bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2026–09–06
fifty-one papers selected by
Christian Frezza, Universität zu Köln
  1. Tumor-derived antioxidants suppress immunity by depriving T cells of reactive oxygen species.
  2. Single-cell profiling of mitochondrial phenotyping-coupled mtDNA genotyping.
  3. Cardiomyocyte-intrinsic somatic mtDNA mutations induce an OXPHOS-dependent immune response and promote progressive heart failure.
  4. NAD+ precursor treatment prevents cardiomyopathy but disrupts erythroid maturation in mitochondrial progeria.
  5. Fructose induces PERK-dependent ER stress and mitochondrial dysfunction via nucleotide depletion in clear cell renal cell carcinoma.
  6. MGRN1 preserves transiently damaged mitochondria for antioxidant-mediated repair.
  7. Spatiotemporal lineage tracing reveals the dynamic spatial architecture of tumor growth and metastasis.
  8. Somatic mutations reveal the ontogeny of microglia in human ageing.
  9. Aging vs. biological age: Conceptual considerations for age reversal claims.
  10. Mapping structural aging across human tissues reveals tissue-specific trajectories and coordinated deterioration.
  11. Cyclin E-CDK2 regulates cancer cell transcriptional program and response to immunotherapy through BRD4.
  12. Multi-stromal organoid co-culture modelling reveals epithelial-fibroblast heterogeneity in pancreatic cancer and pancreatitis.
  13. Mitochondrial superoxide-induced mitohormesis is mediated by citrate and cardioprotective.
  14. Non-canonical activation of VEGFA through TIMM44-dependent mitochondrial remodelling.
  15. The diversity of terminal electron acceptors across eukaryotes.
  16. Metabolite buffering of labile iron governs ferroptosis.
  17. Psychobiological and Metabolic Correlates of Time Perception in Humans: An Exploratory Study.
  18. Maternal metabolic stress regulates progeny intestinal stem cell niche signaling through heritable changes in redox metabolites.
  19. Metalloadaptor and metallochaperone proteins reveal new chemical principles of biological metal homeostasis.
  20. Mitochondrial Lipids in Cellular Adaptation.
  21. De novo pan-rhodamine binders for fluorescence microscopy from mammalian cells to extremophiles.
  22. Redox-dependent synaptic clustering of gephyrin.
  23. A brief guide to the identification and characterization of secreted molecules.
  24. Oxygen-dependent subcellular redistribution of PHD3 links the hypoxic microenvironment to mitochondrial metabolic reprogramming in ccRCC.
  25. A lysis-derived PMSF and orthovanadate oxidant defines a distinct cysteine-engagement profile.
  26. Tissue-Level Transcriptomic Entropy Reveals Organ-Specific Aging Patterns and Predicts Cancer Progression.
  27. Mitochondrial CLPP in Health and Disease: Mechanisms, Therapeutic Duality and Emerging Opportunities.
  28. Horizontal mitochondrial transfer: an emerging field in cell biology.
  29. The regulatory logic linking inflammation and fibrosis.
  30. Lysyl oxidase inhibition disrupts mitochondrial homeostasis to create vulnerability to ferroptosis in TNBC.
  31. Sexual dimorphism in the complete Drosophila male central nervous system connectome.
  32. Cell-matrix interactions drive functional compartmentalization of mitochondria during 3D migration.
  33. Functional chimeric mRNAs encode proteins in mammalian immunity.
  34. Mitochondrial molecular diversity in the brain.
  35. ATP13A4 gates extracellular polyamine levels to control excitatory synaptogenesis.
  36. A single-amino-acid cleavage controls global mitochondrial complex integrity.
  37. Changes in the transcriptome and synthetic lethal dependencies following KRAS mutant expression reveal profound tissue specificity.
  38. Integrated clinicogenomic analysis reveals the evolution and metastatic tropisms of advanced colorectal cancer.
  39. Aging microenvironment induces CD8+ T cell exhaustion by suppressing hepatic β-hydroxybutyrylate synthesis.
  40. Mitochondrial Complex I at the Crossroads of NK cell Dysfunction in Glioblastoma.
  41. Optical multi-physical field imaging within single cells.
  42. Tumor-Secreted ADAMTSL4 Activates Latent TGFβ1 to Drive Cancer Cachexia.
  43. Cardiolipin deficiency disrupts electron transport chain and drives steatohepatitis.
  44. The organization of visual pathways in the Drosophila brain.
  45. Spatial chromatin architecture and accessibility co-profiling of mammalian tissues.
  46. KDM6A loss enhances oxidative phosphorylation uncovering tissue-level convergent evolution.
  47. ACOD1-dependent succinate signalling acts as a metabolic checkpoint for osteoclast differentiation.
  48. ACLY palmitoylation reprograms macrophages histone acetylation rewiring to repress hepatocellular carcinoma.
  49. A step-wise, deterministic and fatal mouse model of myeloid neoplasm with spontaneous acquisition of patient-relevant RTK-RAS mutations.
  50. TRACE: An Integrated Isotope-Tracing Framework for Metabolite Validation and Nutrient Fate Mapping.
  51. Large-Scale Metabolite Annotation in Untargeted Metabolomics Using MetDNA.
  1. Science. 2026 Sep 03. 393(6815): 1036-1044
    Tumor-derived antioxidants suppress immunity by depriving T cells of reactive oxygen species.
    Alexander J Wesolowski, Ardon M Pillay, Panagiota Vardaka, Rabab Nasrallah, Randy Greaves, Housaiyin Li, Iliana Loffreda, Chelsea Jenkin, Andrew M James, Alica Nübling, Christopher J Ward, Teresa von Linde, Alberto G Conti, Sheue-Fen Tzeng, Layla Dahmani, Alexander C Evans, Sarah K Whiteside, Yumi Yamashita-Kanemaru, Charlotte J Imianowski, Jie Yang, Ignacio Moraga Gonzalez, Jack Chapman, Aws Al-Deka, Klaus Okkenhaug, Michael P Murphy, Bartlomiej Swiatczak, Geoffrey Guittard, Enrico Lugli, Lukas Flatz, Ping-Chih Ho, Robert L Eil, Rahul Roychoudhuri.
      Reactive oxygen species (ROS) promote genomic instability and fuel oncogenic signaling in cancer, but antioxidant therapies have so far failed to improve, or worsen, cancer outcomes. Emerging data suggest that T cells depend on ROS for signal transduction. In this study, we show that tumors exploit this dependency, releasing antioxidant enzymes into the tumor environment to suppress T cell-mediated antitumor immunity. The interstitial fluid of tumors possesses potent antioxidant activity, associated with enrichment of the antioxidant enzyme peroxiredoxin 1 (PRDX1). Extracellular PRDX1 deprives T cells of ROS, preventing oxidative inactivation of phosphatases required for T cell receptor-driven kinase signaling and effector function. Prdx1 is up-regulated upon cancer immunoediting, and loss of PRDX1 within tumors enhances antitumor immunity and immunotherapy responses. These findings define a redox-dependent mechanism of tumor immunosuppression that is potentially amenable to therapeutic intervention.
    DOI:  https://doi.org/10.1126/science.adz8203
  2. Proc Natl Acad Sci U S A. 2026 Sep 08. 123(36): e2531151123
    Single-cell profiling of mitochondrial phenotyping-coupled mtDNA genotyping.
    Zhengyang Zhang, Liwei Zhang, Peng An, Xu Zhang, Yi Xia, Yunlu Kang, Xiaoxia Chen, Rongrong Hua, Yinhua Zhu, Yanling Hao, Yuan Huang, Yongting Luo, Junjie Luo, Guisheng Wang.
      Simultaneously profiling mitochondrial DNA (mtDNA) heteroplasmy and phenotypic variability at the single-cell level remains a challenge due to the absence of integrated methods that map mitochondrial genotypes alongside their functional states. We introduce human single-cell mitochondrial phenotype-coupled mtDNA sequencing (scMPCDS), a platform that quantifies mtDNA mutations and heteroplasmy together with mitochondrial membrane potential and reactive oxygen species within individual cells. Unlike bulk sequencing or separate single-omics techniques, scMPCDS directly correlates mitochondrial genomic instability with functional outcomes. Using this approach, we demonstrate that DdCBE-mediated mtDNA editing induces cell-specific off-target mutations in the mitochondrial genome, which coincide with diverse phenotypic changes. Applying scMPCDS to HeLa cells and clear cell renal cell carcinoma tissues, we identify single-cell subpopulations exhibiting distinct mtDNA mutation burdens and altered bioenergetic profiles, implicating potential mitochondrial heterogeneity-driven tumor evolution. Overall, scMPCDS serves as a versatile tool to unravel mitochondrial genotype-phenotype relationships at the single-cell level in both normal and disease states, thereby advancing precise mitochondrial diagnostics and therapeutics.
    Keywords:  cancer; mitochondrial phenotype; mtDNA editing; mtDNA heteroplasmy; single cell
    DOI:  https://doi.org/10.1073/pnas.2531151123
  3. Sci Adv. 2026 Sep 04. 12(36): eaec8606
    Cardiomyocyte-intrinsic somatic mtDNA mutations induce an OXPHOS-dependent immune response and promote progressive heart failure.
    Kristina Bubb, Giovanni Rigoni, Polyxeni Papadea, Gianluigi Pironti, Jelena Misic, Shan Jiang, David Alsina, Diana Rubalcava-Gracia, Daniel C Andersson, Roberta Filograna, Camilla Koolmeister, Patrick Giavalisco, Anna Wredenberg, Matthias Mann, Florian A Rosenberger, Nils-Göran Larsson.
      Mitochondrial DNA (mtDNA) mutations accumulate with age, but their mechanistic contribution to aging remains unclear. The classical mtDNA mutator mouse expresses a proofreading-deficient mtDNA polymerase (POLGD257A) and accumulates mtDNA mutations across all tissues leading to premature aging. However, this model cannot resolve whether the aging phenotype results from systemic dysfunction or cell-intrinsic effects of somatic mtDNA mutations. To overcome this limitation, we generated PolgiMut mice allowing spatial and temporal control of POLGD257A expression. We demonstrate here that mtDNA mutations induced in cardiomyocytes cause progressive contractile dysfunction and respiratory chain deficiency in the heart without accompanying systemic pathology. Proteomic analyses link cardiac mosaic respiratory chain dysfunction to a progressive immune response, characterized by up-regulation of antigen-processing proteins and immune cell infiltration. In contrast, longevity-associated pathways are suppressed and uncoupled from mitochondrial and immune alterations, indicating distinct regulatory mechanisms. These findings demonstrate that mtDNA mutations can drive cardiac dysfunction and reveal a mechanistic link between mitochondrial dysfunction, immune responses, and aging.
    DOI:  https://doi.org/10.1126/sciadv.aec8606
  4. Cell Rep. 2026 Aug 29. pii: S2211-1247(26)00927-7. [Epub ahead of print]45(9): 117849
    NAD+ precursor treatment prevents cardiomyopathy but disrupts erythroid maturation in mitochondrial progeria.
    Nahid A Khan, Kati Ahlqvist, Swagat Pradhan, Juan Landoni, Christopher Jackson, Aleksandra Zhaivoron, Riikka Kivelä, Liliya Euro, Anu Suomalainen.
      Nicotinamide adenine dinucleotide (NAD+) plays a central role in energy metabolism, and its decline is linked to various degenerative diseases. While NAD+ restoration holds therapeutic promise, its long term, tissue-specific consequences remain poorly understood. We investigated effects of nicotinamide riboside (NR) supplementation for "mutator" mice manifesting mitochondrial progeria. Our results reveal strikingly divergent outcomes: in proliferative bone marrow, NR-treated mutators show reductive stress with accumulation of NADH/NADPH, altered amino acid, nucleotide, folate levels, and impaired heme biosynthesis. In blood, erythrocyte maturation defects are aggravated, exacerbating anemia. Conversely, in postmitotic cardiac tissue, NR enhanced contractility, reduces stress response markers and normalized metabolic profile. These findings indicate that while beneficial for heart, chronic NAD+ boosting can compromise erythrocyte maturation in the context of mitochondrial disease. The data emphasize importance of evaluating systemic effects of NAD+ boosting therapies beyond the primary affected tissues and development of tissue-specific metabolic interventions for degenerative diseases.
    Keywords:  CP: metabolism; NAD(+) metabolism; anemia; erythropoiesis; metabolism; mitochondria; post mitotic tissues; progeria
    DOI:  https://doi.org/10.1016/j.celrep.2026.117849
  5. Cell Death Dis. 2026 Aug 07. pii: 766. [Epub ahead of print]17(1):
    Fructose induces PERK-dependent ER stress and mitochondrial dysfunction via nucleotide depletion in clear cell renal cell carcinoma.
    Na Li, Yanhong Ding, Bowen Yu, Yongqiang Wang, Tongbin Gao, Huiyong Yin, Zhenhua Li, Shuzhen Liu, Guohua Yu, Ningning Wang.
      Clear cell renal cell carcinoma (ccRCC) exhibits a paradoxical fructose metabolism signature characterized by upregulation of the fructose transporter GLUT5 alongside downregulation of the catabolic enzymes (ketohexokinase, aldolase B, and triokinase), a pattern associated with poor prognosis. Functionally, unlike the pro-survival effect of fructose under glucose deprivation, in the presence of glucose, fructose co-treatment suppresses ccRCC cell proliferation, and induces profound mitochondrial dysfunction, including impaired oxidative phosphorylation, loss of membrane potential, excessive mitochondrial superoxide production, reduced mtDNA copy number, and downregulation of mitochondria-encoded electron transport chain subunits (notably ND2 and ND4 of complex I). Mechanistically, co-treatment with glucose and fructose creates a metabolic trap resulting in fructose-1-phosphate accumulation and ATP depletion. This energy crisis drives profound depletion of purine and pyrimidine nucleotide pools, which selectively triggers the PERK-eIF2S1-ATF4-CHOP axis of the integrated stress response, thereby mediating mitochondrial impairment and ultimately sensitizing ccRCC cells to intrinsic apoptosis via BID cleavage and caspase-3 activation under nutrient stress. Pharmacological treatment with the chemical chaperone 4-phenylbutyric acid (4-PBA) or nucleoside supplementation reverses mitochondrial dysfunction and fructose-induced cytotoxicity. The tumor-suppressive effect of fructose is validated in patient-derived organoids and xenograft mouse models, where fructose administration significantly attenuates tumor growth via ER stress. These findings reveal fructose-driven nucleotide depletion and PERK-dependent ER stress leading to mitochondrial dysfunction, which underlies the tumor-suppressive toxicity of fructose and exposes a targetable metabolic vulnerability in ccRCC.
    DOI:  https://doi.org/10.1038/s41419-026-09157-3
  6. Cell Rep. 2026 Sep 01. pii: S2211-1247(26)01008-9. [Epub ahead of print]45(9): 117930
    MGRN1 preserves transiently damaged mitochondria for antioxidant-mediated repair.
    Nuo Chen, Zhirong Li, Xiyuan Wang, Hong Xu, Wei Wang, Weina Shang, Liquan Wang, Chao Tong.
      Mitochondria are continuously exposed to damage that contributes to aging and disease. While prolongedly damaged mitochondria are eliminated by mitophagy, how cells respond to transient damage remains unclear. Here, we establish a cell-based system to induce transient mitochondrial stress and resolve its recovery dynamics. We identify the E3 ubiquitin ligase mahogunin ring finger 1 (MGRN1) as a damage-threshold sensor that discriminates between transient and prolonged mitochondrial insults. Under transient stress, MGRN1 shows enhanced association with the outer mitochondrial membrane via MFN1, where it restrains mitophagy, potentially preserving mitochondria for repair. Loss of MGRN1 disrupts this checkpoint, leading to inappropriate mitophagy and impaired recovery. Mechanistically, mitochondrial repair is coordinated by the DELE1-eIF2α-ATF4 axis, Nrf2 signaling, and JUN/FOS activation, which collectively drive an antioxidant program, with TXNRD1 and SLC7A11 as downstream effectors. Together, our findings uncover a damage-sensing checkpoint that gates the decision between recovery and clearance, and reveal active and regulated pathways for mitochondrial repair.
    Keywords:  CP: cell biology; CP: metabolism; antioxidant defenses; mitochondrial integrated stress response; mitochondrial repair; mitophagy; transient mitochondrial damage
    DOI:  https://doi.org/10.1016/j.celrep.2026.117930
  7. Nat Genet. 2026 Sep 02.
    Spatiotemporal lineage tracing reveals the dynamic spatial architecture of tumor growth and metastasis.
    Matthew G Jones, Dawei Sun, Kyung Hoi Joseph Min, William N Colgan, Haoyu Wang, Tivadar Török, Juliano Ribeiro, Jessie Xue, Erik C Cardoso, Yao Rong, Luyi Tian, Jackson A Weir, Victor Z Chen, Luke W Koblan, Kathryn E Yost, Nicolas Mathey-Andrews, Edridge D'Souza, Andrew J C Russell, Robert R Stickels, Karol S Balderrama, William M Rideout, Min Dai, Giovanni Marrero, Vipin Kumar, Anjali Saqi, Benjamin Herzberg, Benjamin Izar, Howard Y Chang, Joo-Hyeon Lee, Tyler Jacks, Fei Chen, Jonathan S Weissman, Nir Yosef, Dian Yang.
      Tumor progression is driven by dynamic interactions between cancer cells and their surrounding microenvironment. Here we integrate high-resolution spatial transcriptomics and evolving lineage-tracing technologies to elucidate how tumor expansion, plasticity and metastasis co-evolve with microenvironmental remodeling in a Kras;Trp53-driven mouse model of lung adenocarcinoma. We find that subclonal expansion contributes to a hypoxic, immunosuppressive and fibrotic microenvironment that is associated with the emergence of prometastatic cancer cell states. We use tumor phylogeography to delineate intercellular interactions that are rewired in the expanding tumor niche and use co-culture systems to dissect how intercellular interactions and hypoxia influence cancer cell state. Furthermore, we find that metastases arise from spatially confined primary tumor subclones and remodel the distant metastatic niche into a fibrotic, collagen-rich microenvironment. Together, we present a comprehensive dataset integrating spatial assays and lineage tracing to elucidate how sequential changes in cancer cell state and microenvironmental structures cooperate to promote tumor progression.
    DOI:  https://doi.org/10.1038/s41588-026-02739-z
  8. Nature. 2026 Jul 30.
    Somatic mutations reveal the ontogeny of microglia in human ageing.
    Julia A Belk, Yaowen Zhang, Emily E Reilly, Quanming Shi, Daniel Dan Liu, Nicole Womack-Gambrel, Maarten van der Linde, Lisa Ma, Debasmita Paul, Alejandro Medina Enciso, Raja Kalluru, Jacob Weiss, Rui Li, Anna E Eastman, Chunfang Zhu, Arnav Chakravarthy, Syed Bukhari, Dipabarna Bhattacharya, Suyash Raj, Daniel Richard, Simone Brioschi, Matthew R Chrostek, Daniel C Nachun, Christopher M Arends, Jayakrishnan Gopakumar, Isak W Tengesdal, Ademar Bynum, Shaneice Mitchell, Katalin Sandor, Wenxi Zhang, Badri N Vardarajan, Inma Cobos, Donald E Born, Robert B West, Anne Brunet, Marco Colonna, Krishna L Bharani, Hannes Vogel, Thomas J Montine, Caitlin S Latimer, Irving L Weissman, Magdalena Matusiak, Jody E Hooper, C Dirk Keene, Howard Y Chang, Siddhartha Jaiswal.
      Microglia are the resident macrophages of the central nervous system1. In mice, microglia seed the brain during embryogenesis and can be maintained throughout life with minimal input from adult haematopoiesis2-4. The origins of human microglia are less clear, but recent evidence suggests that bone-marrow-derived cells contribute to the human microglial pool in certain individuals5-9. Here, to investigate the ontogeny of human microglia, we develop an approach that uses the collection of accumulated somatic mutations that uniquely labels each clone of cells to track the infiltration of bone-marrow-derived cells into the human brain. Applying this approach to 20 older individuals, we find evidence of an influx of bone-marrow-derived cells into the brain in all examined individuals. Single-cell analysis, including single-cell lineage tracing using mitochondrial DNA variants, demonstrates that these infiltrating cells are similar to microglia and can comprise a large fraction of the microglial pool. Analysis of human cohort data demonstrates a protective association between most types of clonal haematopoiesis and Alzheimer's disease. Together, we identify a widespread influx of myeloid cells into the healthy human brain that contributes to the pool of human microglia and becomes common with ageing.
    DOI:  https://doi.org/10.1038/s41586-026-10939-0
  9. Cell Metab. 2026 Sep 01. pii: S1550-4131(26)00241-X. [Epub ahead of print]38(9): 1746-1750
    Aging vs. biological age: Conceptual considerations for age reversal claims.
    Jesse R Poganik, Alibek Moldakozhayev, Jamie N Justice, Matt Kaeberlein, Peter D Adams, Kenneth Rockwood, Luigi Ferrucci, Vadim N Gladyshev.
      Whether reversal of biological age and/or aging is possible is among the most actively debated topics in the field of aging. Here, we consider the meaning of biological age reversal and its burden of proof, focusing on foundational issues and the language we use to debate these questions.
    DOI:  https://doi.org/10.1016/j.cmet.2026.06.015
  10. Nat Aging. 2026 Aug 31.
    Mapping structural aging across human tissues reveals tissue-specific trajectories and coordinated deterioration.
    Anamika Yadav, Kyle Alvarez, Anna Chechenina, Kevin Y Yip, Eytan Ruppin, Alexandre Colas, Jacqueline C Yano Maher, Veronica Gomez-Lobo, Caroline Kumsta, Sanju Sinha.
      Organ structure, including the organization of cells, vasculature and extracellular matrix, underpins its function, yet how structure changes with age remains mostly unknown. Here we developed PathStAR, a framework that quantifies tissue structural aging from routine histopathology images, without being trained to predict chronological age. Applying PathStAR to 25,306 post-mortem biopsies from 40 tissues in 970 donors aged 21-70 years revealed that organ structural aging progresses via distinct, nonlinear temporal trajectories: vascular tissue structural aging accelerates early, uterus and vagina structural aging accelerates late (around menopause) and certain tissues including digestive and male reproductive organs show biphasic accelerations. We show that accelerations of structural aging are characterized across organs by increased inflammation alongside reduced energy production, repair and quality control. Cross-organ analysis reveals coordinated deterioration within individuals, including digestive and male reproductive tissues, linked by sex hormones. Together, our analysis provides a systematic map of structural aging across the human body.
    DOI:  https://doi.org/10.1038/s43587-026-01200-4
  11. Mol Cell. 2026 Sep 02. pii: S1097-2765(26)00554-X. [Epub ahead of print]
    Cyclin E-CDK2 regulates cancer cell transcriptional program and response to immunotherapy through BRD4.
    Chen Chu, Shanshan Zheng, Ning Mitchell, Zheqi Li, Xixi Zhang, Xiaowei Wu, Tian Zhang, Fabin Dang, Wojciech Michowski, Aleksandra Kolodziejczyk, Miranda L Xu, Krzysztof W Kotowski, Zhe Yang, Diego Martinez-Alonso, Joao Paulo, Jindan Sheng, Jane A Kirby, Finn Groezinger, Yubin Zhou, Miao He, Yoshinaga Ito, Anushree C Gulvady, Michael I Cole, Pierre Foidart, Jun Nishida, Xiaohan Ning, Samanta Sharma, Jan M Suski, Anne Fassl, Yu Zhou, Yan Geng, Wenyi Wei, Steven P Gygi, Kornelia Polyak, Kai W Wucherpfennig, Piotr Sicinski.
      The cyclin E-cyclin-dependent kinase 2 (CDK2) complex is a component of mammalian cell-cycle machinery that drives cell division. Hyperactivation of cyclin E-CDK2 is frequent in human cancers. Small-molecule CDK2 inhibitors are tested in clinical trials for cancer patients. Here, we report that cyclin E-CDK2 has a cell-cycle-independent function in regulating the global transcriptional program of cancer cells. CDK2 phosphorylates bromodomain-containing protein-4 (BRD4) and regulates its chromatin association. Overexpression of cyclin E and the resulting activation of CDK2 in cancer cells alter the cancer cell transcriptome, repress the expression of interferon-stimulated genes, and confer resistance to immunotherapy. Conversely, CDK2 inhibition has the opposite effect and augments the efficacy of immune checkpoint blockade. CDK2 inhibition also increases tumor infiltration by dendritic cells (DCs) and enhances antigen cross-presentation to CD8 T cells. These studies reveal an additional function of cyclin E-CDK2 in tumorigenesis and identify inhibition of CDK2 with clinically available compounds as a strategy for enhancing immune checkpoint blockade.
    Keywords:  BRD4; CDK2; antigen cross-presentation; cancer; cyclin E; dendritic cells; immune checkpoint blockade; immunotherapy resistance; interferon-stimulated genes; transcriptional regulation
    DOI:  https://doi.org/10.1016/j.molcel.2026.08.007
  12. Nat Cell Biol. 2026 Sep 02.
    Multi-stromal organoid co-culture modelling reveals epithelial-fibroblast heterogeneity in pancreatic cancer and pancreatitis.
    Wenlong Li, Muntadher Jihad, Eloise G Lloyd, Marta Zaccaria, Gianluca Mucciolo, Gideon Nsubuga, Alwin Koonan-Lonappan, Joaquín Araos Henríquez, Priscilla S W Cheng, Sneha Harish, Sally Mills, Paul M Johnson, Weike Luo, Alejandro Alonso Montero, Rebecca Brais, Alex Deamer, Ania M Piskorz, Julia Jones, Jodi L Miller, Bristi Basu, Paul D W Kirk, Mireia Vallespinos, Giulia Biffi.
      Interactions between epithelial cells and fibroblasts influence disease progression and treatment response in pancreatic ductal adenocarcinoma (PDAC). While the diversity of fibroblasts in PDAC is increasingly recognized, it remains unclear how these cells differ from fibroblasts found in pancreatic inflammation. Chronic pancreatitis is a stroma-rich inflammatory disease and a risk factor for PDAC, making it a useful setting to study how epithelial cells and fibroblasts change during disease. Here we compare fibroblast diversity and epithelial-stromal interactions in pancreatitis and PDAC using human samples, mouse models and mouse pancreatitis-derived epithelial organoids. We also developed pancreatitis and PDAC organoid co-cultures containing pancreatic stellate cells, fibroblasts and mesothelial cells. Combining in vitro and in vivo models better reflected human disease than mouse models alone. Overall, our findings reveal distinct epithelial and fibroblast features in pancreatitis and PDAC and provide models to identify disease-specific markers and therapeutic vulnerabilities.
    DOI:  https://doi.org/10.1038/s41556-026-02057-w
  13. Sci Adv. 2026 Sep 04. 12(36): eaef8132
    Mitochondrial superoxide-induced mitohormesis is mediated by citrate and cardioprotective.
    Matthew P Donnelly, Kailash Chandra Mangalhara, Yuening Liu, Kathryn Lande, Gladys R Rojas, Kym J Grae, Mack B Reynolds, Sagnika Ghosh, Neva Olliffe, Pau B Esparza-Moltó, Melissa A Johnson, Suzanne Dufresne, Allison Y Louie, Alexandra G Moyzis, Deann Guan, Åsa B Gustafsson, Christina G Towers, Pallav Kosuri, Christian M Metallo, Diana C Hargreaves, Gerald S Shadel.
      Mitohormesis, whereby transient mitochondrial stress induces adaptive signaling, promotes organismal resilience and longevity in invertebrates, but how this operates in mammals and the underlying metabolic signals involved remain unclear. Using a mouse model of mitohormesis, we show that transient mitochondrial superoxide stress during embryogenesis reprograms the adult heart to enhance mitochondrial biogenesis and antioxidant capacity. These adaptations confer protection against mitochondrial and oxidative injury in models of doxorubicin-induced cardiotoxicity, preserving mitochondrial content and preventing cardiac dysfunction and remodeling. Using a cell model of superoxide-mediated mitohormesis, we find that inhibition of mitochondrial aconitase promotes citrate export to the cytosol, where its conversion to acetyl-coenzyme A drives histone acetylation and mitohormetic protection from oxidative stress. Preventing mitochondrial citrate export abolishes these adaptations, while Aco2 silencing or citrate supplementation recapitulates the response. Together, our findings identify mitochondrial citrate as a redox-sensitive second messenger linking mitochondrial superoxide stress to durable epigenetic and mitohormetic remodeling.
    DOI:  https://doi.org/10.1126/sciadv.aef8132
  14. Redox Biol. 2026 Sep 02. pii: S2213-2317(26)00380-0. [Epub ahead of print]97 104381
    Non-canonical activation of VEGFA through TIMM44-dependent mitochondrial remodelling.
    Tanvi Chaudhary, Sharath Mohan Bhat, Priyadarshika Pradhan, Manjunath B Joshi, Devanjan Sinha.
      Coordination of mitochondrial functional states with nuclear transcriptional programs remain critical for cellular adaptation. Here, we identify mitochondrial protein import capacity as a regulator of redox-dependent signalling in tumour cells. We show that the mitochondrial import motor component TIMM44, which is upregulated in angiogenesis-driven tumours, drives respiratory remodelling without increasing mitochondrial abundance. This mitochondrial reprogramming establishes a redox-competent state that activates ASK1-p38MAPK, resulting in SP1-dependent upregulation of VEGFA independently of HIF stabilization. Importantly, induction of mitochondrial biogenesis via PGC-1α fails to recapitulate this response despite increased active mitochondrial content, demonstrating that abundance of active mitochondria or generic metabolic activation is insufficient to drive this HIF-independent transcription. Collectively, our findings identify mitochondrial protein import process as an active signalling regulator rather than a passive housekeeping role, which links mitochondrial proteostasis to redox-sensitive kinase activation and transcriptional control. This work highlights a non-canonical mitochondrial signalling mechanism through which cells couple organelle remodelling to gene expression programs.
    DOI:  https://doi.org/10.1016/j.redox.2026.104381
  15. Trends Biochem Sci. 2026 Sep 03. pii: S0968-0004(26)00217-3. [Epub ahead of print]
    The diversity of terminal electron acceptors across eukaryotes.
    Ayush D Midha, Isha H Jain.
      The flow of electrons is essential for life. To sustain metabolic flux, organisms efficiently transfer electrons to terminal electron acceptors, which range from inorganic nutrients to intracellularly derived organic metabolites. While the rise of atmospheric oxygen favored the expansion of high-yield aerobic respiration, the diversity of anaerobic electron acceptors remains important for organismal and ecological health, particularly in response to fluctuations in nutrient availability. This review summarizes respiratory and fermentative electron acceptors across eukaryotes, focusing on the evolution of anaerobic pathways. We highlight how ancient metabolic strategies have been conserved and modified to support organisms' adaptation to diverse environmental niches and to sustain biological resilience.
    Keywords:  anaerobic metabolism; electron transport chain; fermentation; redox biology; respiration; terminal electron acceptors
    DOI:  https://doi.org/10.1016/j.tibs.2026.07.009
  16. Cell. 2026 Sep 03. pii: S0092-8674(26)00869-X. [Epub ahead of print]189(18): 5482-5484
    Metabolite buffering of labile iron governs ferroptosis.
    Amalia H Megarioti, James A Olzmann.
      Iron abundance alone does not determine ferroptosis sensitivity. In this issue of Cell, Sharma and colleagues identify polyamines as endogenous metabolic buffers that reduce the chemical accessibility of labile iron, revealing an unexpected function for one of the cell's most abundant metabolite classes while raising new questions about the organization of intracellular iron metabolism.
    DOI:  https://doi.org/10.1016/j.cell.2026.07.037
  17. Psychophysiology. 2026 Sep;63(9): e70383
    Psychobiological and Metabolic Correlates of Time Perception in Humans: An Exploratory Study.
    Darshana Kapri, Gabriel Sturm, Catherine Kelly, Ke Bo, Cynthia C Liu, Tor D Wager, Michio Hirano, Caroline Trumpff, Martin Picard.
      Time perception-the subjective sense of how quickly or consistently time passes-shows striking variability across individuals, yet its physiological basis remains poorly understood. We hypothesized that internal clock speed and trial-to-trial variability in time perception would be linked to physiological and behavioral states. In a cohort of healthy adults (n = 59) and individuals carrying rare mitochondrial DNA mutations affecting mitochondrial energy transformation (n = 36), we explored the associations between time perception (time estimation and production) with measures of immune mitochondrial bioenergetics, blood catecholamines, working memory, and structural and functional neuroimaging. We found weak evidence suggesting that internal clock speed and time perception variability correlated with age and physiological metrics including resting energy expenditure, serum and urine norepinephrine levels, mood and fatigue, working memory performance, and neuroimaging measures of brain structure and function. Individuals with mitochondrial disorders and those with healthy mitochondria exhibited no main difference in time perception. However, they exhibited differential relations with physiological and neural variables, suggesting that mitochondria may moderate how specific processes influence time perception. These results provide a foundation for future studies to examine how cellular bioenergetics relate to time perception in humans.
    Keywords:  mitochondrial disease; norepinephrine; resting energy expenditure; time perception
    DOI:  https://doi.org/10.1111/psyp.70383
  18. Nat Commun. 2026 08 03. pii: 9338. [Epub ahead of print]17(1):
    Maternal metabolic stress regulates progeny intestinal stem cell niche signaling through heritable changes in redox metabolites.
    Helin Hocaoglu, Shenlu Qin, Leah Eller, Farhan Abu, Benjamin Ohlstein, Lei Wang, Matthew H Sieber.
      Maternal metabolic stress is a major determinant of progeny health and disease susceptibility, yet the mechanisms linking germline metabolism to lifelong changes in tissue physiology remain poorly defined. Here, we show that maternal metabolic stress alters the cellular composition of the progeny intestinal epithelium through a conserved metabolic pathway. Germline metabolic dysfunction depletes NAD⁺ in mature oocytes, reprogramming progeny redox metabolism and impairing the methionine cycle. This metabolic shift reduces protein levels of the Notch ligand Delta, disrupting intestinal stem cell niche signaling and altering progeny intestinal physiology. Across insect and mammalian models, our findings reveal that maternal metabolic health has conserved effects on progeny metabolism and intestinal function. Together, this work identifies heritable redox-metabolic changes as a mechanistic link between maternal metabolic stress, stem cell regulation, and intestinal disease susceptibility.
    DOI:  https://doi.org/10.1038/s41467-026-76249-1
  19. Curr Opin Chem Biol. 2026 Sep 02. pii: S1367-5931(26)00110-9. [Epub ahead of print]94 102761
    Metalloadaptor and metallochaperone proteins reveal new chemical principles of biological metal homeostasis.
    Kelly Deng, Christopher J Chang.
      Transition metals are essential nutrients that serve as metabolic cofactors and signaling agents in every cell type across all kingdoms of life. Owing to their relatively low abundance and high chemical reactivity, living organisms have evolved dedicated biochemical pathways to ensure active acquisition and targeted delivery of transition metals to their proper locations across biological length scales spanning tissues to cells to proteins, thus promoting beneficial physiology and avoiding detrimental pathology. Here we summarize recent advances in the discovery of copper metalloadaptor and zinc metallochaperone proteins that reveal new foundational chemical principles of biological metal homeostasis.
    DOI:  https://doi.org/10.1016/j.cbpa.2026.102761
  20. ACS Chem Biol. 2026 Aug 26.
    Mitochondrial Lipids in Cellular Adaptation.
    Mária Balážová, Lili Jiang, Cunqi Ye.
      Mitochondria serve as central hubs of cellular bioenergetics and signaling, yet the dynamic role of their lipid composition in cellular adaptation remains underappreciated. Unlike most organelles, mitochondria possess a unique dual-bilayer membrane architecture shaped by lipid transport and de novo synthesis. The mitochondrial lipidome, dominated by phosphatidylcholine, phosphatidylethanolamine, and the signature phospholipid cardiolipin, influences cristae organization, oxidative phosphorylation capacity, and metabolite transport, collectively determining whether mitochondria undergo stabilization, remodeling, or degradation. In this review, we explore how mitochondrial lipid dynamics sustain organelle-wide homeostasis while coordinating cellular adaptation across multiple temporal scales and how failure of lipid homeostasis drives rare monogenic disorders and complex pathologies. We propose that environmental shifts transiently disrupt the balance between phospholipid biosynthesis and utilization, generating changes in mitochondrial lipid homeostasis that promote cellular adaptation through complementary biophysical and biochemical signaling mechanisms. Specifically, membrane lipid remodeling rapidly alters membrane biophysical properties to regulate membrane protein activity, whereas bioactive phospholipid intermediates and side-products support long-term adaptive reprogramming. Mitochondrial lipids therefore function not merely as passive structural components but as active regulatory nodes that drive cellular plasticity, positioning lipid dynamics at the nexus of metabolic adaptation and human disease.
    DOI:  https://doi.org/10.1021/acschembio.6c00615
  21. Cell. 2026 Sep 01. pii: S0092-8674(26)00934-7. [Epub ahead of print]
    De novo pan-rhodamine binders for fluorescence microscopy from mammalian cells to extremophiles.
    Yuda Chen, Klaus Yserentant, Kibeom Hong, Kehan Chen, Yiming Kuang, Robert S Picardo, Arghya Bhowmick, Arthur Charles-Orszag, Samuel J Lord, Lei Lu, Kaipeng Hou, Samuel I Mann, Sagar Bhattacharya, Maggie Horst, Jonathan B Grimm, Luke D Lavis, R Dyche Mullins, William F DeGrado, Bo Huang.
      Fluorescent imaging in live cells is a cornerstone of life sciences. While natural fluorescent proteins have been engineered to enhance individual features, no existing tag combines ideal properties into a single system: high brightness, reversible binding, compact size, and stability across diverse conditions. Here, we achieve this through de novo design of rhodamine binders (Rhobin). To harness the broad repertoire of rhodamine fluorophores, we developed a generalizable design strategy for a pan-rhodamine binder compatible with diverse wavelengths and applications. Rhobin enables live- and fixed-cell imaging of various subcellular targets in mammalian cells, showing brightness surpassing existing tags. Its reversible fluorophore binding supports super-resolution stimulated emission depletion (STED) and live-cell single-molecule imaging for extended durations compared with HaloTag. Beyond conventional systems, Rhobin enables live imaging of the extremophile Sulfolobus acidocaldarius at 75°C, previously inaccessible with current tags. Together, these results establish Rhobin as a versatile platform for next-generation imaging and biosensor design.
    Keywords:  de novo protein design; fluorescence microscopy; fluorescent tag; rhodamines; single-molecule imaging; super-resolution imaging; thermophilic microorganisms
    DOI:  https://doi.org/10.1016/j.cell.2026.08.007
  22. Nat Commun. 2026 Sep 03. pii: 9457. [Epub ahead of print]17(1):
    Redox-dependent synaptic clustering of gephyrin.
    Maria-Theresa Gehling, Emanuel H W Bruckisch, Fynn R Eggersmann, Konrad Benting, Lianne J H C Jacobs, Elmar Behrmann, Jan Riemer, Peter Kloppenburg, Filip Liebsch, Günter Schwarz.
      Reactive oxygen species (ROS) have been demonstrated to play central functions as signaling molecules thus extending their role beyond oxidative stress in disease and aging. At inhibitory synapses the scaffolding protein gephyrin clusters glycine and GABA type A receptors. Postsynaptic gephyrin clustering is regulated by post-translational modifications such as phosphorylation, S-palmitoylation, and S-nitrosylation, which all critically impact its scaffolding function. Here, we show that oxidation of surface-exposed cysteine residues in gephyrin triggered reversible, synaptic multimerization providing more receptor binding sites and leading to proteolytic protection. Cys419, located at the previously published E-domain SDII interface important for liquid-liquid phase separation, was identified as a critical residue further regulating liquid-liquid phase separation of gephyrin in a redox-dependent manner. We also observed that surface-exposed cysteines are required to maintain fast miniature inhibitory postsynaptic current rise times, supporting the functional relevance of gephyrin redox regulation. Collectively, our findings suggest that cysteines in gephyrin regulate synaptic localization and clustering as redox-switches, thereby establishing a so far undefined link between neuronal and metabolic activity at inhibitory synapses.
    DOI:  https://doi.org/10.1038/s41467-026-77147-2
  23. Nat Metab. 2026 Aug 31.
    A brief guide to the identification and characterization of secreted molecules.
    Avinash D Londhe, Niels B Danneskiold-Samsøe, Katrin J Svensson.
      
    DOI:  https://doi.org/10.1038/s42255-026-01607-8
  24. Exp Mol Med. 2026 Sep 02.
    Oxygen-dependent subcellular redistribution of PHD3 links the hypoxic microenvironment to mitochondrial metabolic reprogramming in ccRCC.
    Jaelim Sim, Soyeon Lim, Changjun Lee, Hani Jieun Kim, Wonseok Lee, Hyeonki Kim, Hojun Lee, Kimyeong Kim, Mahesh Kumar Teli, Kyeong Beom Jo, Jacob Wright, Jee Soo Park, Myung Eun Lee, Minsun Jung, Minsoo Noh, Dae-Kyum Kim, Mi-Hyun Kim, Dong Wook Choi, Tae Su Choi, Won Sik Ham, Hunsang Lee, Haejin Yoon.
      Clear cell renal cell carcinoma (ccRCC) is characterized by profound metabolic dysregulation, with both prolyl hydroxylase domain protein 3 (PHD3) and pyruvate carboxylase (PC) independently implicated in disease progression. Although each influences patient outcomes, a direct mechanistic interplay between these two regulators has remained elusive. Here, we uncover a novel regulatory axis involving PHD3 and PC by identifying an unexpected subcellular behavior of PHD3, namely, its dual localization to the cytosol and the mitochondrial matrix. We show that mitochondrial import of PHD3 is associated with its intracellular clustering, a process modulated by PHD3 hydroxylase activity and oxygen levels. Once in the matrix, PHD3 directly hydroxylates PC, suppressing its enzymatic activity. In ccRCC with elevated PHD3 expression, this modification restricts anaplerotic flux into the tricarboxylic acid cycle, leading to impaired proliferation, reduced metastasis, and enhanced apoptosis. Together, our findings provide a new framework for targeting cancer metabolism by establishing a previously unrecognized mechanistic link between PHD3-mediated oxygen sensing within the tumor microenvironment and the regulation of ccRCC mitochondrial metabolism through the subcellular re-localization of PHD3.
    DOI:  https://doi.org/10.1038/s12276-026-01814-z
  25. Cell Chem Biol. 2026 Aug 31. pii: S2451-9456(26)00292-8. [Epub ahead of print]
    A lysis-derived PMSF and orthovanadate oxidant defines a distinct cysteine-engagement profile.
    Bethany E Schaffer, Jung Seung Nam, Ceci A Cohen, Clementina Mesaros, Robert W Myers, Leigh Baxt, Kathryn E Wellen, Lewis C Cantley, Noah Dephoure, Nathaniel W Snyder, Iok In Christine Chio, John Blenis.
      Reactive cysteines serve important functions in proteins, and characterizing their engagement by different electrophiles facilitates biological discovery and covalent drug development. Here, we show that the common lysis buffer components phenylmethylsulfonyl fluoride (PMSF) and orthovanadate generate a lysis-derived oxidant that engages cysteines during cell lysis. This oxidant sulfonylates N-acetyl-D-glucosamine kinase (NAGK) C217, producing a mobility shift on SDS-PAGE. C217 lies within the ATP-binding pocket, and a C217S mutant exhibits reduced ATP affinity and enzymatic activity. Competitive iodoacetamide-alkyne activity-based protein profiling (IAA-ABPP) chemoproteomics further showed that the PMSF/orthovanadate oxidant defines a cysteine-engagement profile that partially differs from that of pervanadate. These findings reveal an unrecognized source of chemical reactivity during protein extraction that expands the toolkit for cysteine-engagement profiling and underscores how sample preparation chemistry shapes chemoproteomic measurements.
    Keywords:  N-acetyl-D-glucosamine kinase; NAGK; PMSF; cysteine oxidation; cysteine reactivity; orthovanadate; phenylmethylsulfonyl fluoride
    DOI:  https://doi.org/10.1016/j.chembiol.2026.08.005
  26. Aging Cell. 2026 Sep;25(9): e70696
    Tissue-Level Transcriptomic Entropy Reveals Organ-Specific Aging Patterns and Predicts Cancer Progression.
    Gabriel Arantes Dos Santos, José Pedro Castro, Gabriela D A Guardia, Filipe F Dos Santos, Alexander Birbrair, Pedro A F Galante.
      Although aging and cancer share complex molecular mechanisms, distinguishing causative factors from byproducts remains challenging. Here, we investigated the role of tissue transcriptomic entropy-a measure of transcriptional disorder-in aging and cancer processes by analyzing RNA-sequencing data from over 25,000 samples from human and mouse tissues. We found that entropy changes during aging are highly tissue-specific, with some tissues showing increased entropy while others exhibit decreased or stable entropy levels. Moreover, transcriptomic entropy strongly correlates with age-related processes, showing positive associations with proliferation, cellular senescence, somatic mutation burden, and cellular reprogramming, whereas it negatively correlates with stemness. In cancer, we observed that primary tumors generally display higher entropy than normal tissue, with its levels further increasing in metastatic stages. Cancer treatment modulated entropy patterns in multiple contexts, with changes suggesting a role for transcriptional complexity in tumor plasticity and therapy resistance. Elevated entropy levels predicted poor survival outcomes in multiple cancer types, suggesting its potential as a prognostic marker. Furthermore, differential expression analysis revealed that entropy-associated genes are enriched in developmental processes and depleted in metabolic pathways, indicating a possible link to cellular dedifferentiation. Finally, we found increased entropy in various age-related disorders beyond cancer, suggesting that transcriptomic entropy may be a common feature in age-related diseases. Our findings establish transcriptomic entropy as a fundamental parameter in aging and cancer progression, offering new insights into disease mechanisms.
    Keywords:  biogerontology; functional genomics; geriatric oncology
    DOI:  https://doi.org/10.1111/acel.70696
  27. J Inherit Metab Dis. 2026 Sep;49(5): e70247
    Mitochondrial CLPP in Health and Disease: Mechanisms, Therapeutic Duality and Emerging Opportunities.
    Lea Isermann, Aleksandra Trifunovic.
      Mitochondrial CLPP has emerged as an unusual therapeutic target because both increasing and decreasing its proteolytic activity can be beneficial, depending on the cellular and disease context. Pharmacological CLPP hyperactivation drives broad degradation of mitochondrial proteins and can selectively collapse mitochondrial fitness in susceptible tumor cells, an approach now clinically validated by the approval of dordaviprone for mutant diffuse midline glioma. Conversely, reduced CLPP activity can preserve respiratory-chain components and promote adaptive metabolic and redox remodelling in selected models of mitochondrial disease, neurodegeneration and metabolic dysfunction, with emerging potential in ischaemia-reperfusion injury. These opposing outcomes reflect the broader role of CLPXP in controlling mitochondrial translation, respiratory-chain integrity and metabolism rather than acting simply as a general protein quality-control system. In this review, we discuss the physiological functions and substrate selectivity of CLPXP, the mechanistic basis and clinical development of CLPP inhibitors and activators, and the growing evidence that therapeutic responses depend strongly on tissue identity, metabolic state and the nature of the underlying mitochondrial defect. Together, these findings position CLPP as a context-dependent therapeutic switch whose activity may need to be tuned in opposite directions to either preserve mitochondrial resilience or selectively dismantle mitochondrial fitness.
    DOI:  https://doi.org/10.1002/jimd.70247
  28. Trends Cell Biol. 2026 Sep 04. pii: S0962-8924(26)00168-6. [Epub ahead of print]
    Horizontal mitochondrial transfer: an emerging field in cell biology.
    Michael V Berridge, Zuzana Nahacka, Katerina Komrskova, Minghao Zheng, Jiri Neuzil.
      The field of horizontal mitochondrial transfer (HMT), also referred to as intercellular mitochondrial transfer, has recently gained momentum due to an increasing number of publications that go well beyond diseases such as cancer. From co-culture experiments to in vivo evidence in mouse cancer models, noncancerous diseases, and normal tissue and organ homeostasis and development, it is becoming increasingly clear that HMT is a fundamental physiological phenomenon broadly relevant to complex organisms. Recent methodological advances, epitomized by ultra-high-resolution microscopy and spatial and single-cell multiomics technologies, allow for research that strongly supports HMT as an emerging area of cell biology.
    DOI:  https://doi.org/10.1016/j.tcb.2026.08.012
  29. Cell. 2026 Sep 03. pii: S0092-8674(26)00928-1. [Epub ahead of print]189(18): 5488-5503
    The regulatory logic linking inflammation and fibrosis.
    Michael Alexanian, Deepak Srivastava.
      Whether tissue injury resolves or progresses to chronic scarring is determined by regulatory choices that remain only partially understood. In this review, we propose that immune cells and fibroblasts function as dynamic interpreters of intercellular cues, integrating these signals through chromatin-regulated gene circuits that govern cell state and fate. Drawing on insights from cardiac biology and from settings where tissues regenerate or resolve injury without scarring, we outline a molecular framework in which immune-stromal crosstalk and gene regulatory networks dictate the choice between recovery and chronic fibrosis across organs, including the heart, lung, liver, and kidney. Reframing fibrosis as a reversible state shaped by disrupted regulatory logic opens therapeutic avenues that move beyond suppressing fibrotic outputs toward rewiring the regulatory programs that sustain them.
    DOI:  https://doi.org/10.1016/j.cell.2026.08.001
  30. Cell Rep Med. 2026 Aug 31. pii: S2666-3791(26)00432-5. [Epub ahead of print] 103015
    Lysyl oxidase inhibition disrupts mitochondrial homeostasis to create vulnerability to ferroptosis in TNBC.
    Ozge Saatci, Burge Ulukan, Metin Cetin, Hellen Kuasne, Constanza Martinez, Elif Percin, Natalia Oleinik, Matthew T Savoca, Ali Nehme, Aldo Hernández-Corchado, Evelyn Zavacky, Kukkamudi Sreenivas, Abdol H Rezaeian, Jennifer R Bethard, Jean-Sebastien Anoma, Ozlem Sener Sahin, Adriana Aguilar-Mahecha, Marguerite Buchanan, Mertkaya Aras, Genevieve DeBlois, Mark Basik, Elizabeth G Hill, Lauren E Ball, Chintada Nageswara Rao, Campbell McInnes, Yasser Riazalhosseini, Hamed S Najafabadi, John J Lemasters, Besim Ogretmen, Morag Park, Ozgur Sahin.
      High metabolic heterogeneity and plasticity of triple-negative breast cancer (TNBC) contribute to therapy resistance, necessitating identification of therapeutic vulnerabilities. Here, we identify non-canonical functions of the extracellular matrix (ECM) remodeler, lysyl oxidase (LOX), in regulating glucose metabolism and mitochondrial homeostasis and show that inhibiting LOX generates targetable vulnerability to ferroptosis. Mechanistically, LOX interacts with PARKIN and its upstream kinase PINK1, which we identified as a substrate of LOX. LOX-mediated PINK1 oxidation suppresses PARKIN phosphorylation, stabilizing hypoxia-inducible factor 1-alpha (HIF-1α) and increasing glycolysis. Concomitantly, LOX inhibits PARKIN-mediated mitophagy and maintains mitochondria-ER contacts through VDAC1 stabilization, while the LOX-HSP90 complex promotes mitochondrial Ca2+ transport and ATP production. Inhibiting LOX suppresses glycolysis, disrupts mitochondrial dynamics, reduces OXPHOS and GPX4/FSP1, and induces compensatory DHODH activity. Our "one-two punch" approach combining LOX inhibition with clinical DHODH inhibitor suppresses tumor growth in vivo in chemo-free setting. Notably, LOX protein correlates with HIF-1α/GLUT1/GPX4 in TNBC patient tumors, supporting its clinical relevance.
    Keywords:  DHODH; LOX; MERCS; TNBC; ferroptosis; glucose metabolism; lysyl oxidase; mitochondria-ER contacts; mitophagy
    DOI:  https://doi.org/10.1016/j.xcrm.2026.103015
  31. Cell. 2026 Sep 03. pii: S0092-8674(26)00942-6. [Epub ahead of print]189(18): 5504-5526.e15
    Sexual dimorphism in the complete Drosophila male central nervous system connectome.
    Stuart Berg, Isabella R Beckett, Marta Costa, Philipp Schlegel, Michał Januszewski, Elizabeth C Marin, Aljoscha Nern, Stephan Preibisch, Wei Qiu, Shin-Ya Takemura, Alexandra M C Fragniere, Andrew S Champion, Diane-Yayra Adjavon, Michael Cook, Marina Gkantia, Kenneth J Hayworth, Gary B Huang, William T Katz, Florian Kämpf, Zhiyuan Lu, Christopher Ordish, Tyler Paterson, Tomke Stürner, Eric T Trautman, Catherine R Whittle, Laura E Burnett, Judith Hoeller, Feng Li, Frank Loesche, Billy J Morris, Tobias Pietzsch, Markus W Pleijzier, Valeria Silva, Yijie Yin, Iris Ali, Griffin Badalamente, Alexander Shakeel Bates, Rory J Beresford, John Bogovic, Paul Brooks, Sebastian Cachero, Brandon S Canino, Bhumpanya Chaisrisawatsuk, Jody Clements, Arthur Crowe, Inês de Haan Vicente, Georgia Dempsey, Erika Donà, Márcia Dos Santos, Marisa Dreher, Christopher R Dunne, Katharina Eichler, Samantha Finley-May, Miriam A Flynn, Imran Hameed, Gary Patrick Hopkins, Philip M Hubbard, Ladann Kiassat, Julie Kovalyak, Shirley A Lauchie, Meghan Leonard, Alanna Lohff, Kit D Longden, Charli A Maldonado, Ilina Moitra, Sung Soo Moon, Caroline Mooney, Eva J Munnelly, Nneoma Okeoma, Donald J Olbris, Anika Pai, Birava Patel, Emily M Phillips, Stephen M Plaza, Alana Richards, Jennifer Rivas Salinas, Ruairí J V Roberts, Edward M Rogers, Ashley L Scott, Louis A Scuderi, Pavithraa Seenivasan, Laia Serratosa Capdevila, Claire Smith, Rob Svirskas, Satoko Takemura, Ibrahim Tastekin, Alexander Thomson, Lowell Umayam, John J Walsh, Holly Whittome, C Shan Xu, Emily A Yakal, Tansy Yang, Arthur Zhao, Reed George, Viren Jain, Vivek Jayaraman, Wyatt Korff, Geoffrey W Meissner, Sandro Romani, Jan Funke, Christopher Knecht, Stephan Saalfeld, Louis K Scheffer, Scott Waddell, Gwyneth M Card, Carlos Ribeiro, Michael B Reiser, Harald F Hess, Gerald M Rubin, Gregory S X E Jefferis.
      Sex differences in behavior exist across all animals, typically under strong genetic regulation. In Drosophila, fruitless/doublesex transcription factors identify dimorphic neurons, but their organization into functional circuits remains unclear. We present the connectome of the entire Drosophila male central nervous system. This contains 166,700 neurons spanning the brain and nerve cord, fully proofread and annotated, including fruitless/doublesex expression and 11,710 neuron types. We provide the first comprehensive comparison between male and female brain connectomes to synaptic resolution, finding 8,069 isomorphic, 138 dimorphic, 289 male-specific, and 71 female-specific types. This resource enables analysis of full sensory-to-motor circuits underlying complex behaviors and the impact of dimorphic elements. Sex-specific/dimorphic neurons are concentrated in higher brain centers, while the sensory and motor periphery is largely isomorphic. Within higher centers, male-specific connections are organized into hotspots defined by male-specific neurons or arbors. Dimorphic neurons reroute information across sexes.
    Keywords:  Drosophila; central nervous system; connectome; dimorphic circuits; neural circuits; sex differences
    DOI:  https://doi.org/10.1016/j.cell.2026.08.015
  32. Mol Biol Cell. 2026 Sep 02. mbcE26060250
    Cell-matrix interactions drive functional compartmentalization of mitochondria during 3D migration.
    Breanne R Hewitt, Jacob J Duggan, Ryan J Petrie.
      Cells migrating through three-dimensional (3D) tissues adapt their mechanical properties in response to extracellular matrix architecture through migratory plasticity. In primary human dermal fibroblasts, matrix elasticity drives distinct low- and high-pressure migration modes in which forces either push or pull the nucleus, respectively. How these mechanically distinct modes of nuclear translocation influence mitochondrial organization and function is not known. Here, we show that mitochondria become enriched anterior to the nucleus during 3D migration and segregate into spatially distinct populations with different motility and energetic states. During high-pressure, nuclear-pulling migration, a highly energized mitochondrial pool forms immediately anterior to the nucleus. This mitochondrial pool occupies a specialized perinuclear compartment organized by ROCK-dependent contractility and vimentin intermediate filaments and is selectively lost when this machinery is disrupted. Together, these findings reveal that extracellular matrix mechanics spatially organize mitochondrial dynamics and energetics during 3D migration, coupling localized mitochondrial function to the mechanical requirements of nuclear translocation. [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text].
    DOI:  https://doi.org/10.1091/mbc.E26-06-0250
  33. Nature. 2026 Sep 02.
    Functional chimeric mRNAs encode proteins in mammalian immunity.
    Olivia Venezia, Harry Kane, Gang Du, Hannah D Coughlan, Timothy M Johanson, Hongshen Wang, Pathricia Tilstam, Samuel W Kazer, Georgia Gunner, Daisy A Hoagland, Megha G Basavappa, Kanchana Ravichandran, Eren Ada, Ademi Zhakyp, Sandhya Kumar, Coco Duizer, Owen Searle, Chris Geo Provido, Leonel Joannas, Shilong Yang, Liam B Healy, Qiankun Wang, Joia Capocchi, Bahawar Sharif Dhillon, Sarah Slavoff, Liang Shan, Jorge Henao-Mejia, Ruth A Franklin, Isaac M Chiu, Jose Ordovas-Montanes, Kate L Jeffrey, Judy Lieberman, Rhys S Allan, Jonathan C Kagan, Hao Wu, Ruaidhrí Jackson.
      Individual mammalian mRNAs and proteins are typically believed to originate from single genomic loci, with isoform diversity arising through cis-splicing of pre-mRNA. Whether mRNA from distant genes can undergo trans-splicing to generate functionally relevant chimeric transcripts has remained unclear. Here we develop a pipeline combining long-read direct RNA sequencing with non-targeted and targeted validation to identify chimeric transcripts in macrophages. Chromatin conformation capture studies reveal that inflammation induces interchromosomal DNA interactions, positioning parent genes proximally to facilitate the formation of chimeric mRNA. Notably, we identify a protein-coding chimeric mRNA representing a fusion between the pore-forming protein gasdermin D (GSDMD)1,2 and a C-terminal domain translated out of frame from Tmem106a (Gsdmd-Tmem106a) in mice. We show that inflammasome priming upregulates Gsdmd-Tmem106a, with the protein localizing to the plasma membrane. After activation of the inflammasome, GSDMD-TMEM106A directly interacts with canonical GSDMD N termini to accelerate and enhance pore formation and IL-1β release. Finally, we show that GSDMD-TMEM106A balances host defence and immunopathology in vivo: its loss protects against lethal sepsis but compromises antibacterial defence, whereas overexpression enhances host protection while increasing sepsis lethality. We establish that protein-coding chimeric mRNAs formed by regulated transcript fusion events are operative during inflammation and immunity.
    DOI:  https://doi.org/10.1038/s41586-026-10982-x
  34. Curr Opin Neurobiol. 2026 Sep 03. pii: S0959-4388(26)00106-6. [Epub ahead of print]101 103270
    Mitochondrial molecular diversity in the brain.
    Alva G Sainz, Xinnan Wang.
      Mitochondria are not uniform organelles. Across the brain, they exhibit profound molecular, biochemical, and functional diversity shaped by cell type, anatomical region, subcellular compartment, and lived experience. Recent advances in cell-type- and subcellular domain-targeted proteomics, transcriptomics, advanced live imaging, and functional biochemistry have begun to map this landscape with unprecedented resolution. Together, these findings challenge the conventional view of mitochondria as generic metabolic engines and position mitochondrial molecular diversity as a fundamental feature of brain organization, with direct relevance to behavior, aging, and neurological disease. This mini review synthesizes key recent studies in this field, highlighting their findings, methodological novelty, and significance, and formulates theories and hypotheses for future investigations.
    DOI:  https://doi.org/10.1016/j.conb.2026.103270
  35. Nat Commun. 2026 08 04. pii: 9395. [Epub ahead of print]17(1):
    ATP13A4 gates extracellular polyamine levels to control excitatory synaptogenesis.
    Sarah van Veen, Emily Meeus, Dolores Irala, Kristina Sakers, Zhaolin Liu, Justin Savage, Gabrielle Séjourné, Dhanesh Sivadasan Bindu, Elke Ausloos, Hanna Elzbieta Grzesik, Hanne Dhondt, Nina Schoonvliet, Chris Van den Haute, Joris Van Asselberghs, Marta Montpeyó Garcia-Moreno, Keimpe Wierda, Veerle Baekelandt, Konrad Platzer, Kevin Rostasy, Kai Lee Yap, Jan Eggermont, Matthew G Holt, Cagla Eroglu, Peter Vangheluwe.
      Polyamines, such as spermidine, are essential regulators of brain development, yet how cells control their uptake and extracellular levels remains unclear. Here we show that ATP13A4, a transport protein enriched in glia and prominently expressed in astrocytes, governs brain polyamine balance. Using biochemical, cellular, and animal models, we find that ATP13A4 imports polyamines into cells and thereby limits their availability outside cells. Loss of ATP13A4 simplifies astrocyte morphology and increases the excitatory connections, or synapses, that astrocytes promote between neurons; adding spermidine reproduces these effects, identifying extracellular spermidine as a synapse-promoting signal. In mice lacking Atp13a4, brain polyamines are redistributed, with reduced levels in the cortex and accumulation in cerebrospinal fluid. This is accompanied by excess excitatory synapses, delayed early development, and mild, female-biased behavioral changes in adulthood. Rare ATP13A4 variants linked to neurodevelopmental disorders disrupt its function. Thus, astrocytic polyamine clearance via ATP13A4 tunes extracellular spermidine to shape synapse formation during development.
    DOI:  https://doi.org/10.1038/s41467-026-76132-z
  36. Nat Struct Mol Biol. 2026 Aug 31.
    A single-amino-acid cleavage controls global mitochondrial complex integrity.
    Cansu Kücükköse, Marcin Luzarowski, Fabian Stockert, Annette Flotho, Miguel Cosenza-Contreras, Fatih Demir, Max Gilbert, Jörn Dengjel, Friedel Drepper, Mandy Jeske, Hans-Georg Koch, Pitter F Huesgen, F-Nora Vögtle.
      Mitochondrial proteostasis depends on precise N-terminal processing of imported precursor proteins. Defects in this maturation step are implicated in disease, yet the functional impact in humans remains unclear. Here we show that the intermediate cleaving peptidase ICP55, which removes a single amino acid, acts as a key stabilizer of multimeric mitochondrial protein complexes. Using proteomics and complexome profiling, we identify over 100 human ICP55 substrates and demonstrate that loss of ICP55 triggers widespread destabilization of protein assemblies, with a global shift toward smaller subcomplexes. Thus, we uncover a conserved, post-translational mechanism that safeguards mitochondrial proteostasis by regulating complex integrity through a single amino-acid cleavage, and we reveal N-terminal proteoform control as an unexpected layer of organellar homeostasis.
    DOI:  https://doi.org/10.1038/s41594-026-01876-7
  37. Proc Natl Acad Sci U S A. 2026 Sep 08. 123(36): e2614664123
    Changes in the transcriptome and synthetic lethal dependencies following KRAS mutant expression reveal profound tissue specificity.
    Timothy D Martin, Mei Yuk Choi, Julia C McBride, Stephen J Elledge.
      Oncogenic KRAS mutations exhibit a striking tissue-restricted tropism, occurring with high frequency in pancreatic, colorectal, and lung adenocarcinomas while remaining rare in other lineages. The molecular basis for why these specific tissues are uniquely permissive to KRAS transformation, and how this context shapes therapeutic vulnerabilities, remains poorly defined. Here, we utilized CRISPR-mediated genome engineering to generate endogenous, conditional KRAS-mutant isogenic cell line models across three primary permissive lineages (lung, colon, and pancreas) and the nonpermissive breast lineage. Integrated genome-wide CRISPR fitness screens and comparative transcriptome analyses revealed that KRAS-driven synthetic lethal (SL) dependencies are profoundly shaped by their tissue of origin. Strikingly, we observed minimal overlap in SL hits across lineages, with only three genes shared among the permissive lines, suggesting that the KRAS oncogene operates through divergent, context-specific genetic networks. Mechanistically, we show that KRAS activation induces a universal MYC-driven metabolic signature, but the specific machinery required to sustain this state is lineage-restricted. We identified a dependency on the diphthamide synthesis pathway to maintain translational fidelity amid a KRAS-induced hypertranslational state. These findings demonstrate that even when driven by the same oncogene, tumors exhibit distinct regulatory landscapes and unique genetic vulnerabilities. Our results provide a framework for developing lineage-aware therapeutic strategies, moving beyond universal KRAS inhibition toward targeted interventions tailored to a tumor's specific tissue context.
    Keywords:  KRAS; cancer; synthetic lethality; tissue specificity
    DOI:  https://doi.org/10.1073/pnas.2614664123
  38. Cancer Cell. 2026 Sep 01. pii: S1535-6108(26)00360-0. [Epub ahead of print]
    Integrated clinicogenomic analysis reveals the evolution and metastatic tropisms of advanced colorectal cancer.
    Paolo Manca, Henry Walch, Jierui Xu, Natalie Small, Ayush Kris, Evan Seffar, Allison Richards, Tiffany Xue, Adam Price, Mark T A Donoghue, Christopher Fong, Michele Waters, Justin Jee, Sachin Kumar Deshmukh, George W Sledge, Midhun Malla, Andrea Cercek, Leonard Saltz, Neil H Segal, Zsofia K Stadler, Maliha Nusrat, Michael B Foote, Avni Desai, Sree Chalasani, Devika Rao, Louise Connell, Richard K G Do, Karuna Ganesh, Martin R Weiser, Michael F Berger, David B Solit, Jinru Shia, Efsevia Vakiani, Julio Garcia-Aguilar, Nikolaus Schultz, Francisco Sanchez-Vega, Walid K Chatila, Rona Yaeger.
      We performed an integrated clinical and genomic analysis of over 7,000 consecutively sequenced colorectal cancer (CRC) samples to comprehensively characterize genetic drivers and metastatic tropisms of CRC. We find that genomic evolutionary changes, such as clonal mutations and oncogenic mutant allelic imbalance, selectively enhance the impact of recurrent oncogenic alterations. We identify the relative timing of organ-specific metastasis, showing sequential metastatic progression in microsatellite stable CRC with brain and adrenal metastases as late events; metastatic sites that cluster together, such as lung, bone, and brain metastases; and genomic events that enhance or decrease risk for each metastatic site, with WNT pathway activation as overall protective while RAS pathway activation increased risk for spread to all metastatic sites. Our data suggest that despite the heterogeneity in CRC, genomic evolution increases the impact of recurrent alterations, and integrating information about tumor primary location and genomics can be used to predict organ-specific metastasis risk.
    Keywords:  colorectal cancer; metastatic tropisms; tumor genomics
    DOI:  https://doi.org/10.1016/j.ccell.2026.08.004
  39. Cell Metab. 2026 Sep 03. pii: S1550-4131(26)00334-7. [Epub ahead of print]
    Aging microenvironment induces CD8+ T cell exhaustion by suppressing hepatic β-hydroxybutyrylate synthesis.
    Yifeng Xiao, Yanling Zhang, Zihao Zhao, Zijian Zhang, Xiaohui Zhang, Pengju Chen, Jin Gu, Haichuan Zhu, Peng Jiang, Jie Cheng.
      The metabolic mechanisms by which aging blunts CD8+ T cell antitumor and pathogen defense remain unknown. We demonstrate that the aged microenvironment induces CD8+ T cell exhaustion by reducing β-hydroxybutyrate (3HB) bioavailability. Aging represses hepatic BDH1-dependent 3HB synthesis, restricting SLC16A1-mediated 3HB uptake. Hepatic BDH1 ablation recapitulates age-associated CD8+ T cell dysfunction, compromising antiviral and antitumor immunity, whereas 3HB supplementation reverses these deficits via protein β-hydroxybutyrylation. Using a 3HB-derived chemical probe, 3Halk, together with functional screening, we identify PRKAR1B as a primary effector of 3HB signaling. PRKAR1B β-hydroxybutyrylation inhibits the transcription factor cyclic AMP (cAMP)-responsive element modulator (CREM), which activates T cell exhaustion-related gene expression. Age-associated 3HB depletion enhances CREM-dependent transcription, sustaining CD8+ T cell exhaustion. Consistently, the aged microenvironment compromises chimeric antigen receptor (CAR) T antitumor activity, which is substantially restored by 3HB treatment. Collectively, this study uncovers a hepatic metabolism-derived 3HB-CREM axis governing CD8+ T cell immunosenescence, highlighting 3HB as a viable immunorestorative strategy to improve immunotherapy outcomes in aged individuals.
    Keywords:  3HB; CD8(+) T cell exhaustion; aging; liver metabolism; β-hydroxybutyrylate
    DOI:  https://doi.org/10.1016/j.cmet.2026.08.009
  40. Cancer Discov. 2026 Sep 01. 16(9): 1727-1729
    Mitochondrial Complex I at the Crossroads of NK cell Dysfunction in Glioblastoma.
    Silvia Tiberti, Katayoun Rezvani, May Daher.
      Zhou and colleagues identify mitochondrial complex I activity, mediated through NDUFA9, as a critical determinant of natural killer (NK) cell metabolic fitness and antitumor function in glioblastoma. Their study links impaired oxidative phosphorylation to glutamine dependence, epigenetic repression of effector programs, and loss of NK cell activity, highlighting mitochondrial fitness as an actionable axis for improving cellular immunotherapy in solid tumors. See related article by Zhou et al., p. 1924.
    DOI:  https://doi.org/10.1158/2159-8290.CD-26-1267
  41. Chem Soc Rev. 2026 Sep 04.
    Optical multi-physical field imaging within single cells.
    Yang Xu, Cailing Ji, Jie Tan, Jiandong Feng.
      Intracellular energy conversion and information transfer are associated with local fluctuations of multiple physical fields, including chemical concentration field, thermal field, magnetic field, electric field and mechanical force field. How these fields coordinately influence cellular activities in space and time remains largely unknown. Imaging platforms that convert physical field fluctuations into optical signals provide essential tools for in situ sensing of these invisible physical fields at the single cell level. While existing reviews largely focus on optical probes for a single physical field, a systematic discussion linking cellular activities to multi-field synergy is still lacking. In this review, we propose the concept of "physical field-optical signal conversion" as a bridge that links physical field fluctuations to optical signals, and then systematically summarize signal readout systems designed for imaging multiple physical fields in single living cells. We summarize in detail how multi-physical field imaging can address biological questions that single dimensional detection cannot resolve. Finally, we comprehensively discuss the challenges and future prospects of single cell multi-physical field imaging, with the aim of fostering a deeper understanding of intracellular signalling pathways and life processes.
    DOI:  https://doi.org/10.1039/d6cs00641h
  42. Cancer Discov. 2026 Sep 01. OF1-OF25
    Tumor-Secreted ADAMTSL4 Activates Latent TGFβ1 to Drive Cancer Cachexia.
    Juliano Machado, Vignesh Karthikaisamy, Hermine Mohr, Doris Kaltenecker, Pia Benedikt, Pauline Morigny, Amit Mhamane, Julia Geppert, Amy Rose Fumo, Kerstin Haase, Estefania Simoes, Joanna D C C Lima, Anastasia Georgiadi, Achim Krüger, José Pinhata Otoch, Marc E Martignoni, Vickie E Baracos, Mariam Jamal-Hanjani, Marilia C L Seelaender, Olga Prokopchuk, Julia Szendrödi, Maria Rohm, Stephan Herzig, Mauricio Berriel Diaz.
      Cancer cachexia is a devastating wasting syndrome with no approved therapies. In this study, we identify the tumor-derived glycoprotein ADAMTSL4 as a circulating factor associated with body weight loss in preclinical cachexia models and patients with colorectal and lung cancers. In mice, Adamtsl4 overexpression converted non-cachexia-inducing tumors into cachexia-inducing tumors, whereas its deletion in cachexia-inducing tumors spared fat and muscle, blunted muscle atrophy signatures, and reduced cachexia severity. ADAMTSL4 engages the latency-associated peptide (LAP) of TGFβ1, promoting local activation of TGFβ1 at muscle cell membranes. Genetic blockade of proTGFβ1 or pharmacologic inhibition of TGFβ signaling reduced ADAMTSL4-dependent wasting in adipocytes and muscle cells. Suppression of tumor-derived ADAMTSL4 attenuated skeletal muscle fibrosis in mice. Together, the association between increased circulating ADAMTSL4 levels and TGFβ-driven muscle atrophy and fibrosis gene signatures in patients with cachectic cancer identifies ADAMTSL4 as an upstream regulator of TGFβ1 and a potential therapeutic target in cancer cachexia.
    SIGNIFICANCE: Cancer cachexia lacks effective therapies and remains a major cause of cancer-related morbidity and mortality. We identify tumor-derived ADAMTSL4 as an upstream regulator of latent TGFβ activation via LAP engagement that promotes multiorgan wasting and fibrosis-related remodeling. Targeting ADAMTSL4 may provide a selective therapeutic strategy without systemic TGFβ pathway blockade.
    DOI:  https://doi.org/10.1158/2159-8290.CD-26-0045
  43. Elife. 2026 Sep 02. pii: RP106976. [Epub ahead of print]14
    Cardiolipin deficiency disrupts electron transport chain and drives steatohepatitis.
    Marisa J Brothwell, Guoshen Cao, J Alan Maschek, Annelise M Poss, Alek D Peterlin, Liping Wang, Talia B Baker, Justin L Shahtout, Piyarat Siripoksup, Quentinn J Pearce, Jordan M Johnson, Fabian M Finger, Alexandre Prola, Sarah A Pellizzari, Gillian L Hale, Allison M Manuel, Shinya Watanabe, Edwin R Miranda, Kajsa E Affolter, Trevor S Tippetts, Linda S Nikolova, Ran Hee Choi, Stephen T Decker, Mallikarjun Patil, J Leon Catrow, William L Holland, Sara M Nowinski, Daniel S Lark, Kelsey H Fisher-Wellman, Patrice N Mimche, Kimberley Evason, James E Cox, Scott A Summers, Zach Gerhart-Hines, Katsuhiko Funai.
      Metabolic dysfunction-associated steatotic liver disease (MASLD) is a progressive disorder marked by lipid accumulation, leading to metabolic dysfunction-associated steatohepatitis (MASH). A key feature of the transition to MASH involves oxidative stress resulting from defects in mitochondrial oxidative phosphorylation (OXPHOS). Here, we show that pathological alterations in the lipid composition of the inner mitochondrial membrane (IMM) directly instigate electron transfer inefficiency to promote oxidative stress. Specifically, mitochondrial cardiolipin (CL) was downregulated with MASLD/MASH in humans and in mice. Hepatocyte-specific CL synthase knockout (CLS-LKO) led to spontaneous and robust MASH with extensive steatotic and fibrotic phenotype. Loss of CL paradoxically increased mitochondrial respiratory capacity but also promoted electron leak primarily at sites IIIQO and IIF of the electron transport chain (ETC), reduced the formation of I + III2 + IV respiratory supercomplex, and disrupted the propensity of coenzyme Q to become reduced. Thus, low mitochondrial CL disrupts the ETC to promote oxidative stress and contributes to the pathogenesis of MASH.
    Keywords:  cardiolipin; cell biology; human; liver; mitochondria; mouse
    DOI:  https://doi.org/10.7554/eLife.106976
  44. Cell. 2026 Sep 03. pii: S0092-8674(26)00941-4. [Epub ahead of print]189(18): 5552-5570.e10
    The organization of visual pathways in the Drosophila brain.
    Judith Hoeller, Arthur Zhao, Aljoscha Nern, Edward M Rogers, Sandro Romani, Michael B Reiser.
      Visual systems transform photoreceptor inputs into rich perceptual representations through hierarchical networks that extract features along parallel pathways. Although this architecture is conserved across species, how visual information is routed throughout an entire brain remains elusive in any animal. Using the male Drosophila connectome, we trace signals from photoreceptors through the optic lobes-layered, retinotopic regions containing two-thirds of the brain's neurons-and onward into the central brain. Network-based analyses reveal a multilayered architecture of pathway classes with distinct input mixtures. Signals from visual-input channels spread broadly yet converge in focal regions apparently specialized for particular features and fine spatial sampling. Predictions of receptive-field structure and feature-related input biases are consistent with physiological data and extend to thousands of uncharacterized neuron types. These analyses provide a neuron-by-neuron account of how a visual system organizes and integrates information across an entire brain.
    Keywords:  Drosophila; connectomics; eye maps; hierarchy; pathways; receptive field; vision
    DOI:  https://doi.org/10.1016/j.cell.2026.08.014
  45. Nat Methods. 2026 Sep 01.
    Spatial chromatin architecture and accessibility co-profiling of mammalian tissues.
    Ping Wang, Juan Wang, Qixuan Wang, Mark W Youngblood, Yang Cheng, Bo Tao, Josiah Hiu-Yuen Wong, Yu Luan, Shaojun Yu, Alok Swaroop, Khizar R Nandoliya, Hinda Najem, Yihao Fu, Kathleen McCortney, Di Zhang, Yarui Diao, Amy B Heimberger, Adam M Sonabend, Craig M Horbinski, Rong Fan, Feng Yue.
      Cellular function depends on the spatial organization of cells and biomolecules within the tissue microenvironment. Advances in spatial omics have enabled profiling of molecular features such as transcriptome, proteome and epigenome, and there has been rapid progress of imaging-based approaches to study spatial three-dimensional (3D) genome organization. Here we present Spatial-ATAC-Hi-C, a microfluidic‑based platform for genome-wide, spatially resolved joint-profiling of 3D genome organization and chromatin accessibility on tissue slides. Applied to mouse and human brains, Spatial-ATAC-Hi-C revealed distinct chromatin architecture and gene regulatory programs in neuronal and non-neuronal populations in their native tissue context. In glioblastoma and astrocytoma samples, we detected spatially resolved 3D genome alterations, copy number variations and structural variations across tumor regions, revealing clinically relevant oncogenic events and clonal heterogeneity. By co-profiling of genome architecture and chromatin accessibility while preserving tissue architecture, Spatial-ATAC-Hi-C provides a powerful tool for studying spatial gene regulation in human biology and disease.
    DOI:  https://doi.org/10.1038/s41592-026-03217-4
  46. EMBO J. 2026 Sep 04.
    KDM6A loss enhances oxidative phosphorylation uncovering tissue-level convergent evolution.
    Antonino Alex Cartalemi, Dalia Rosano, Camilla Ferrari, Gemma Crupi, Laura Cassina, Guido Gatti, Federica Corigliano, Simona Punzi, Ilaria Villanti, Daphné Dupéré-Richer, Chiara D'Ercole, Veronica Ruggieri, Annarita Miluzio, Tiziana Bruno, Jose Manuel Garcia Manteiga, Valentina Giansanti, Richard L Bennett, Davide Cittaro, Luca Madaro, Alessandra Boletta, Telmo Pievani, Stefano Biffo, Maurizio Fanciulli, Michele Ciboddo, Jonathan Licht, Giovanni Tonon.
      The tumor suppressor KDM6A/UTX, a histone demethylase and a 2-oxoglutarate-dependent dioxygenase, is frequently lost in many cancer types. We show that KDM6A loss pervasively activates oxidative phosphorylation in several solid tumors, generating a pseudo-hyperoxic environment, opposite from the pseudo-hypoxia observed in VHL-mutated renal carcinomas. Mechanistically, KDM6A sustains the expression of the coil-coil domain gene CCDC3, which inhibits CREB1-driven transcription of the mitochondrial regulator PPARGC1A. In the hematological cancer multiple myeloma where KDM6A is frequently deleted, its loss similarly promotes oxidative phosphorylation, but via an alternative mechanism: the increased transfer of mitochondria from stromal to myeloma cells via tunneling nanotubes, triggered by the loss of the mTORC1 inhibitor TRAF3IP3. Beyond cancer, KDM6A regulates oxidative phosphorylation also during development and in adult tissues, engaging either the CCDC3-CREB1 or the TRAF3IP3-mTORC1 pathways. These mutually exclusive associations suggest a tissue-level convergent evolution, positioning KDM6A as a central modulator of mitochondrial activity through context-specific partners.
    DOI:  https://doi.org/10.1038/s44318-026-00891-0
  47. Biol Chem. 2026 Sep 07.
    ACOD1-dependent succinate signalling acts as a metabolic checkpoint for osteoclast differentiation.
    Yue Gao, Genyang Xin, Elisabeth Seebach, Dominik Schaack, Markus A Weigand, Katharina F Kubatzky.
      Immune cells undergo metabolic reprogramming in response to inflammatory stimuli. The immuneresponsive gene 1 (Irg1) encodes aconitate decarboxylase (ACOD1), which generates itaconate from cis-aconitate in the TCA cycle. Itaconate inhibits succinate dehydrogenase, resulting in succinate accumulation. Stable ACOD1 overexpression in RAW264.7 cells shifted cellular metabolism towards glycolysis, as indicated by enhanced mTOR activation, increased 4E-BP1 phosphorylation, and reduced ATP levels. ACOD1 cells displayed impaired osteoclastogenesis with reduced expression of osteoclast-associated genes and fewer TRAP-positive multinucleated osteoclasts. Unexpectedly, NFATc1 was constitutively present in the nucleus of untreated ACOD1 cells, resulting in residual NFAT activity and induction of inflammatory genes. Upon RANKL stimulation, these pre-activated cells showed delayed osteoclastogenic signalling accompanied by sustained expression of the transcriptional repressors BCL6, MafB, and IRF8. Using a GPR91 antagonist and a Gαq inhibitor, we demonstrate that extracellular succinate activates NFATc1 via GPR91-Gαq signalling. RNA sequencing further revealed that ACOD1 overexpression promotes an innate immune transcriptional program rather than osteoclast differentiation. Together, our findings identify succinate-GPR91 signalling as a regulator of the transition between inflammatory activation and osteoclastogenesis.
    Keywords:  ACOD1; GPR91; Gαq; metabolism; osteoclast; succinate
    DOI:  https://doi.org/10.1515/hsz-2026-0168
  48. Cell Rep. 2026 Sep 03. pii: S2211-1247(26)01000-4. [Epub ahead of print]45(9): 117922
    ACLY palmitoylation reprograms macrophages histone acetylation rewiring to repress hepatocellular carcinoma.
    Junlong Zhao, Dongkun Xie, Jingwen Si, Fan Fan, Chunchen Gao, Zhiwei Yang, Hengchao Yu, Huan Zhang, Yiyang Hu, Liang Wang, Xiuli Cao, Shiqian Liang, Shilin Cheng, Lan Feng, Feng Guan, Xiaodi Zhao, Lei Shang, Yongzhan Nie, Lei Liu, Hongyan Qin.
      The tumor microenvironment (TME) domesticates macrophage function by decreasing chromatin accessibility. The activation and nuclear translocation of ATP-citrate lyase (ACLY) convert citrate to acetyl-CoA, providing a substrate necessary for histone acetylation. However, the underlying mechanisms in macrophage remodeling are poorly understood. Here, we found that saturated fatty acids (sFA), especially palmitic acid (PA), were lower in TAMs of patients with hepatocellular carcinoma (HCC). Scd1 knockout promoted PA accumulation, resulting in both primary and metastatic liver cancer retardation and overall survival improvement. Mechanisms indicated that ACLY-C893 palmitoylation via PA maintained tetramer stability against CUL3-mediated degradation, facilitating histone acetylation of M1-related genes. Notably, both dietary PA with Scd1KO macrophage infusion and TAM-targeted in vivo PA/shSCD1 reprogramming improved the TME to repress HCC progression. Collectively, our research highlights the crucial role of ACLY palmitoylation in the connection between macrophage FA metabolism and histone acetylation reprogramming, which sheds light on the strategy of macrophage-based HCC immunotherapy.
    Keywords:  ACLY; CP: cancer; CP: metabolism; SCD1; hepatocellular carcinoma; histone acylation; macrophage; palmitoylation
    DOI:  https://doi.org/10.1016/j.celrep.2026.117922
  49. Oncogene. 2026 Sep 04.
    A step-wise, deterministic and fatal mouse model of myeloid neoplasm with spontaneous acquisition of patient-relevant RTK-RAS mutations.
    Marija A Zarocsinceva, Moosa Qureshi, Nicola K Wilson, George Giotopoulos, Blaise Musabe, Katherine H M Sturgess, M S Vijayabaskar, Sarah J Kinston, Ryan Asby, David J Adams, Brian J P Huntly, Fernando J Calero-Nieto, Berthold Göttgens.
      Leukaemia arises through the stepwise transformation of healthy haematopoietic cells, yet the asymptomatic premalignant phase and its progression to overt disease remain poorly understood. To model this process, we engineered a patient-derived CEBPA mutation into Hoxb8-FL multipotent murine progenitors and transplanted them into syngeneic mice, capturing a clinically silent premalignant stage. All recipients developed overt disease after ~12 months with 100% penetrance and all acquired secondary RTK-RAS mutations, often with identical amino acid changes to those in patients. Single-cell transcriptomics and phenotypic profiling showed that premalignant mutant cells adopt a plasmacytoid dendritic progenitor-like state in vitro which generates both myeloid and B-lymphoid lineages during premalignancy in vivo, with individual tumours restricted to one lineage. The specificity for RTK-RAS mutations coupled with ongoing differentiation, reflects clinically relevant biological contexts thus providing a tractable model of myeloid neoplasm for mechanistic studies and drug discovery.
    DOI:  https://doi.org/10.1038/s41388-026-03964-w
  50. Anal Chem. 2026 Sep 01. 98(34): 24964-24975
    TRACE: An Integrated Isotope-Tracing Framework for Metabolite Validation and Nutrient Fate Mapping.
    Rui Li, Junyao Wang, Yuanhong Shan, Zuohan Xie, Yuzhe Xiao, Weidong Zhuang, Yongzhen Tao, Jinyu Zhou, Lifeng Yang, Lin Wang.
      Untargeted LC-MS metabolomics offers a broad view of the microbial metabolism. However, its application is hindered by two intertwined challenges: distinguishing true biological signals from chemical artifacts and quantifying nutrient partitioning under nutrient-competitive conditions. Here, we present TRACE, an integrated experimental and computational framework that dynamically calibrates mass and retention time tolerances from the data itself to construct isotope-informed peak networks, enabling rigorous discrimination of biological metabolites from artifacts. Across four LC-MS platforms, TRACE reveals that the proportion of high-confidence annotations fell from 2.94 to 1.48%, while the total features increased by 331% from lower- to higher-sensitivity instruments. TRACE also maps nutrient fates into metabolic pathways by detecting isotopic dilution in Saccharomyces cerevisiae cultured with 13C-glucose, 15N-ammonium, and other unlabeled nutrients. Specifically, labeling of glutathione, a linear assembly of three amino acids, accurately reflect direct incorporation from its constituent amino acids; NAD+, whose biosynthesis proceeds through concurrent salvage and de novo pathways, revealed how adenine, tryptophan, and glutamine shaped its final isotopologue pattern. By converting untargeted LC-MS data into functional maps of nutrient flow, TRACE establishes a system-level approach to interrogate microbial metabolism under physiologically relevant competitive conditions.
    DOI:  https://doi.org/10.1021/acs.analchem.6c02292
  51. Methods Mol Biol. 2026 ;3063 189-204
    Large-Scale Metabolite Annotation in Untargeted Metabolomics Using MetDNA.
    Haosong Zhang, Zheng-Jiang Zhu.
      MetDNA ( http://metdna.zhulab.cn/ ) is a network-based computational platform for large-scale metabolite annotation in untargeted metabolomics using liquid chromatography-mass spectrometry (LC-MS). By using a metabolic reaction network (MRN) to guide recursive MS2 spectral similarity matching, MetDNA can accurately annotate both known and unknown metabolites, going beyond the limits of conventional spectral libraries. Since 2019, the platform has evolved from MetDNA to MetDNA2 and now to MetDNA3, with improvements in efficiency, coverage, and confidence in metabolite annotation for untargeted metabolomics. In this protocol, we outline best practices for data preparation, parameter configuration, and result interpretation, offering users a practical workflow to maximize the utility of MetDNA for high-confidence metabolite annotation.
    Keywords:  LC–MS; MetDNA; Metabolite annotation; Untargeted metabolomics
    DOI:  https://doi.org/10.1007/978-1-0716-5452-1_11
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