywords:  ATFS-1; CP: molecular biology; NHR-180; OXPHOS; RSKS-1, S6K, ATF5; mitochondria; mtDNA; protein synthesis
    DOI:  https://doi.org/10.1016/j.celrep.2026.118161
  38. Res Sq. 2026 Sep 28. pii: rs.3.rs-11077727. [Epub ahead of print]
    SQOR regulates H2S detoxification and lipid metabolism to maintain glioblastoma metabolic fitness.
    Christopher Hine, András Ponti, Taylor Gatesman, Sarah Hatem, Jordyn Smith, Ishana Senthil, Arjun Akula, Lilly Stanley, Matthew Godwin, Kewal Asosingh, Isaac Ampong, Belinda Willard, Naseer Sangwan, Andrew Dhawan, Daniel Silver, Sameer Agnihotri, Justin Lathia.
      Glioblastoma (GBM) adapts to metabolic stress through mitochondrial pathways that are not fully defined. Here, we show sulfide quinone oxidoreductase (SQOR) is upregulated in human GBM and functions as a mitochondrial checkpoint linking hydrogen sulfide (H 2 S) clearance to electron transport chain activity. In patient-derived GBM cells and immunocompetent syngeneic tumors, SQOR channels H 2 S-derived electrons into the ubiquinone pool to sustain oxidative phosphorylation during stress. Genetic or pharmacologic SQOR inhibition causes intracellular H 2 S accumulation, collapse of mitochondrial respiration, tricarboxylic acid cycle dysfunction, and compensatory glycolytic engagement. SQOR loss also redirects carbon into lipid synthesis and storage while impairing lipid mobilization, thereby limiting metabolic flexibility and stem-like cell maintenance. Increasing endogenous H 2 S production further exacerbates the bioenergetic defects caused by SQOR blockade. Functionally, genetic or pharmacologic SQOR inhibition suppresses tumor growth and prolongs survival in vivo . Together, these data identify SQOR-dependent sulfide oxidation as a mitochondrial liability that supports GBM metabolic plasticity.
    DOI:  https://doi.org/10.21203/rs.3.rs-11077727/v1
  39. bioRxiv. 2026 Sep 28. pii: 2026.09.22.753597. [Epub ahead of print]
    The p53-p21-Cyclin D2 regulatory axis drives metabolic reprogramming and a distinct senescent macrophage senotype during aging and MASLD.
    Grasiela Torres, Ivan A Salladay-Perez, Christina Y Deng, Itzetl Avila, Yennifer Delgado, Gregory Tong, Jesús Muñoz-Estrada, Lizeth Estrada, Anika Dhingra, Wesley R Armstrong, Aishini Singh, Isabella Cooper, Eduardo Enriquez, Prashant Kaushal, Jocelyn Ni, Kushan Chowdhury, Calvin Pan, Linsey Stiles, Cristiane Beninca, Simon T Hui, Abbigail S Krall, Heather R Christofk, Aldons J Lusis, Timothy E O'Sullivan, Jesse G Meyer, Rajat Singh, Valerie A Tornini, Orian S Shirihai, Mehdi Bouhaddou, Anthony J Covarrubias.
      Aging drives chronic disease in part through senescent cells, including macrophages, which fuel inflammation. Senescent macrophages are functionally heterogeneous: canonical p16-high macrophages promote tumorigenesis or, in other contexts, disease tolerance, whereas we previously identified a distinct p21-high, p16-low senotype that drives metabolic dysfunction-associated steatotic liver disease (MASLD). The molecular basis of this senotype has remained undefined. Using genetic and multi-omic approaches, we show that a p53-p21-dependent program actively represses p16 and is required for senescent macrophage viability. We identify Cyclin D2 as a non-canonical downstream effector that redistributes from the nucleus to mitochondria and lipid droplets, where it partners with MIC60 to drive metabolic reprogramming and modulates AKT1-mTORC1 signaling that sustains the SASP. Cyclin D2-p21 double-positive macrophages accumulate with aging and MASLD in mice and in human liver cirrhosis, and can be selectively depleted by senolytic treatment. Together, these findings define a druggable p53-p21-Cyclin D2 axis that specifies macrophage senotype.
    Highlights: ● A p53-p21-dependent program drives macrophage senescence while actively repressing p16● p16 repression promotes cell survival during acute genotoxic stress, but is dispensable for cell-cycle arrest and core senescence features in macrophages● Cyclin D2 is a non-canonical p53-p21 effector that relocalizes from nucleus to the cytosol and mitochondria● Cyclin D2 engages the AKT1-mTORC1 pathway and interacts with MIC60 to drive metabolic reprogramming● Cyclin D2+p21+ macrophages are abundant in aging, MASLD, and human liver cirrhosis, and can be targeted by senolytics.
    DOI:  https://doi.org/10.64898/2026.09.22.753597
  40. Mol Cell. 2026 Oct 12. pii: S1097-2765(26)00666-0. [Epub ahead of print]
    A CK2-β-TrCP kinase-E3 ubiquitin ligase cascade is a metabolic sensor regulating tryptophan 2,3-dioxygenase stability.
    Alina S Thielen, Bastian Bräuning, Karthik V Gottemukkala, Judith Müller, J Rajan Prabu, Pooja Verma, Simon Klaessens, Benoit J Van den Eynde, Gary Kleiger, Peter J Murray, Brenda A Schulman.
      Small molecules toggling the ubiquitin-proteasome system (UPS) are powerful regulators of protein degradation, yet how endogenous ligands gate UPS decisions remains poorly understood. Here, we define control of UPS access to human tryptophan 2,3-dioxygenase (TDO2), which converts the amino acid tryptophan (Trp) to N-formylkynurenine. When Trp concentrations are limiting, TDO2 is degraded to avert hypotryptophanemia. We discovered that a CK2-β-TrCP kinase-E3 ligase cascade generates and recognizes phosphodegrons in TDO2 unless they are shielded by Trp binding at an exosite distal from the catalytic site. Effects of Trp analogs on CK2-β-TrCP-dependent ubiquitylation indicated that the indole, amino, and carboxylate groups collectively protect TDO2. Cryo-EM reveals that these moieties organize a Trp-ordered flap that covers the exosite and thereby restricts generation of adjacent phosphodegrons. In the absence of Trp, the flap is flexible, enabling phosphorylation-coupled ubiquitylation. Overall, our data uncovered an endogenous small molecule conformationally stabilizing its own metabolizing enzyme through protection from a phosphorylation-ubiquitylation cascade.
    Keywords:  BTRC; CK2; CUL1; E3 ligase; FBXW11; feedback regulation; kinase; metabolism; phosphodegron; tryptophan; ubiquitin; ubiquitin-proteasome system; ubiquitylation; β-TrCP
    DOI:  https://doi.org/10.1016/j.molcel.2026.09.023
  41. Cell Metab. 2026 Oct 14. pii: S1550-4131(26)00391-8. [Epub ahead of print]
    An NAD+-responsive adipose signal coordinates inter-organ defense against muscle atrophy.
    Na Liang, Jia He, Xiangji Guo, Jiaqi Yan, Xiaoqian Zhang, Xiaozhong Peng, Jun Li.
      Loss of skeletal muscle mass is a major driver of frailty and disability, yet how systemic metabolic cues protect muscle integrity remains unclear. We identify Serpina3n, an adipose-derived adipokine, as a key mediator of the protective effects of nicotinamide adenine dinucleotide (NAD+) supplementation against muscle atrophy. Elevation of NAD+ in adipose tissue activates signal transducer and activator of transcription (STAT)1-dependent transcription of Serpina3n, leading to its systemic release and muscle protection across models of aging, disuse, and cancer cachexia. In muscle, Serpina3n preserves pyruvate carboxylase protein level, promoting anaplerosis, oxidative metabolism, and protein synthesis. These findings define an NAD+-responsive adipose-to-muscle signaling axis that links metabolic status to tissue preservation, defining a systemic mechanism by which inter-organ communication maintains muscle integrity and suggesting potential strategies to counteract muscle degeneration.
    Keywords:  NAD(+); adipokine; aging; inter-organ communication; muscle atrophy
    DOI:  https://doi.org/10.1016/j.cmet.2026.09.016
  42. Int J Mol Sci. 2026 Sep 26. pii: 8626. [Epub ahead of print]27(19):
    Deoxythymidylate Kinase (DTYMK)-Driven Pyrimidine Hypermetabolism Is Associated with a Folate-Dependent Macrophage Programme in Triple-Negative Breast Cancer.
    Gaoge Peng, Dequan Liu, Wucheng Zhu, Beibei Xin, Yi Wu, Yifeng Hou, Hefen Sun, Wei Jin.
      Immune checkpoint blockade benefits only a minority of patients with triple-negative breast cancer (TNBC), and the tumour-intrinsic programmes that establish its immunosuppressive microenvironment remain poorly defined. Pyrimidine metabolism supplies nucleotides and one-carbon units in malignant cells, but whether it shapes the immune microenvironment is unknown. Integrating single-cell, bulk breast cancer transcriptomics with Xenium spatial transcriptomics, DTYMK knockdown, tumour-conditioned-medium co-culture and folate rescue, we found that pyrimidine pathway activity was elevated in the malignant epithelium of TNBC, within which we identified Epi4, a high-potency subpopulation coupling pyrimidine and folate metabolism and predicted to export folate. Furthermore, this folate was predicted to be taken up by FOLR2+ tumour-associated macrophages (TAMs) and was associated with S-adenosylmethionine(SAM)-dependent methylation signatures and MAFB activity. Spatially, Epi4 and FOLR2+ TAMs co-localised at the tumour-stroma margin, a region of reduced T-cell density. DTYMK depletion reduced tumour fitness and attenuated folate-mediated macrophage reprogramming, which was largely restored by exogenous folate. Here, we therefore identify a DTYMK-folate-MAFB axis in which tumour metabolic rewiring is associated with epigenetic reprogramming of macrophages.
    Keywords:  DTYMK; FOLR2+ macrophages; metabolic crosstalk; multi-omics; triple-negative breast cancer
    DOI:  https://doi.org/10.3390/ijms27198626
  43. Nat Commun. 2026 Oct 16. pii: 10572. [Epub ahead of print]17(1):
    The molecular heterogeneity and clinical impact of genomic driver alterations in prostate cancer.
    Pan Prostate Cancer Group
      Prostate cancer is a common malignancy with a heterogeneous disease course. Prior studies have identified a paucity of point mutations in protein-coding genes and only a few clinically relevant driver alterations. Here, using the Pan Prostate Cancer Group whole genome sequencing dataset from 1001 men, we perform an integrative analysis of cancer driver genes by quantifying recurrent genomic alterations among small mutations, structural variants, and copy number alterations in 961 primary prostate tumour samples. We identify at least one recurrent somatic or germline alteration in 97% of tumours and identify putative driver genes and mechanisms of dysregulation including frequently altered regulatory elements. A prominent example is the activation of oncogenes by structural variation-mediated hijacking of onco-enhancers of the solute carrier gene family including SLC30A4. Other recurrent alterations including FOXA1, MDM4, COL5A1, TP53, and BRCA1 stratify with metastatic disease, with additional drivers enriched in African-ancestry tumours. One quarter of tumours have acquired genome-informed therapeutic targets. Unsupervised analysis of alterations reveals four oncotypes with distinct genetic and clinical characteristics, including two clinically unfavourable oncotypes with shorter metastasis-free survival. Our study uncovers the full spectrum and recurrence patterns of genomic driver alterations in primary prostate cancers and delivers targets for biomarker development, mechanistic studies, and potential therapeutic interventions.
    DOI:  https://doi.org/10.1038/s41467-026-77900-7
  44. EMBO Mol Med. 2026 Oct 15.
    PTEN-loss confers dependence on the guanylate synthesis enzyme IMPDH in T-cell acute lymphoblastic leukemia.
    Rayees A Padder, Thu Le Le, Emily Hyde, Maria E D Rubio, Eric Chiles, Jay N Joshi, Nanda Singh, Masuda Akther, Namratha Sheshadri, Kelly Mulraney, Wei-Xing Zong, Xiaoyang Su, Daniel Herranz, Alexander J Valvezan.
      Loss of the tumor suppressor PTEN is common in T-cell acute lymphoblastic leukemia (T-ALL) and is associated with poor prognosis. PTEN-loss drives AKT/mTORC1 signaling to promote leukemic cell growth. We find that PTEN-loss in T-ALL confers dependence on the guanylate nucleotide synthesis enzyme inosine 5'-monophosphate dehydrogenase (IMPDH) for cell growth and viability. This metabolic vulnerability is dependent on sustained AKT/mTORC1 signaling and can be exploited using clinically approved IMPDH inhibitors to selectively kill PTEN-deficient T-ALL cells, and extend survival in genetic and xenograft T-ALL models in mice. Mechanistically, IMPDH inhibitors cause DNA replication stress early on, followed by DNA damage. In contrast to treatment with mTORC1 inhibitors, these events culminate in robust and selective cell death in PTEN-deficient T-ALL cells. We also find that p53 enhances, but is not required for, IMPDH inhibitor-induced cell death. These findings reveal a targetable metabolic vulnerability in T-ALL, providing rationale for repurposing clinically approved IMPDH inhibitors.
    DOI:  https://doi.org/10.1038/s44321-026-00533-2
  45. J Biol Chem. 2026 Oct 13. pii: S0021-9258(26)02507-X. [Epub ahead of print] 113635
    METTL10 trimethylation of eEF1A at K318 enhances protein synthesis and tumorigenesis.
    Lauren Buie, Simone Hausmann, Juhyung Park, Sabeen Ikram, Tourkian Chasan, Xiaojie Yang, Natasha M Flores, Pawel Mazur, Or Gozani.
      eEF1A is an essential non-ribosomal translation elongation factor that mediates the high-fidelity delivery of aminoacyl-tRNAs to elongating ribosomes. Like histone H3, eEF1A undergoes extensive lysine methylation, with five distinct residues targeted by dedicated lysine methyltransferases (KMTs). However, compared with histone methylation, relatively little is known about the molecular and physiological functions of eEF1A lysine methylation. Here, we focus on METTL10, the KMT that catalyzes trimethylation of eEF1A at lysine 318 (eEF1AK318me3). We show that the METTL10-eEF1AK318me3 axis modestly enhances global protein synthesis and supports pancreatic ductal adenocarcinoma (PDAC) tumorigenesis in vivo. We identify the 236 amino-acid isoform as the catalytically active endogenous form of METTL10 and demonstrate that it is required for eEF1AK318me3 generation in multiple human cell lines. Further, we provide evidence that eEF1AK318 is the principal physiologic target of METT10. Loss of eEF1AK318 modestly reduces global protein synthesis across multiple cancer cell lines without substantially impacting polysome formation. METTL10 depletion attenuates proliferation of multiple cancer cell lines, an effect that depends on its catalytic activity. Moreover, elevated eEF1AK318me3 levels in PDAC tumors are associated with poor patient outcomes. Finally, METTL10 ablation attenuates tumor growth and extends survival in a KRASG12D-driven PDAC mouse model. Together, our work identifies the METTL10-eEF1AK318me3 axis as a regulator of protein synthesis and implicates it in PDAC pathogenesis.
    DOI:  https://doi.org/10.1016/j.jbc.2026.113635
  46. Nat Metab. 2026 Oct 12.
    Systemic proteomic dynamics of acute exercise reveal genetic links to health and disease.
    Nigel Kurgan, Jeppe Kjærgaard, Naja Zenius Jespersen, Virginia Díez-Obrero, Victor Svenstrup, Roger Moreno-Justicia, Sarah Elizabeth Heywood, Cecilie Bergmann Lindqvist, Lisa Ottander, Diana Samodova-Sommer, Alina Malita, Olga Kubrak, Nadja Ahrentløv, Nina Sloth Nielsen, Cody Garett Durrer, Michael Texada, Mathias Ried-Larsen, Simon Rasmussen, Kim Rewitz, Ruth J F Loos, Roelof Adriaan Johan Smit, Bente Klarlund Pedersen, Atul Shahaji Deshmukh.
      Physical activity improves metabolic health, but the molecular responses that mediate its benefits are not fully characterized. Here we present a high-resolution, time-resolved proteomics atlas across plasma, saliva and urine from 25 healthy men in response to acute exercise. We find that exercise regulates more than 3,000 proteins through distinct, fluid-specific temporal dynamics. Network analysis uncovers coordinated remodelling of protein secretion, extracellular matrix and immune activation across body fluids. Replication in an independent cohort shows that many exercise-responsive plasma proteins exhibit consistent responses across age, sex and exercise modalities. Integration with human genome-wide association study data links secreted, exercise-responsive proteins to cardiometabolic diseases. Functional validation of genetically prioritized muscle-specific secreted proteins in Drosophila confirms their role in endurance, behaviour and metabolism. Overall, this open-access atlas ( https://cbmr.ku.dk/research/research-groups/deshmukh-group/shiny-apps/ ) provides a multifluid resource that complements existing exercise-omics efforts for defining molecular adaptations to exercise and for prioritizing candidate exerkines.
    DOI:  https://doi.org/10.1038/s42255-026-01621-w
  47. Nat Immunol. 2026 Oct 14.
    Compartment-specific PPARδ activity controls the outcome of cancer-immune cell competition and immunotherapy efficacy.
    Paul Bunk, Ilgin Ergin, Timothy Maher, Vyom Shah, Julia R Bonney, Lokesh B S S Kumar, Charlie Chung, Nils Wellhausen, Philip Moresco, Sarah Shao, Jill Habel, Vinay Mandati, Rachel Rubino, David E Rivadeneira, John E Wilkinson, Laura Herrero, Peter M K Westcott, Samuel E Weinberg, Saar I Gill, Nathalie Y R Agar, Semir Beyaz.
      Most patients with solid tumors fail to sustain antitumor immunity, in part because immune cells cannot outcompete cancer cells inside the immunosuppressive tumor microenvironment. Here, we show the lipid-sensing transcription factor PPARδ is a compartment-specific determinant of cancer-immune fitness balance and immunotherapy efficacy. Activating PPARδ in cancer cells promotes their growth and impairs antitumor immunity, whereas activating it in immune cells drives tumor suppression and overrides tumor-promoting effects of cancer-intrinsic activation. Mechanistically, PPARδ enhances CD8+ T cell fitness against cancer through effector-associated chromatin remodeling and Cpt1a-mediated fatty acid oxidation. Therapeutically, PPARδ-activated CD8+ T cells sensitize immunotherapy-resistant microsatellite stable metastatic colorectal cancer to checkpoint blockade in mice, and pharmacological or genetic PPARδ activation enhances human chimeric antigen receptor T cell function. These findings identify compartment-specific PPARδ activity as a targetable driver of immune cell fitness that can be harnessed to improve outcomes in immunotherapy-resistant tumors.
    DOI:  https://doi.org/10.1038/s41590-026-02685-2
  48. Cell Rep. 2026 Oct 15. pii: S2211-1247(26)01198-8. [Epub ahead of print]45(10): 118119
    Neoplastic and non-neoplastic astrocyte states converge on mesenchymal and injury-response programs during glioblastoma recurrence.
    David Lindgren, Rebecca Rosberg, Karolina I Smolag, Elinn Johansson, Sebastian Braun, Jonas Sjölund, Dimitra Manou, Enrico Pracucci, Bengt Phung, Katja Harbst, Pauline Jeannot, Yu Ching So, Paulina Bolivar, Maria Malmberg, Crister Ceberg, Johan Bengzon, Henrik Ahlenius, Göran B Jönsson, Kristian Pietras, Alexander Pietras.
      Glioblastomas initially respond to radiotherapy but invariably recur, often within high-dose radiation treatment fields. Although stromal radiation responses are incompletely understood, evidence suggests that the tumor microenvironment becomes tumor-supportive after therapy. Using a genetically engineered glioblastoma mouse model, we profiled healthy brain, primary tumors, and post-radiotherapy recurrences with single-cell and spatial transcriptomics and immunofluorescence. Across 13 non-neoplastic cell types and 10 tumor cell states, we mapped transcriptional adaptations accompanying progression from healthy brain to primary and recurrent glioblastoma. We find distinct astrocyte states linked to disease stage, including reactive, non-neoplastic astrocytes and tumor cells adopting reactive astrocyte-like phenotypes. Reactive astrocyte-like tumor cells with mesenchymal and injury-response signatures are enriched after radiotherapy and persist in recurrent tumors. Receptor-ligand interactions between reactive astrocytes and tumor cells include known and putative drivers of aggressiveness. These findings highlight convergent reactive astrocyte programs in astrocytes and tumor cells as potential mediators of glioblastoma radioresistance.
    Keywords:  CP: cancer; CP: neuroscience; GBM; GBM plasticity; glioblastoma; radiotherapy; reactive astrocytes; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.celrep.2026.118119
  49. Sci Adv. 2026 Oct 16. 12(42): eaeh9198
    WNK1 links ionic signals to microtubule dynamics to control pyrin inflammasome assembly.
    Genevieve Lewis, Lindsey Mayes-Hopfinger, Md Kaisar Ali, Jian Xie, Chou-Long Huang, Hanping Feng, Teresa Fernandes-Alnemri, Emad S Alnemri.
      WNK1 [with no lysine (K)] is a chloride- and potassium-sensitive kinase that regulates cellular ion homeostasis. Although WNK1 negatively regulates the NLRP3 and AIM2 inflammasomes, its role in pyrin inflammasome activation has remained unknown. Here, we identify WNK1 as a critical regulator of pyrin inflammasome assembly. In macrophages, genetic or pharmacologic inhibition of WNK1 suppresses pyrin activation without affecting pyrin dephosphorylation, demonstrating that WNK1 acts downstream of the canonical licensing step. This function occurs largely independently of the canonical SPAK/OXSR1 pathway. Mechanistically, WNK1 regulates microtubule dynamics: Its inhibition stabilizes microtubules, reduces plus-end growth, and impairs pyrin inflammasome assembly. Extracellular ionic conditions bidirectionally regulate this pathway, with hypotonic stress enhancing WNK1 activity and pyrin activation, whereas elevated extracellular potassium chloride suppresses WNK1 activity and inhibits pyrin assembly independently of osmotic stress. Together, these findings define an ion-sensitive WNK1-microtubule axis linking ionic signals to cytoskeletal dynamics to control pyrin inflammasome assembly and explain how WNK1 exerts opposing effects on distinct inflammasome pathways.
    DOI:  https://doi.org/10.1126/sciadv.aeh9198
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