bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2026–02–01
48 papers selected by
Christian Frezza, Universität zu Köln
  1. Lysosomes as hubs of metabolic sensing and cellular homeostasis.
  2. Coordination of cell organelles to promote metabolon formation.
  3. DNA-protein cross-links promote cGAS-STING-driven premature aging and embryonic lethality.
  4. Methylation, acetylation and cell fate.
  5. Heritability of intrinsic human life span is about 50% when confounding factors are addressed.
  6. Mitochondrial DNA: A Key Alarmin Igniting the Inflammasome Fire in Health and Disease.
  7. Spatial FBA reveals heterogeneous Warburg niches in renal tumors and lactate consumption in colorectal cancer.
  8. Lamin A/C-regulated cysteine catabolic flux modulates stem cell fate through epigenome reprogramming.
  9. Mitochondrial Ca2+ Signaling at the Tripartite Synapse: A Unifying Framework for Glutamate Homeostasis, Metabolic Coupling, and Network Vulnerability.
  10. Mitochondria as sources and targets of cellular signaling.
  11. Mitochondria and Epigenetic Regulation: Bidirectional Crosstalk and Emerging Mitochondria-Targeted Degron Tools.
  12. Energy stress activates AMPK to arrest mitochondria via phosphorylation of TRAK1.
  13. A Thermodynamic Constraint on GPx4 Flux Links Glutathione Redox State to Ferroptotic Commitment.
  14. SREBP-1 upregulates SOAT1 to promote tumor growth by preventing lipotoxicity.
  15. Intraoperative arteriovenous patient sampling to assess in situ non-small cell lung cancer metabolism.
  16. Scar-associated endothelial-stellate cellular crosstalk drives fibrosis resolution in MASH.
  17. Breast Cancer Metastases Harbor Tissue-Specific Metabolic Dependencies.
  18. Molecular profiling of primary versus paired asynchronous metastatic clear cell renal cell carcinoma reveals heterogeneity in tumor immune microenvironment.
  19. The Role of Mitochondrial Ion Channels in the Evolution of Anticancer Drug Resistance.
  20. Spontaneous behavior is a succession of self-directed tasks.
  21. Mitochondrial succinate transport is required for cardiac ischemia/reperfusion injury.
  22. In Vivo Chemical Reprogramming Is Associated With a Toxic Accumulation of Lipid Droplets Hindering Rejuvenation.
  23. Circadian rhythms and glucocorticoid dynamics in the kidney matrix.
  24. Mitochondrial protein carboxyl-terminal alanine-threonine tailing promotes human glioblastoma growth by regulating mitochondrial function.
  25. Cytochrome c Oxidase Subunit COX4-1 Reprograms Erastin-Induced Cell Death from Ferroptosis to Apoptosis: A Transmitochondrial Study.
  26. Newcastle disease virus hijacks mitophagy to reprogram amino acid metabolism for enhanced replication.
  27. Modulation of Nudt21 levels reveals dose-dependent roles of alternative polyadenylation in tissue regeneration.
  28. Axonal distribution of mitochondria maintains neuronal autophagy during aging via eIF2β.
  29. Sensitivity of primary mitochondrial disease fibroblasts to ferroptosis: The role of intracellular iron.
  30. Signaling to make human ribosomes: Connections between the cytoplasm and the nucleolus.
  31. ALKB-1-dependent tRNA methylation is required for efficient paternal mitochondrial elimination.
  32. FASN at the Crossroads of Tumor Metabolism, Immune Evasion, and Therapy Resistance: Mechanistic Insights and Therapeutic Opportunities.
  33. Five dominant amino acid substitution signatures shape tumour immunity.
  34. Comparative analysis of senolytic drugs reveals mitochondrial determinants of efficacy and resistance.
  35. Mito-nuclear communication: From cellular responses to organismal health.
  36. Liver metastases dampen IL18-driven γδ T cell activity and immunotherapy responsiveness in colorectal cancer.
  37. Biomolecular condensates sustain pH gradients at equilibrium through charge neutralization.
  38. A type I interferon-mitochondrial axis regulates efferocytosis and interferon-stimulated gene induction in macrophages.
  39. Pan-Epigenetic Age Prediction in Mammals.
  40. Scalable and multiplexed recorders of gene regulation dynamics across weeks.
  41. Rethinking the heritability of aging.
  42. A spatially resolved atlas of gastric cancer characterises a lymphocyte-aggregated region.
  43. Technology is changing how we write - and how we think about writing.
  44. Bempedoic acid directly binds and activates PPARα.
  45. α-Ketoglutarate couples cellular metabolism to developmental growth via hydroxylation-dependent degradation of Yorkie.
  46. Resolving clonal evolution and selection of extrachromosomal DNA at single-cell resolution.
  47. Altered Magnesium Environments Restrict Colorectal HT-29 Spheroid Growth by Disturbing Cellular Mg2+ Homeostasis.
  48. TORC1-dependent translation drives chromatin remodeling during the germ-cell-to-maternal transition in Drosophila.
  1. Mol Cell. 2026 Jan 28. pii: S1097-2765(26)00031-6. [Epub ahead of print]
    Lysosomes as hubs of metabolic sensing and cellular homeostasis.
    Aakriti Jain, Roberto Zoncu.
      Lysosomes are hubs that couple macromolecular breakdown to cell-wide signaling by sensing metabolic, damage-associated, and environmental cues. Nutrients liberated in the lysosomal lumen as end-products of macromolecular degradation, including amino acids, lipids, and iron, are exported by dedicated transporters for utilization in the cytoplasm. Nutrient transport across the lysosomal membrane is coupled to its sensing by specialized signaling complexes on the cytoplasmic face, which, in response, mediate communication with other organelles and control cell-wide programs for growth, catabolism, and stress response. Lysosomes acquire specialized sensing-signaling features in immune cells, where they shape antigen processing, innate immune signaling, and inflammatory cell death, and in neurons, where they act as sentinels of proteostatic and mitochondrial stress, supporting local translation, organelle quality control, and neuroimmune crosstalk. We highlight recently identified pathways and players that position lysosomes as integrators of nutrient status and organelle health to drive tissue-specific physiology.
    Keywords:  amyloid; autophagy; inflammation; lysosome; mTORC1; metabolites; neurodegeneration; organelle contacts; signaling
    DOI:  https://doi.org/10.1016/j.molcel.2026.01.011
  2. Proc Natl Acad Sci U S A. 2026 Feb 03. 123(5): e2532504123
    Coordination of cell organelles to promote metabolon formation.
    Zhou Sha, Anthony M Pedley, Timothy D Iles, Shaoqing Zhang, Jack R Staub, Ruobo Zhou, Stephen J Benkovic.
      The spatial coordination between cellular organelles and metabolic enzyme assemblies represents a fundamental mechanism for maintaining metabolic efficiency under stress. While previous work has shown that membrane-bound organelles regulate metabolic activities and that membrane-less condensates conduct metabolic reactions, the coordination between these two organizations remains unaddressed. By using a combination of proximity labeling, superresolution fluorescence microscopy, and metabolite analyses using isotopic tracing, we investigated the relationships between these metabolic hotspots. Here, we show that nutrient deficiency elongates mitochondria and transforms the ER from a tubular to sheet-like morphology, coinciding with increased mitochondrial respiration and inosine 5'-monophosphate levels. These structural changes promote the colocalization of purinosomes with these organelles, enhancing metabolic channeling. Disruption of ER sheet formation via MTM1 knockout destabilizes purinosomes, impairs substrate channeling, and reduces intracellular purine nucleotide pools without altering enzyme expression. Our findings reveal that organelle morphology and interorganelle contacts dynamically regulate the assembly and function of metabolic condensates, providing a structural basis for coordinated metabolic control in response to nutrient availability.
    Keywords:  biomolecular condensates; cell metabolism; de novo purine biosynthesis; metabolon; purine
    DOI:  https://doi.org/10.1073/pnas.2532504123
  3. Science. 2026 Jan 29. 391(6784): eadx9445
    DNA-protein cross-links promote cGAS-STING-driven premature aging and embryonic lethality.
    Ines Tomaskovic, Cristian Prieto-Garcia, Maria Boskovic, Mateo Glumac, Tsung-Lin Tsai, Thorsten Mosler, Rubina Kazi, Rajeshwari Rathore, Jorge Andrade, Marina Hoffmann, Giulio Giuliani, Anne-Claire Jacomin, Raquel S Pereira, Elias Knop, Laurens Wachsmuth, Petra Beli, Koraljka Husnjak, Manolis Pasparakis, Andrea Ablasser, Daniela S Krause, Michael Potente, Stamatis Papathanasiou, Janos Terzic, Ivan Dikic.
      DNA-protein cross-links (DPCs) are highly toxic DNA lesions that block replication and transcription, but their impact on organismal physiology is unclear. We identified a role for the metalloprotease SPRTN in preventing DPC-driven immunity and its pathological consequences. Loss of SPRTN activity during replication and mitosis lead to unresolved DNA damage, chromosome segregation errors, micronuclei formation, and cytosolic DNA release that activates the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway. In a Sprtn knock-in mouse model of Ruijs-Aalfs progeria syndrome, chronic cGas-Sting signaling caused embryonic lethality through inflammation and innate immune responses. Surviving mice displayed aging phenotypes beginning in embryogenesis, which persisted into adulthood. Genetic or pharmacological inhibition of cGas-Sting rescued embryonic lethality and alleviated progeroid phenotypes.
    DOI:  https://doi.org/10.1126/science.adx9445
  4. Nat Metab. 2026 Jan 28.
    Methylation, acetylation and cell fate.
    Dan Huang, Ziwei Dai.
      
    DOI:  https://doi.org/10.1038/s42255-025-01449-w
  5. Science. 2026 Jan 29. 391(6784): 504-510
    Heritability of intrinsic human life span is about 50% when confounding factors are addressed.
    Ben Shenhar, Glen Pridham, Thaís Lopes De Oliveira, Naveh Raz, Yifan Yang, Joris Deelen, Sara Hägg, Uri Alon.
      How heritable is human life span? If genetic heritability is high, longevity genes can reveal aging mechanisms and inform medicine and public health. However, current estimates of heritability are low-twin studies show heritability of only 20 to 25%, and recent large pedigree studies suggest it is as low as 6%. Here we show that these estimates are confounded by extrinsic mortality-deaths caused by extrinsic factors such as accidents or infections. We use mathematical modeling and analyses of twin cohorts raised together and apart to correct for this factor, revealing that heritability of human life span due to intrinsic mortality is above 50%. Such high heritability is similar to that of most other complex human traits and to life-span heritability in other species.
    DOI:  https://doi.org/10.1126/science.adz1187
  6. Immunology. 2026 Jan 29.
    Mitochondrial DNA: A Key Alarmin Igniting the Inflammasome Fire in Health and Disease.
    Woo Hyun Park.
      Beyond their classical role as cellular powerhouses, mitochondria are now recognised as indispensable hubs for innate immune signalling. A pivotal aspect of this function is the release of mitochondrial DNA (mtDNA), a potent damage-associated molecular pattern (DAMP) that, when misplaced, acts as a powerful alarmin due to its prokaryotic origins. In response to cellular stress or infection, mtDNA translocates to the cytosol and activates intracellular protein platforms known as inflammasomes, triggering the maturation of cytokines like interleukin-1β (IL-1β) and inducing a lytic form of cell death, pyroptosis. This review synthesises current research on this intricate relationship. Whilst potassium (K+) efflux remains the canonical trigger for the NLR family pyrin domain containing 3 (NLRP3) inflammasome, emerging and debated roles of oxidised mtDNA (ox-mtDNA) as a potential direct ligand or critical upstream amplifier are explored. The manuscript elucidates mtDNA release mechanisms, such as mitochondrial permeability transition pore (mPTP) opening, and explores the role of amplifying pathways like the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) axis and cytidine/uridine monophosphate kinase 2 (CMPK2)-mediated mtDNA synthesis. The profound involvement of the mtDNA-inflammasome axis is surveyed across a spectrum of pathologies, including autoimmune, metabolic, neurodegenerative, and cardiovascular diseases. The compiled evidence establishes mtDNA as a universal trigger of inflammation and a unifying pathogenic driver across this diverse disease landscape, highlighting the significant therapeutic potential of modulating this fundamental immune signalling axis to treat a multitude of human diseases.
    Keywords:  immunogenic cell death; inflammasome; innate immunity; mitochondrial DNA; pyroptosis; sterile inflammation
    DOI:  https://doi.org/10.1111/imm.70111
  7. NPJ Syst Biol Appl. 2026 Jan 27.
    Spatial FBA reveals heterogeneous Warburg niches in renal tumors and lactate consumption in colorectal cancer.
    Davide Maspero, Giovanni Marteletto, Francesco Lapi, Bruno G Galuzzi, Irene Ruano, Ben Vandenbosch, Ke Yin, Sabine Tejpar, Alex Graudenzi, Holger Heyn, Anna Pascual-Reguant, Chiara Damiani.
      To investigate how spatial constraints shape cancer metabolism, we devised the spatial Flux Balance Analysis (spFBA) framework for the enrichment of spatial transcriptomics data with relative estimates of metabolic fluxes. Applying spFBA to newly generated high-resolution datasets of paired primary colorectal tumors (CRC) and liver metastases revealed lactate consumption in both primary and metastatic regions. The presence of lactate-consuming niches was confirmed in an independent public dataset, suggesting this may be a recurrent metabolic feature of CRC. Importantly, application to public datasets of renal cancer showed widespread lactate production, consistent with a dominant but heterogeneous Warburg phenotype, ruling out general prediction biases or algorithmic artifacts. spFBA also consistently identified regions of increased proliferation across datasets, supporting the biological validity of its predictions. The framework is applicable to any sequencing-based spatial dataset to effectively uncover metabolic programs that remain invisible to gene expression analysis alone.
    DOI:  https://doi.org/10.1038/s41540-026-00654-x
  8. Nat Metab. 2026 Jan 28.
    Lamin A/C-regulated cysteine catabolic flux modulates stem cell fate through epigenome reprogramming.
    Yinuo Wang, Haojie Shi, Janina Wittig, Yonggang Ren, Julio Cordero, Matthias Dewenter, Jessica Mella, Abigail Buchwalter, Johannes Backs, Thomas Wieland, Joerg Heineke, Ingrid Fleming, Sofia-Iris Bibli, Gergana Dobreva.
      Spatiotemporal changes in the nuclear lamina and cell metabolism shape cell fate, yet their interplay is poorly understood. Here we identify lamin A/C as a key regulator of cysteine catabolic flux essential for proper cell fate and longevity. Its loss in naive mouse pluripotent stem cells leads to upregulation of the cysteine-generating and catabolizing enzymes, cystathionine γ-lyase (CTH) and cystathionine β-synthase (CBS), thereby promoting de novo cysteine synthesis. Increased cysteine flux into acetyl-CoA fosters histone H3K9 and H3K27 acetylation, triggering a transition from naive to primed pluripotency and abnormal cell fate and function. Conversely, the toxic gain-of-function mutation of Lmna, encoding lamin A/C and associated with premature ageing, reduces CTH and CBS levels. This reroutes cysteine catabolic flux and alters the balance between H3K9 acetylation and methylation, crucially impacting germ layer formation and genome stability. Notably, modulation of Cth and Cbs rescues the abnormal cell fate and function, restores the DNA damage repair capacity and alleviates the senescent phenotype caused by lamin A/C mutations, highlighting the potential of modulating cell metabolism to mitigate epigenetic diseases.
    DOI:  https://doi.org/10.1038/s42255-025-01443-2
  9. Biomolecules. 2026 Jan 20. pii: 171. [Epub ahead of print]16(1):
    Mitochondrial Ca2+ Signaling at the Tripartite Synapse: A Unifying Framework for Glutamate Homeostasis, Metabolic Coupling, and Network Vulnerability.
    Mariagrazia Mancuso, Federico Mezzalira, Beatrice Vignoli, Elisa Greotti.
      Mitochondrial Ca2+ signaling is increasingly recognized as a key integrator of synaptic activity, metabolism, and redox balance within the tripartite synapse. At excitatory synapses, Ca2+ influx through ionotropic glutamate receptors and voltage-gated channels is sensed and transduced by strategically positioned mitochondria, whose Ca2+ uptake and release tune tricarboxylic acid cycle activity, adenosine triphosphate synthesis, and reactive oxygen species (ROS) generation. Through these Ca2+-dependent processes, mitochondria are proposed to help set the threshold at which glutamatergic activity supports synaptic plasticity and homeostasis or, instead, drives hyperexcitability and excitotoxic stress. Here, we synthesize how mitochondrial Ca2+ dynamics in presynaptic terminals, postsynaptic spines, and perisynaptic astrocytic processes regulate glutamate uptake, recycling, and release, and how subtle impairments in these pathways may prime synapses for failure well before overt energetic collapse. We further examine the reciprocal interplay between Ca2+-dependent metabolic adaptations and glutamate homeostasis, the crosstalk between mitochondrial Ca2+ and ROS signals, and the distinct vulnerabilities of neuronal and astrocytic mitochondria. Finally, we discuss how disruption of this Ca2+-centered mitochondria-glutamatergic axis contributes to synaptic dysfunction and circuit vulnerability in neurodegenerative diseases, with a particular focus on Alzheimer's disease.
    Keywords:  Alzheimer’s disease; astrocyte–neuron communication; excitotoxicity; glutamate homeostasis; glutamatergic synapse; metabolic coupling; mitochondrial Ca2+ signaling; mitochondrial signaling; neuronal hyperexcitability; synaptic vulnerability
    DOI:  https://doi.org/10.3390/biom16010171
  10. Mol Cell. 2026 Jan 28. pii: S1097-2765(26)00028-6. [Epub ahead of print]
    Mitochondria as sources and targets of cellular signaling.
    Anna Meichsner, Verian Bader, Konstanze F Winklhofer.
      Mitochondria are multifunctional organelles that, in addition to providing energy, coordinate various signaling pathways essential for maintaining cellular homeostasis. Their suitability as signaling organelles arises from a unique combination of structural and functional plasticity, allowing them to sense, integrate, and respond to a wide variety of cellular cues. Mitochondria are highly dynamic-they can fuse and divide, pinch off vesicles, and move around, facilitating interorganellar communication. Moreover, their ultrastructural peculiarities enable tight regulation of fluxes across the inner and outer mitochondrial membranes. As organelles of proteobacterial origin, mitochondria harbor danger signals and require protection from the consequences of membrane damage by efficient quality control mechanisms. However, mitochondria have also been co-opted by eukaryotic cells to react to cellular damage and promote effective immune responses. In this review, we provide an overview of our current knowledge of mitochondria as both sources and targets of cellular signaling.
    Keywords:  ISR; MAVS; NEMO; NF-κB; UPRmt; cGAS/STING; cardiolipin; inflammation; innate immune signaling; membrane contact sites; mitochondria; mtDNA; mtRNA; signaling
    DOI:  https://doi.org/10.1016/j.molcel.2026.01.008
  11. Cells. 2026 Jan 06. pii: 95. [Epub ahead of print]15(2):
    Mitochondria and Epigenetic Regulation: Bidirectional Crosstalk and Emerging Mitochondria-Targeted Degron Tools.
    Yingwei Xu, Xiaokun Jian, Lei Shi, Lisa S Shock, Lanming Chen, Louise T Chow, Hengbin Wang.
      Mitochondria not only generate ATP and metabolites essential for nuclear and cytoplasmic processes but also actively shape nuclear epigenetic regulation. Conversely, the nucleus encodes most of the proteins required for mitochondrial functions, and intriguingly, certain nuclear-encoded epigenetic factors-such as DNA and histone modifiers-also localize to mitochondria, where they modulate mitochondria genome stability, gene expression, metabolic flux, and organelle integrity. This reciprocal interplay defines mitochondria as both a source and a target of epigenetic regulation, integrating energy metabolism with gene expression and cellular homeostasis. This review highlights emerging mechanisms that link mitochondrial metabolism to chromatin remodeling, DNA and histone modifications, and transcriptional control, as well as how nuclear epigenetic enzymes translocate into mitochondria and regulates their functions. We also briefly introduce recent methodological advances that enable spatially selective depletion of mitochondrial proteins, offering new tools to dissect this bidirectional communication. Together, these insights underscore mitochondria's central role as an energetic and epigenetic hub coordinating nuclear function, development, and disease.
    Keywords:  epigenetics; gene expression; metabolism; mitochondria
    DOI:  https://doi.org/10.3390/cells15020095
  12. J Cell Biol. 2026 Apr 06. pii: e202501023. [Epub ahead of print]225(4):
    Energy stress activates AMPK to arrest mitochondria via phosphorylation of TRAK1.
    Jill E Falk, Tobias Henke, Sindhuja Gowrisankaran, Simone Wanderoy, Himanish Basu, Sinead Greally, Judith Steen, Thomas L Schwarz.
      Neuronal signaling requires large amounts of ATP, making neurons particularly sensitive to defects in energy homeostasis. Mitochondrial movement and energy production are therefore regulated to align local demands with mitochondrial output. Here, we report a pathway that arrests mitochondria in response to decreases in the ATP-to-AMP ratio, an indication that ATP consumption exceeds supply. In neurons and cell lines, low concentrations of the electron transport chain inhibitor antimycin A decrease the production of ATP and concomitantly arrest mitochondrial movement without triggering mitophagy. This arrest is accompanied by the accumulation of actin fibers adjacent to the mitochondria, which serve as an anchor that resists the associated motors. This arrest is mediated by activation of the energy-sensing kinase AMPK, which phosphorylates TRAK1. This mechanism likely helps maintain cellular energy homeostasis by anchoring energy-producing mitochondria in places where they are most needed.
    DOI:  https://doi.org/10.1083/jcb.202501023
  13. Free Radic Biol Med. 2026 Jan 23. pii: S0891-5849(26)00057-2. [Epub ahead of print]
    A Thermodynamic Constraint on GPx4 Flux Links Glutathione Redox State to Ferroptotic Commitment.
    Fulvio Ursini, Antonella Roveri, Matilde Maiorino, Laura Orian.
      Ferroptosis is a non-accidental form of cell death driven by lipid peroxidation and critically controlled by the selenoenzyme Glutathione Peroxidase 4 (GPx4). By integrating molecular modeling, redox thermodynamics, and enzymatic evidence, we propose that ferroptosis is governed by the redox potential of the glutathione couple, elevating current mechanistic descriptions to a quantitative physical-chemical framework. The terminal step of the GPx4 catalytic cycle-responsible for enzyme regeneration and oxidized glutathione (GSSG) formation-is intrinsically endergonic, and its driving force declines continuously as the glutathione redox potential becomes less reducing. As a result, GPx4 activity decreases linearly in accordance with Nernstian principle, independently of discrete inhibitory events. Within this framework, ferroptosis is not initiated by a discrete molecular trigger or canonical signaling cascade; rather, it emerges when a critical biological threshold is surpassed, such that GPx4-dependent detoxification capacity is no longer sufficient to counteract ongoing lipid peroxidation within a given pro-oxidant context. Thus, a discrete cell-death outcome executed by GSSG emerges from the continuous variation of a thermodynamic control variable. This mode of regulation is unique to selenium chemistry and provides a physical-chemical rationale for the indispensability of selenocysteine in the redox control of cellular life and death.
    Keywords:  Ferroptosis; GPx4; Glutathione peroxidases; Glutathione redox potential; Lipid peroxidation; Redox homeostasis; Redox thermodynamics; Selenocysteine
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.01.039
  14. Cell Rep. 2026 Jan 24. pii: S2211-1247(25)01668-7. [Epub ahead of print]45(2): 116896
    SREBP-1 upregulates SOAT1 to promote tumor growth by preventing lipotoxicity.
    Yaogang Zhong, Logan Mazik, Huali Su, Cheng-Yao Chiang, Feng Geng, Xiaokui Mo, Qiang Wang, Yongjun Kou, Wei Chen, Zaibo Li, Craig Horbinski, Arnab Chakravarti, Qi-En Wang, Deliang Guo.
      Rapidly growing tumors require abundant supplies of cholesterol, but excess cholesterol can be cytotoxic. How cancer cells balance this demand while avoiding lipotoxicity remains unclear. Our study found that SOAT1, the enzyme that converts cholesterol into cholesteryl esters for storage in lipid droplets, is concurrently upregulated with SREBP-1, a master transcription factor that governs cholesterol uptake and biosynthesis across multiple cancer types. Mechanistically, SREBP-1 binds the SOAT1 promoter and transcriptionally activates its expression, coupling cholesterol acquisition with intracellular storage. Genetic silencing of SOAT1, while preserving SREBP-1 activity, resulted in the accumulation of free cholesterol and induced mitochondrial oxidative stress, impairing the growth of patient-derived organoids and xenografts from lung cancer and glioblastoma, the most lethal brain tumor, and significantly prolonging survival in preclinical mouse models. These findings reveal a dual role of SREBP-1 in controlling both cholesterol acquisition and storage to maintain cholesterol homeostasis, prevent lipotoxicity, and sustain tumor growth.
    Keywords:  CP: cancer; CP: metabolism; ROS; SOAT1; SREBP-1; cholesterol; glioblastoma; lipotoxicity; lung cancer; tumor growth
    DOI:  https://doi.org/10.1016/j.celrep.2025.116896
  15. J Clin Invest. 2026 Jan 27. pii: e198821. [Epub ahead of print]
    Intraoperative arteriovenous patient sampling to assess in situ non-small cell lung cancer metabolism.
    Johnathan R Kent, Keene L Abbott, Rachel Nordgren, Amy Deik, Nupur K Das, Millenia Waite, Tenzin Kunchok, Anna Shevzov-Zebrun, Nathaniel Christiansen, Amir Sadek, Darren S Bryan, Mark K Ferguson, Jessica S Donington, Alexander Muir, Yatrik M Shah, Clary B Clish, Matthew G Vander Heiden, Maria Lucia L Madariaga, Peggy P Hsu.
      
    Keywords:  Glucose metabolism; Lung cancer; Metabolism; Metabolomics; Oncology
    DOI:  https://doi.org/10.1172/JCI198821
  16. Cell Rep. 2026 Jan 23. pii: S2211-1247(25)01687-0. [Epub ahead of print]45(2): 116915
    Scar-associated endothelial-stellate cellular crosstalk drives fibrosis resolution in MASH.
    Kenneth Li, Vardhman Kumar, Tran To, Álvaro González-Domínguez, Janvi Huria, Maylene Yu, Bruno Cogliati, Chittampalli N Yashaswini, Mark Miller, Andrea D Branch, Bruno Giotti, Alexander M Tsankov, Li Chen, Mathieu Petitjean, Jesse D Kirkpatrick, Sangeeta N Bhatia, Scott L Friedman, Shuang Wang.
      Fibrosis contributes to ∼40% of mortality in the industrialized world. Fibrosis in the liver can spontaneously resolve when injury terminates. In this study, we establish a robust mouse model of fibrosis regression in MASH (metabolic dysfunction-associated steatohepatitis), a highly prevalent chronic liver disease worldwide, and perform single-cell and in situ molecular profiling to define the molecular drivers of fibrosis regression. Prediction of cell-cell communication identifies a Wnt9b-Sfrp2 crosstalk that emerges as fibrosis resolves, the perturbation of which attenuates spontaneous fibrosis regression. We further identify a subset of liver endothelial cells termed "Endo4" as the source of Wnt9b. Immunostaining for the Endo4 marker VWF using tissue clearing and 3D imaging reveals VWF+ vasculature juxtaposing activated hepatic stellate cells that penetrate deep into the fibrotic septa and exhibit in situ protease activity, establishing them as de facto scar-associated endothelial cells and a regulatory node in murine MASH fibrosis regression.
    Keywords:  CP: metabolism; MASH mouse model; WNT signaling; endo-stellate crosstalk; fibrosis regression; in situ protease activity; liver endothelial cells; scar-associated endothelial cells; scar-associated niche; single-cell/nucleus RNA sequencing; tissue clearing and 3D imaging
    DOI:  https://doi.org/10.1016/j.celrep.2025.116915
  17. Cancer Discov. 2026 Jan 23. OF1
    Breast Cancer Metastases Harbor Tissue-Specific Metabolic Dependencies.
      
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2026-012
  18. Sci Rep. 2026 Jan 28.
    Molecular profiling of primary versus paired asynchronous metastatic clear cell renal cell carcinoma reveals heterogeneity in tumor immune microenvironment.
    Brittney Cotta, Srinivas Nallandhighal, Steven Monda, Zayne Knuth, Daniel Triner, Yuping Zhang, Rui Wang, Fengyun Su, Amy Kasputis, Xuhong Cao, Aaron Udager, Saravana M Dhanasekaran, Ganesh S Palapattu, Rohit Mehra, Marcin P Cieslik, Todd M Morgan, Simpa S Salami.
      
    Keywords:  Kidney cancer metastasis; Oncologic outcomes; Survival; Tumor immune microenvironment
    DOI:  https://doi.org/10.1038/s41598-026-35021-7
  19. Curr Protein Pept Sci. 2026 Jan 22.
    The Role of Mitochondrial Ion Channels in the Evolution of Anticancer Drug Resistance.
    Swaroop Kumar Pandey, Ayush Kulshreshtha, Anuja Mishra.
      Apoptosis, drug resistance, and cellular metabolism are all crucially regulated by mitochondria, especially through ion channels and translocases embedded in their membranes. The outer mitochondrial membrane (OMM) contains the voltage dependent anion channel (VDAC), which acts with proteins such as hexokinase II and BAX to regulate apoptosis and metabolic reprogramming in cancer while facilitating the flow of important metabolites and ions. Anti apoptotic proteins like Bcl2 and Mcl1 closely regulate the mitochondrial apoptosis induced channel (MAC), which is created by pro-apoptotic Bcl2 family members BAX and BAK and controls cytochrome c release when overexpressed, leading to drug resistance. Furthermore, the translocase of the outer membrane (TOM) complex, which regulates mitochondrial protein import, is frequently dysregulated in cancers. Numerous ion channels, such as potassium channels, the mitochondrial calcium uniporter (MCU), and the mitochondrial permeability transition pore (m-PTP), are found within the inner mitochondrial membrane (IMM) and regulate important functions like ATP synthesis, the control of reactive oxygen species (ROS), and apoptotic signaling. Cancer cells can avoid apoptosis, adapt to environmental stress, and become resistant to treatments like doxorubicin and cisplatin when these channels are dysregulated. Metabolic flexibility and antioxidant defense are improved by overexpressing or functionally modifying IMM potassium channels and calcium transporters. Additionally, drug resistance is facilitated by increased mitophagy and anti-apoptotic proteins that inhibit m-PTP opening. This review discusses the functions of mitochondrial ion channels.
    Keywords:  Apoptosis; cancer; cellular metabolism.; drug resistance; ion channels; mitochondria
    DOI:  https://doi.org/10.2174/0113892037410334251021155546
  20. Neuron. 2026 Jan 28. pii: S0896-6273(25)00894-3. [Epub ahead of print]
    Spontaneous behavior is a succession of self-directed tasks.
    Caleb Weinreb, Lakshanyaa Thamarai Kannan, Alia Newman-Boulle, Tim Sainburg, Winthrop F Gillis, Alex Plotnikoff, Sofia Makowska, Jonah E Pearl, Mohammed Abdal Monium Osman, Scott W Linderman, Sandeep Robert Datta.
      Animals achieve high-level goals by sequencing low-level actions. This transformation is best understood in structured tasks that impose a specific mapping between goals and actions. However, it remains unclear whether spontaneous behavior is similarly organized in the service of identifiable goals or how it might be supported by brain regions responsible for goal-oriented behavior, such as the prefrontal cortex (PFC). Here, we show that low-level actions in freely exploring mice are hierarchically organized into seconds-long behavioral states that correspond to task-like programs of behavior. These persistent states structure neural activity in the PFC, which preferentially encodes the identity of states relative to low-level behavioral features and shapes which states are expressed in a given context. These findings argue that spontaneous behavior is organized as a succession of self-directed tasks and identify principles of neural control that are common to structured tasks and spontaneous exploration.
    Keywords:  computational ethology; computational neuroethology; ethology; goal-oriented behavior; machine learning; modeling; motivated behavior; natural behavior; prefrontal cortex; spontaneous behavior
    DOI:  https://doi.org/10.1016/j.neuron.2025.11.021
  21. Cardiovasc Res. 2026 Jan 28. pii: cvag031. [Epub ahead of print]
    Mitochondrial succinate transport is required for cardiac ischemia/reperfusion injury.
    Laura Pala, María Torres-López, Stuart T Caldwell, Joyce Valadares, Emily M Smith, Katherine L Hammond, Olga Sauchanka, Jiro Abe, Thomas Krieg, Richard C Hartley, Michael P Murphy, Hiran A Prag.
       BACKGROUND: Succinate accumulates significantly during myocardial ischemia, and its rapid oxidation upon reperfusion is a critical driver of ischemia/reperfusion (I/R) injury. The transport of succinate across the mitochondrial inner membrane, particularly by the dicarboxylate carrier (DIC; SLC25A10), is hypothesized to play a crucial role in mediating these pathological succinate dynamics. However, tools to test this hypothesis by modulating mitochondrial succinate transport in biological systems are lacking.
    METHODS AND RESULTS: C57BL/6J mice, isolated Wistar Rat heart mitochondria, bovine heart mitochondrial membranes, C2C12 mouse myoblasts and primary adult cardiomyocytes were used as in vitro and in vivo models. Butylmalonate prodrugs were synthesized and tested. Isolated mitochondria were used to assess succinate-dependent respiration and reactive oxygen species (ROS) production. Cells were treated with succinate dehydrogenase (SDH) inhibitors or exposed to anoxia and butylmalonate esters. Mouse hearts were subjected to in vivo left anterior descending coronary artery ligation. Succinate and butylmalonate levels were measured by targeted liquid chromatography-tandem mass spectrometry, and infarct size by TTC (2,3,5-triphenyl-2H-tetrazolium chloride) staining.Knockdown of DIC, but not of the oxoglutarate carrier OGC, in C2C12 cells prevented succinate accumulation by SDH inhibition and anoxia. The only extant DIC inhibitor butylmalonate, is limited by poor cell permeability. We synthesized diacetoxymethyl butylmalonate (DAB), which efficiently delivers butylmalonate intramitochondrially in isolated heart mitochondria and cells. DAB inhibited succinate-dependent respiration and ROS production. DAB prevented succinate accumulation in cells treated with SDH inhibitors. DAB delivered butylmalonate to cardiac mitochondria when administered to mice in vivo and reduced infarct size by perturbing mitochondrial succinate transport.
    CONCLUSIONS: The DIC is a key node in the cellular distribution of succinate, controlling its transport between mitochondria and the cytosol. These findings highlight the potential of DIC as a promising therapeutic target for conditions where succinate elevation contributes to pathogenesis, such as cardiac I/R injury.
    Keywords:  SLC25A10; Succinate; butylmalonate; ischemia/reperfusion injury; mitochondrial dicarboxylate carrier; mitochondrial transport; myocardial infarction
    DOI:  https://doi.org/10.1093/cvr/cvag031
  22. Aging Cell. 2026 Feb;25(2): e70390
    In Vivo Chemical Reprogramming Is Associated With a Toxic Accumulation of Lipid Droplets Hindering Rejuvenation.
    Wayne Mitchell, Cecília G de Magalhães, Alexander Tyshkovskiy, Yushi Uchida, Ludger J E Goeminne, Takaharu Ichimura, Emery L Ng, Alibek Moldakozhayev, Joseph V Bonventre, Vadim N Gladyshev.
      Partial reprogramming has emerged as a promising strategy to reset the epigenetic landscape of aged cells towards more youthful profiles. Recent advancements have included the development of chemical reprogramming cocktails that can lower the epigenetic and transcriptomic age of cells and upregulate mitochondrial biogenesis and oxidative phosphorylation. However, the ability of these cocktails to affect biological age in a mammalian aging model has yet to be tested. Here, we have characterized the effects of partial chemical reprogramming on mitochondrial structure and function in aged mouse fibroblasts and tested its in vivo efficacy in genetically diverse male UM-HET3 mice. This approach increases the size of mitochondria, alters cristae morphology, causes an increased fusing of mitochondrial networks, and speeds up movement velocity. At lower doses, the chemical reprogramming cocktail can be safely administered to middle-aged mice using implantable osmotic pumps, albeit with no effect on the transcriptomic age of kidney or liver tissues and only a modest effect on the expression of OXPHOS complexes. However, at higher doses, the cocktail causes a drastic reduction in body weight necessitating euthanasia. In the livers and kidneys of these animals, we observe significant increases in lipid droplet accumulation, as well as changes in mitochondrial morphology in the livers that are associated with mitochondrial stress. Thus, partial chemical reprogramming may induce mitochondrial stress and lead to significant lipid accumulation, which may cause toxicity and hinder the rejuvenation of cells and tissues in aged mammals.
    Keywords:  aging; aging biomarkers; chemical reprogramming; lipid droplets; mitochondria; mitochondrial morphology; oxidative phosphorylation; rejuvenation; reprogramming
    DOI:  https://doi.org/10.1111/acel.70390
  23. Nephron. 2026 Jan 29. 1-15
    Circadian rhythms and glucocorticoid dynamics in the kidney matrix.
    Charles Gyasi, Rachel Lennon, Rebecca Preston.
      The kidney matrix, once viewed as a static scaffold, is now recognised as a dynamic microenvironment that undergoes continual remodelling in response to physiological cues. Emerging evidence demonstrates that this remodelling follows circadian patterns driven by molecular clocks within specific kidney cell types. This review synthesises recent advances on circadian regulation of the kidney matrisome, with emphasis on glomerular compartments. Circadian clocks in the glomerulus coordinate the timing of matrix turnover to preserve structural integrity, maintain filtration, and promote repair. Disruption of these rhythms contributes to maladaptive matrix accumulation, fibrosis, and kidney disease progression. Finally, we discuss mechanistic insights and translational opportunities, including chronotherapy and clock-targeted interventions. Understanding circadian control of glomerular matrix dynamics provides a framework for linking temporal biology to kidney health and disease.
    DOI:  https://doi.org/10.1159/000550773
  24. Elife. 2026 Jan 29. pii: RP99438. [Epub ahead of print]13
    Mitochondrial protein carboxyl-terminal alanine-threonine tailing promotes human glioblastoma growth by regulating mitochondrial function.
    Bei Zhang, Ting Cai, Esha Reddy, Yuanna Wu, Isha Mondal, Yinglu Tang, Adaeze Scholastical Gbufor, Jerry Wang, Yawei Shen, Qing Liu, Raymond Sun, Winson S Ho, Rongze Olivia Lu, Zhihao Wu.
      The rapid and sustained proliferation of cancer cells necessitates increased protein production, which, along with their disrupted metabolism, elevates the likelihood of translation errors. Ribosome-associated quality control (RQC), a recently identified mechanism, mitigates ribosome collisions resulting from frequent translation stalls. However, the precise pathophysiological role of the RQC pathway in oncogenesis remains ambiguous. Our research centered on the pathogenic implications of mitochondrial stress-induced protein carboxyl-terminal alanine and threonine tailing (msiCAT-tailing), a specific RQC response to translational arrest on the outer mitochondrial membrane, in human glioblastoma multiforme (GBM). The presence of msiCAT-tailed mitochondrial proteins was observed commonly in glioblastoma stem cells (GSCs). The exogenous introduction of the mitochondrial ATP synthase F1 subunit alpha (ATP5α) protein, accompanied by artificial CAT-tail mimicking sequences, enhanced mitochondrial membrane potential (ΔΨm) and inhibited the formation of the mitochondrial permeability transition pore (MPTP). These alterations in mitochondrial characteristics provided resistance to staurosporine (STS)-induced apoptosis in GBM cells. Consequently, msiCAT-tailing can foster cell survival and migration, whereas blocking msiCAT-tailing via genetic or pharmacological intervention can impede GBM cell overgrowth.
    Keywords:  cancer biology; carboxyl-terminal alanine and threonine tailing; cell biology; glioblastoma; human; mitochondria; ribosome-associated quality control
    DOI:  https://doi.org/10.7554/eLife.99438
  25. Antioxidants (Basel). 2025 Dec 28. pii: 40. [Epub ahead of print]15(1):
    Cytochrome c Oxidase Subunit COX4-1 Reprograms Erastin-Induced Cell Death from Ferroptosis to Apoptosis: A Transmitochondrial Study.
    Claudia R Oliva, Susanne Flor, Corinne E Griguer.
      Ferroptosis is an iron-dependent, oxidative form of regulated cell death that has emerged as a therapeutic vulnerability in glioblastoma; however, the mitochondrial determinants that govern ferroptotic sensitivity remain poorly defined. Cytochrome c oxidase (CcO/Complex IV), a key regulator of mitochondrial respiration, contains two isoforms of subunit IV (COX4): COX4-1, a housekeeping isoform, and COX4-2, a stress-inducible variant. We previously found that COX4-1 expression protects glioma cells from erastin-induced ferroptosis, suggesting that mitochondria influence cell-death decisions independently of canonical ferroptotic regulators. Here, we used CRISPR-generated POLG-knockout ρ0 cells and transmitochondrial cybrids to isolate mitochondrial from nuclear contributions to ferroptosis sensitivity. Cybrids reconstituted with COX4-1-containing mitochondria restored CcO activity and recapitulated the ferroptosis-resistant phenotype, whereas COX4-2 cybrids remained insensitive to erastin. COX4-1 cybrids exhibited reduced labile iron, diminished cystine uptake, and low expression of SLC7A11 and GPX4, yet underwent apoptosis rather than ferroptosis upon erastin treatment. These findings demonstrate that mitochondrial COX4-1 rewires redox metabolism and diverts cell-death signaling away from ferroptosis toward apoptosis. Our results identify isoform-specific mitochondrial composition as a previously unrecognized determinant of regulated cell death and highlight COX4-1-driven mitochondrial remodeling as a potential mechanism of therapeutic resistance in glioblastoma.
    Keywords:  COX4-1 isoform; apoptosis; erastin; ferroptosis; glioma; transmitochondrial cybrids
    DOI:  https://doi.org/10.3390/antiox15010040
  26. Autophagy. 2026 Jan 29.
    Newcastle disease virus hijacks mitophagy to reprogram amino acid metabolism for enhanced replication.
    Yang Qu, Shanhui Ren, Ying Liao, Xusheng Qiu, Lei Tan, Cuiping Song, Yingjie Sun, Chan Ding.
      Mitochondria serve as the cellular "power plants," supplying energy and regulating metabolism, signal transduction, and other physiological processes. To successfully replicate within host cells, viruses have evolved multiple strategies to hijack mitochondrial functions. The oncolytic Newcastle disease virus (NDV) causes severe organelle damage in tumor cells; however, how it manipulates mitochondrial architecture to facilitate its own replication remains poorly understood. Here, we provide evidence that NDV infection disrupts mitochondrial spatial distribution and imbalances mitochondrial fusion and fission, leading to mitochondrial structural damage. The resulting accumulation of fragmented mitochondria is cleared via PRKN-dependent mitophagy, a process that supports NDV replication. Interestingly, although MAVS (mitochondrial antiviral signaling protein) is degraded along with mitophagy, genetic ablation of PRKN - while blocking MAVS degradation - does not restore downstream innate immune responses. This indicates that NDV exploits mitophagy to enhance replication through mechanisms not entirely dependent on the suppression of MAVS-mediated immunity. Given the central role of mitochondria, we further explored the link between amino acid metabolism and viral proliferation after NDV infection. Our results show that NDV-induced mitophagy leads to the accumulation of free amino acids in host cells, and this metabolic reprogramming promotes viral replication. In summary, we show that NDV drives its replication by remodeling mitochondrial dynamics to induce mitophagy, which in turn triggers an amino acid metabolic reprogramming that benefits the virus. This provides new insights into the mechanisms supporting efficient oncolytic NDV replication, offering potential avenues for therapeutic intervention in oncolytic virus therapy.
    Keywords:  Amino acid metabolism; MAVS; NDV, PINK1-PRKN; mitochondrial dynamics; mitophagy
    DOI:  https://doi.org/10.1080/15548627.2026.2624746
  27. Nat Commun. 2026 Jan 24.
    Modulation of Nudt21 levels reveals dose-dependent roles of alternative polyadenylation in tissue regeneration.
    Nikolaos Tsopoulidis, Masaki Yagi, Justin Brumbaugh, Shinya Ito, Víctor López-Soriano, Robert Morris, Yoseop Yoon, Kathleen A Messemer, Kuan-Hung Lin, Eric F Zaniewski, Rebecca Gorelov, Aaron J Huebner, Amy J Wagers, Hanno Hock, Günter Kramer, Bernd Bukau, Michael S Hoetker, Yongsheng Shi, Wilhelm Haas, Konrad Hochedlinger.
      Stem cells continually self-renew and differentiate to sustain tissue homeostasis, yet the role of post-transcriptional mechanisms in guiding these processes remains incompletely understood. Here, we demonstrate that the regulation of 3'UTR length via alternative mRNA polyadenylation (APA) is essential for stem cell function across diverse tissues. Modulating the APA regulator Nudt21 reveals that stem cell self-renewal and differentiation depend on distinct dosage thresholds and thus can be uncoupled. Specifically, moderate Nudt21 suppression  elicits a maturation arrest of stem cells due to 3'UTR-shortening of differentiation-associated mRNAs that escape miRNA regulation and perturb ceRNA networks. By contrast, complete Nudt21 suppression additionally shortens the 3'UTRs of mRNAs encoding essential multiprotein complexes, including the nuclear pore, leading to complex destabilization, proteotoxic stress, DNA damage, and cell cycle arrest. Critically, deletion of the alternative 3'UTRs of individual nucleoporins recapitulates defects observed with Nudt21 loss. We further demonstrate that the co-translational assembly of dozens of protein complexes is impaired in Nudt21-deficient cells, providing a mechanistic framework for compromised complex integrity. Collectively, our results show that APA plays distinct, dose-dependent roles in stem cell homeostasis by fine-tuning the expression of differentiation-associated genes and coordinating the biogenesis of multiprotein complexes essential for cell cycle progression.
    DOI:  https://doi.org/10.1038/s41467-026-68630-x
  28. Elife. 2026 Jan 26. pii: RP95576. [Epub ahead of print]13
    Axonal distribution of mitochondria maintains neuronal autophagy during aging via eIF2β.
    Kanako Shinno, Yuri Miura, Koichi M Iijima, Emiko Suzuki, Kanae Ando.
      Neuronal aging and neurodegenerative diseases are accompanied by proteostasis collapse, while the cellular factors that trigger it have not been identified. Impaired mitochondrial transport in the axon is another feature of aging and neurodegenerative diseases. Using Drosophila, we found that genetic depletion of axonal mitochondria causes dysregulation of protein degradation. Axons with mitochondrial depletion showed abnormal protein accumulation and autophagic defects. Lowering neuronal ATP levels by blocking glycolysis did not reduce autophagy, suggesting that autophagic defects are associated with mitochondrial distribution. We found that eIF2β was increased by the depletion of axonal mitochondria via proteome analysis. Phosphorylation of eIF2α, another subunit of eIF2, was lowered, and global translation was suppressed. Neuronal overexpression of eIF2β phenocopied the autophagic defects and neuronal dysfunctions, and lowering eIF2β expression rescued those perturbations caused by depletion of axonal mitochondria. These results indicate the mitochondria-eIF2β axis maintains proteostasis in the axon, of which disruption may underlie the onset and progression of age-related neurodegenerative diseases.
    Keywords:  D. melanogaster; aging; autophagy; cell biology; mitochondria; neuronal proteostasis; protein aggregation; proteome
    DOI:  https://doi.org/10.7554/eLife.95576
  29. Mitochondrion. 2026 Jan 23. pii: S1567-7249(26)00002-4. [Epub ahead of print]87 102112
    Sensitivity of primary mitochondrial disease fibroblasts to ferroptosis: The role of intracellular iron.
    Svetlana Pecheritsyna, Melisa Emel Ermert, Emina Podhumljak, Bas Pennings, Ruth Zondag, Eligio F Iannetti, Herma Renkema, Jan Smeitink.
      Primary mitochondrial diseases (PMDs) are directly linked to oxidative phosphorylation (OXPHOS) dysfunction. Here, we investigated the selective sensitivity of PMD patient fibroblasts compared to healthy control primary human skin fibroblasts (PHSF) to ferroptosis, and the role of iron in this cell death mechanism. To address this, we investigated sensitivity to ferroptosis inducers, the effects of iron supplementation, and intracellular iron pools. The selectivity of PMD fibroblasts ferroptotic cell death was found to be more pronounced with class 1 ferroptosis inducers (FINs) that deplete GSH than upon direct GPX4 inhibitors. Notably, exogenous iron discriminatory triggered ferroptosis in patient fibroblasts and enhanced BSO-induced cell death in both patient and control cells. Further study revealed elevated basal levels of labile iron in patient fibroblasts, but mRNA analysis of iron-regulating genes did not reveal major expression differences. These findings suggest that increased labile iron predisposes PMD fibroblasts to ferroptosis. Complementation of defective OXPHOS restored ferroptosis sensitivity and LIP levels in a cell line with an NDUFS7 mutation, indicating a functional relationship caused by OXPHOS deficiency. Further understanding this interplay may provide insights into therapeutic strategies targeting iron homeostasis to mitigate ferroptotic cell death in PMDs.
    Keywords:  Ferroptosis; Labile iron pool; Primary mitochondrial disease
    DOI:  https://doi.org/10.1016/j.mito.2026.102112
  30. Mol Cell. 2026 Jan 28. pii: S1097-2765(26)00027-4. [Epub ahead of print]
    Signaling to make human ribosomes: Connections between the cytoplasm and the nucleolus.
    Isabella R Lawrence, Emily C Sutton, Shivang Bhaskar, Susan J Baserga.
      Ribosome biogenesis is a complex, multi-step cellular process that begins in the nucleolus and produces ribosomes that translate mRNA into proteins in the cytoplasm. This process is essential for cellular growth yet is resource intensive. It is therefore tightly coordinated with cytoplasmic requirements, energy availability, and the cell cycle through several kinase signaling pathways. Increasing evidence indicates that proteins shared between the cytoplasm and nucleolus may enhance this coordination. Here, we evaluate the interplay between the cytoplasm and nucleolus in human cells, presenting an intricate bidirectional regulatory network with emerging clinical relevance. We describe the phosphorylation events that promote ribosome biogenesis during interphase, focusing on mammalian target of rapamycin complex 1 (mTORC1), extracellular signal-regulated kinase (ERK), and casein kinase II (CK2). By contrast, protein phosphorylation inactivates ribosome biogenesis during mitosis. We further summarize several factors shared among the mitotic machinery, cytoplasmic organelles, and the nucleolus. Moreover, we highlight the mounting evidence that dysregulated cytoplasmic-nucleolar feedback contributes to the progression of several diseases.
    Keywords:  cancer; endoplasmic reticulum; lysosome; mTOR; mitochondria; mitosis; muscle atrophy; rRNA; ribosome biogenesis; ribosomopathies
    DOI:  https://doi.org/10.1016/j.molcel.2026.01.007
  31. Nat Commun. 2026 Jan 29.
    ALKB-1-dependent tRNA methylation is required for efficient paternal mitochondrial elimination.
    Zhenhuan Luo, Yimin Li, Chenyang He, Dan Wu, Wenyu Dai, Liubing Hu, Jing Yang, Brian L Harry, Zhenyu Ju, Nektarios Tavernarakis, Hao Wang, Qin-Li Wan, Qinghua Zhou.
      Maternal mitochondrial inheritance is secured by mechanisms that exclude paternal mitochondrial DNA (mtDNA). While, epigenetic modifications are vital for spermatogenesis and embryo development, their roles in the paternal mitochondrial elimination (PME) remain poorly understood. Here, we identify ALKB-1, a DNA/RNA demethylase, as a pivotal factor for efficient PME in Caenorhabditis elegans (C. elegans), acting through ALKB-1-dependent modulation of tRNA m1A methylation. Mechanistically, ALKB-1 inactivation leads to m1A hypermethylation of tRNA, which subsequently disrupts protein translation, impairs mitochondrial proteostasis, and increases ROS levels. This cascade activates the oxidative stress response factor SKN-1/Nrf2 and initiates the mitochondrial unfolded protein response (UPRmt) through ATFS-1, causing accumulation of mitochondria and mtDNA in sperm, which ultimately impedes efficient paternal mitochondrial removal and negatively impacts male fertility and embryonic development. Our findings describe a mechanism whereby ALKB-1-mediated tRNA m1A epitranscriptomic modifications are necessary for maintaining mitochondrial quality control, thereby influencing PME efficiency, underscoring the importance of this epitranscriptomic stress checkpoint in upholding proper mitochondrial inheritance during reproduction.
    DOI:  https://doi.org/10.1038/s41467-026-68813-6
  32. Crit Rev Oncol Hematol. 2026 Jan 26. pii: S1040-8428(26)00042-9. [Epub ahead of print] 105155
    FASN at the Crossroads of Tumor Metabolism, Immune Evasion, and Therapy Resistance: Mechanistic Insights and Therapeutic Opportunities.
    Xuefeng Jiang, Guotao Fang, Wen Li, Yusheng Liu, Gang Chen, Silvio E Perea, Yasser Perera, Rong Ma, Xiaofei Hu, Xinan Long.
      Fatty acid synthase (FASN), the key enzyme driving de novo lipogenesis, has emerged as a central metabolic hub in cancer, linking aberrant lipid synthesis to tumor progression, immune escape, and therapy resistance. This review provides a comprehensive overview of the regulatory landscape and oncogenic functions of FASN, highlighting its modulation at transcriptional, post-transcriptional, and post-translational levels. We discuss how FASN-driven lipid remodeling supports tumor proliferation, disrupts antigen presentation, alters immune cell metabolism, and suppresses ferroptosis, thereby enabling resistance to chemotherapy, radiotherapy, targeted therapy, and immune checkpoint inhibitors. Emerging therapeutic strategies-including direct FASN inhibition, targeting upstream regulators, and rational metabolic-immune-ferroptosis combinatorial regimens-are explored in the context of precision oncology. Given the metabolic plasticity of cancer cells and the heterogeneous response of the tumor immune microenvironment, future advances will rely on dynamic biomarker-guided therapy and spatiotemporal profiling of FASN activity. Together, these insights position FASN not merely as a metabolic enzyme but as a versatile therapeutic axis at the intersection of cancer metabolism, immunity, and resistance.
    Keywords:  FASN; combination therapy; ferroptosis; immune evasion; metabolic checkpoint; therapy resistance; tumor metabolism
    DOI:  https://doi.org/10.1016/j.critrevonc.2026.105155
  33. Mol Syst Biol. 2026 Jan 28.
    Five dominant amino acid substitution signatures shape tumour immunity.
    Szilvia Juhász, Benjamin Tamás Papp, Anna Tácia Fülöp, Zoltán Farkas, Dávid Kókai, Dóra Alexandra Gyémánt, Franciska Tóth, Zsófia Nacsa, Dóra Spekhardt, Balázs Koncz, Péter Burkovics, Csaba Pál, Máté Manczinger.
      Although numerous mutational processes operate in cancer, their functional impacts are unclear. We hypothesised that certain mutation sources preferentially generate amino acid substitutions that evade immune recognition, producing immune-cold tumours regardless of tissue or mutation load. By analysing 9300 cancer exomes and performing mutagenesis experiments, we mapped links between mutagens, DNA-repair defects, and amino acid substitution signatures (AAS). Surprisingly, the spectrum collapsed into five recurrent AAS with distinct functional profiles. AAS4-generated by alkylating agents and mismatch-repair (MMR) deficiency and enriched in kidney and liver cancers-is less likely to accumulate hydrophobic residues, yielding poorly immunogenic neopeptides. These tumours display immune-desert microenvironments and respond poorly to immunotherapy. However, certain human leukocyte antigen (HLA) class I variants, such as HLA-B*07:02, correlate with immune-hot tumours in this subgroup. HLA-B*07:02, common in Europeans, presents proline-enriched neopeptides derived from AAS4 mutations. Supporting this, B*07:02-positive cancer cells harbouring AAS4-type mutations stimulated T-cell proliferation in vitro. These results show that neoantigen quality, not merely quantity, dictates anti-tumour immunity, explain inconsistent immunotherapy responses in MMR-deficient cancers, and advocate incorporating amino acid substitution patterns into predictive biomarkers and therapy design.
    Keywords:  Antitumor Immunity; Cancer; Immunotherapy; Mutational Signatures; Mutations
    DOI:  https://doi.org/10.1038/s44320-026-00193-x
  34. Nat Aging. 2026 Jan 29.
    Comparative analysis of senolytic drugs reveals mitochondrial determinants of efficacy and resistance.
    Masahiro Wakita, Koyu Ito, Kaho Fujii, Dai Sakamoto, Takumi Mikawa, Sho Sugawara, Xiangyu Zhou, Jeong Hoon Park, Hideka Miyagawa, Daisuke Motooka, Emi Ogasawara, Naotada Ishihara, Akiko Takahashi, Hiroshi Kondoh, Eiji Hara.
      Cellular senescence contributes to aging and disease, and senolytic drugs that selectively eliminate senescent cells hold therapeutic promise. Although over 20 candidates have been reported, their relative efficacies remain unclear. Here we systematically compared 21 senolytic agents using a senolytic specificity index, identifying the Bcl-2 inhibitor ABT263 and the BET inhibitor ARV825 as most effective senolytics across fibroblast and epithelial senescence models. However, even upon extended treatment with these most potent senolytics, a proportion of senescent cells remained viable. We found that senolytic resistance was driven by maintenance of mitochondrial integrity through V-ATPase-mediated clearance of damaged mitochondria. Imposing mitochondrial stress via metabolic workload enhanced the senolytic efficacies of ABT263 and ARV825 in vitro, and in mouse models, ketogenic diet adoption or SGLT2 inhibition similarly potentiated ABT263-induced and ARV825-induced senolysis, reducing metastasis and tumor growth. These findings suggest that mitochondrial quality control is a key determinant of resistance to ABT263-induced and ARV825-induced senolysis, providing a possible framework for rational combination senotherapies.
    DOI:  https://doi.org/10.1038/s43587-025-01057-z
  35. Mol Cell. 2026 Jan 28. pii: S1097-2765(26)00021-3. [Epub ahead of print]
    Mito-nuclear communication: From cellular responses to organismal health.
    Guanyu Chen, Hangyu Dong, Ye Tian.
      The co-evolution of mitochondria and the nucleus established constant mito-nuclear communication that is essential for both cellular and organismal homeostasis. At the cell-autonomous level, mitochondrial perturbations activate retrograde pathways such as the mitochondrial unfolded protein response (UPRmt) and the mitochondrial integrated stress response (ISRmt), which couple organelle dysfunction to nuclear transcriptional programs, thereby promoting mitochondrial function and preserving cellular integrity. Importantly, this communication is not confined to individual cells but extends across tissues to coordinate systemic adaptations. Stress signals can be sensed, broadcasted through secreted mitokines and neural circuits, and then interpreted by distal organs to coordinate systemic adaptations. These systemic responses integrate metabolism, immunity, and behavior, conferring resilience to stress and shaping the trajectory of aging. Understanding this multi-layered communication, from the organelle to the organism and its microbial ecosystem, promises new therapeutic strategies to enhance mitochondrial function, promote resilience, and extend healthspan.
    Keywords:  ISRmt; UPRmt; aging; mito-nuclear communication; mitokine; proteostasis
    DOI:  https://doi.org/10.1016/j.molcel.2026.01.001
  36. Cell Rep Med. 2026 Jan 26. pii: S2666-3791(25)00652-4. [Epub ahead of print] 102579
    Liver metastases dampen IL18-driven γδ T cell activity and immunotherapy responsiveness in colorectal cancer.
    Allard W J van Renterghem, Miguel Parra-Martinez, Maartje Witsen, Karlijn Verkerk, Marit Steur, Laurien J Zeverijn, Krijn K Dijkstra, Leila Akkari, Emile E Voest.
      Patients with liver metastases (LMs) derive less benefit from immune checkpoint blockade (ICB), yet the mechanism remains poorly understood. In the liver tumor microenvironment of patients with mismatch repair-deficient (MMR-d) cancers treated with immunotherapy, we observe a reduction of Vδ1+ γδ T cells. Hepatic Vδ1+ T cells express high levels of IFNγ at baseline compared to other organs. In patients with LMs, we identify elevated systemic IL18 levels compared to metastatic patients without LMs and find that its intratumoral expression is associated with ICB success exclusively in patients with LMs. While liver γδ T cells are specifically sensitive to IL18 stimulation ex vivo, cancer cells counteract IL18-driven immunity by secretion of IL18 binding protein (IL18BP). Blockade of IL18BP enhances interferon (IFN) γ-driven immunity against organoids in vitro. Taken together, we identify the IL18/IL18BP/Vδ1+ axis as an important regulator of ICB response and a therapeutic vulnerability for patients with LMs of MMR-d tumors.
    Keywords:  IL18; IL18bp; colorectal cancer; gamma delta T cells; hepatic tolerance; immunotherapy; innate lymphocyte; liver metastases
    DOI:  https://doi.org/10.1016/j.xcrm.2025.102579
  37. Nat Chem. 2026 Jan 29.
    Biomolecular condensates sustain pH gradients at equilibrium through charge neutralization.
    Hannes Ausserwöger, Rob Scrutton, Charlotte M Fischer, Tomas Sneideris, Daoyuan Qian, Ella de Csilléry, Ieva Baronaite, Kadi L Saar, Alan Z Białek, Marc Oeller, Georg Krainer, Titus M Franzmann, Sina Wittmann, Juan M Iglesias-Artola, Gaetano Invernizzi, Anthony A Hyman, Simon Alberti, Nikolai Lorenzen, Tuomas P J Knowles.
      Electrochemical gradients are essential to the functioning of cells and form across membranes using active transporters. Here we show in contrast that condensed biomolecular systems-often termed condensates-sustain pH gradients without any external energy input. By studying individual condensates on the micrometre scale using a microdroplet platform, we reveal dense-phase pH shifts towards conditions of minimal electrostatic repulsion. We demonstrate that protein condensates can drive substantial alkaline and acidic gradients, which are compositionally tunable and can extend to complex architectures sustaining multiple unique pH conditions simultaneously. Through in silico characterization of human proteomic condensate networks, we further highlight potential wide-ranging electrochemical properties emerging from condensation in nature, while correlating intracellular condensate pH gradients with complex biomolecular composition. Together, the emergent nature of condensation shapes distinct pH microenvironments, thereby creating a regulatory mechanism to modulate biochemical activity in living and artificial systems.
    DOI:  https://doi.org/10.1038/s41557-025-02039-9
  38. Immunity. 2026 Jan 28. pii: S1074-7613(25)00566-7. [Epub ahead of print]
    A type I interferon-mitochondrial axis regulates efferocytosis and interferon-stimulated gene induction in macrophages.
    Gillian Dunphy, Irene Adán-Barrientos, Irene Fernández-Delgado, Carolina Villarroya-Beltri, Ignacio Heras-Murillo, Elena Moya-Ruiz, Miguel Sánchez-Álvarez, Aitor Jarit-Cabanillas, Miguel A Del Pozo, Susana Guerra, Francisco Sánchez-Madrid, David Sancho.
      Macrophage metabolism is intricately linked to cellular function. Contrasting with Toll-like receptor (TLR) stimulation, cytosolic nucleic acid sensing induced a decrease in mitochondrial membrane potential (MMP) while maintaining mitochondrial respiration. Interferon α/β (IFN-I) receptor (IFNAR) signaling was necessary and sufficient for this metabolic response. IFNAR signaling induced interferon-stimulated gene 15 (ISG15) expression and ISGylation of mitochondrial proteins, including subunits of mitochondrial complex V, increasing ATP production and decreasing MMP, thus enhancing macrophage efferocytic capacity. Moreover, the IFNAR-ISG15-mediated drop in MMP activated the mitochondrial protease OMA1, inducing mitochondrial fission and decreasing endoplasmic reticulum-mitochondria communication, thus dampening IFN-stimulated gene (ISG) induction. Loss of ISG15 or OMA1 enhanced histone acetylation and ISG induction upon IFN-I stimulation, in a manner dependent on mitochondrial calcium uptake. This increase in ISG induction provided protection against acute viral infections. These data indicate that IFNAR-ISG15 signaling boosts efferocytosis while limiting ISG induction, thereby promoting the resolution of inflammation.
    Keywords:  efferocytosis; interferon-stimulated genes; macrophage; metabolism; mitochondrial endoplasmic reticulum contacts; mitochondrial fission; mitochondrial membrane potential; oxidative phosphorylation; type I interferon; viral infection
    DOI:  https://doi.org/10.1016/j.immuni.2025.12.010
  39. Aging Cell. 2026 Feb;25(2): e70380
    Pan-Epigenetic Age Prediction in Mammals.
    Zane Koch, Adam Li, Trey Ideker.
      Epigenetic remodeling is a hallmark of aging, yet which epigenetic layers are most affected during aging-and the extent to which they are interrelated-is not well understood. Here, we perform a comprehensive analysis of epigenetic aging encompassing 6 histone marks and DNA methylation measured across 12 tissues from > 1000 humans and mice. We identify a synchronized pattern of age-related changes across these epigenetic layers, with all changes converging upon a common set of genes. Notably, an epigenetic clock based on these genes can accurately predict age using data from any layer (Spearman ρ: 0.70 in humans, 0.81 in mice). Applying this "pan-epigenetic" clock, we observe that histone modification and DNA methylation profiles agree in the prediction of which individuals are aging more rapidly or slowly. These results demonstrate that epigenetic modifications are subject to coordinated remodeling over the lifespan, offering a unified view of epigenetic aging.
    DOI:  https://doi.org/10.1111/acel.70380
  40. Nature. 2026 Jan 26.
    Scalable and multiplexed recorders of gene regulation dynamics across weeks.
    Lirong Zheng, Dongqing Shi, Yixiao Yan, Bingxin Zhou, Jormay Lim, Yongjie Hou, Bobae An, Jason K Adhinarta, Michael Lin, BumJin Ko, William C Joesten, Mehul Gautam, Elie D M Huez, Eung Chang Kim, Emily G Klyder, Boxuan Chang, Sethuramasundaram Pitchiaya, Michael T Roberts, Denise J Cai, Edward S Boyden, Donglai Wei, Pietro Liò, Changyang Linghu.
      Gene expression is dynamically regulated by gene regulatory networks comprising multiple regulatory components to mediate cellular functions1. An ideal tool for analyzing these processes would track multiple-component dynamics with both spatiotemporal resolution and scalability within the same cells, a capability not yet achieved. Here, we present CytoTape, a genetically encoded, modular protein tape recorder for multiplexed and spatiotemporally scalable recording of gene regulation dynamics continuously for up to three weeks, physiologically compatible, with single-cell, minutes-scale resolution. CytoTape employs a flexible, thread-like, elongating intracellular protein self-assembly engineered via computationally assisted rational design, built on earlier XRI technology2. We demonstrated its utility across multiple mammalian cell types, achieving simultaneous recording of five transcription factor activities and gene transcriptional activities. CytoTape reveals that divergent transcriptional trajectories correlate with transcriptional history and signal integration, and that distinct immediate early genes (IEGs) exhibit complex temporal correlations within single cells. We further extended CytoTape into CytoTape-vivo for scalable, spatiotemporally resolved single-cell recording in the living brain, enabling simultaneous weeks-long recording of doxycycline- and IEG promoter-dependent gene expression histories across up to 14,123 neurons spanning multiple brain regions per mouse. Together, the CytoTape toolkit establishes a versatile platform for scalable and multiplexed analysis of cell physiological processes in vitro and in vivo.
    DOI:  https://doi.org/10.1038/s41586-026-10156-9
  41. Science. 2026 Jan 29. 391(6784): 448
    Rethinking the heritability of aging.
    Daniela Bakula, Morten Scheibye-Knudsen.
      The genetic contribution to human longevity is greater than previously thought.
    DOI:  https://doi.org/10.1126/science.aee3844
  42. Nat Commun. 2026 Jan 27.
    A spatially resolved atlas of gastric cancer characterises a lymphocyte-aggregated region.
    Sen Gao, Shishang Qin, Dongfang Wang, Anqiang Wang, Linnan Zhu, Yang Li, Qiang Shi, Hongtao Fan, Yufei Bo, Yunshan Zhong, Yuxuan Sun, Kun Dong, Liqin Fu, Ranran Gao, Yan Wu, Ye Liang, Luyujie Huang, Xueda Hu, Xianwen Ren, Zhaode Bu, Jiafu Ji, Zemin Zhang.
      The tumour microenvironment is a focal point in cancer immunotherapy: its cellular composition and spatial organisation can affect the clinical outcomes of cancer patients. By integrating single-cell and spatial transcriptomics, we identify four spatial regions and survey how cellular spatial distribution varies across them in gastric cancer. One region, the Lymphocyte Aggregated Region, consists of lymphocyte aggregates and tertiary lymphoid structures. Within it, we observe associations between naive T cell abundance and T cell activation-associated pathways, and correlations exist between distribution patterns of different lymphocytes and two transcriptomically distinct groups - more activated lymphocytes reside in the adjacent cancerous regions of Group A, while more resting lymphocytes settle in those of Group B. Within Group A, PD1+CD27+ CD8 T cells cluster in closer proximity to CD70+LAMP3+ dendritic cells. Our study unveils the gastric cancer tumour microenvironment at a spatial resolution and provides insights into the exploration of immunotherapy biomarkers.
    DOI:  https://doi.org/10.1038/s41467-026-68612-z
  43. Nature. 2026 Jan;649(8099): 1099-1101
    Technology is changing how we write - and how we think about writing.
    Andrew Robinson.
      
    Keywords:  History; Language; Machine learning; Technology
    DOI:  https://doi.org/10.1038/d41586-026-00245-0
  44. Cell Metab. 2026 Jan 26. pii: S1550-4131(25)00549-2. [Epub ahead of print]
    Bempedoic acid directly binds and activates PPARα.
    Christina Papa, Alina Rose, Hugo N G Martin, Abibe Useini, Florian Geier, Longsheng Liao, Jesús Rafael Rodríguez-Aguilera, Philipp Valina-Allo, Anne Hoffmann, Andrey Tvardovskiy, Faiqa Zulfqar, Andrea Zimmerman, Gerda Schicht, Fritzi Ott, Christiane Körner, Beatrice Engelmann, Ulrike Rolle-Kampczyk, Martin von Bergen, Matthias Meier, Till Bartke, Daniel Seehofer, Nora Klöting, Madlen Matz-Soja, Georg Damm, Jes-Niels Boeckel, Joerg M Buescher, Matthias Blüher, Ulrich Laufs, Olga Bondareva, Norbert Sträter, Georg Künze, John T Heiker, Bilal N Sheikh.
      Bempedoic acid (BA) is a recently approved drug that lowers cholesterol and hepatic lipids, yet its mechanism of action remains incompletely understood. Here, we combine transcriptomic, biochemical, and structural approaches to show that BA directly binds to and activates peroxisome proliferator-activated receptor alpha (PPARα). BA treatment robustly induced PPARα signaling and fatty acid oxidation in primary hepatocytes and mouse liver. Through X-ray crystallography, we uncovered that BA binds to the ligand-binding domain of PPARα and stabilizes its active conformation. BA activated PPARα target genes independently of very-long-chain acyl-coenzyme A (CoA) synthetase (ACSVL1), the liver-enriched enzyme that converts BA to its bempedoyl-CoA form. Notably, BA-mediated induction of fatty acid oxidation required PPARα. Together, this work reveals direct PPARα activation as a key mechanism of BA action, providing a molecular basis for its lipid-lowering effects and suggesting broader therapeutic potential beyond the liver.
    Keywords:  PPAR; cardiovascular; cholesterol; lipids; metabolism; transcription
    DOI:  https://doi.org/10.1016/j.cmet.2025.12.018
  45. Cell Rep. 2026 Jan 28. pii: S2211-1247(25)01694-8. [Epub ahead of print]45(2): 116922
    α-Ketoglutarate couples cellular metabolism to developmental growth via hydroxylation-dependent degradation of Yorkie.
    Tao He, Yongchang Zeng, Jie Zhou, Yuqi Tian, Donggui Wang, Jingchao Ma, Jiyong Liu, Wenqi Wu, Chuanxian Wei, Renjie Jiao.
      The evolutionarily conserved Hippo signaling pathway, essential for development and tissue homeostasis, is intimately linked to cellular metabolism. While cellular α-ketoglutarate (α-KG) levels fluctuate with metabolic state, the functional significance of these fluctuations for development remains poorly defined. Here, this study uncovers an evolutionarily conserved mechanism whereby α-KG directly regulates Hippo signaling activity during development. We demonstrate that elevated α-KG promotes the degradation of Yki, the key Hippo pathway effector in Drosophila, in a concentration-dependent manner. Mechanistically, α-KG drives PH4αEFB-mediated prolyl hydroxylation of specific proline residues in Yki, thereby targeting it for ubiquitination and proteasomal degradation. Critically, mutation of these hydroxylation sites of Yki abolishes its sensitivity to α-KG, resulting in Yki protein hyperstabilization, aberrant activation of Hippo targets, and organ overgrowth in Drosophila. Overall, these findings establish α-KG as a central metabolic regulator of Hippo activity, thereby coupling metabolic status to developmental growth control.
    Keywords:  CP: metabolism; Hippo signaling; Yorkie; organ size control; prolyl hydroxylation; α-ketoglutarate
    DOI:  https://doi.org/10.1016/j.celrep.2025.116922
  46. Genome Biol. 2026 Jan 29. 27(1): 10
    Resolving clonal evolution and selection of extrachromosomal DNA at single-cell resolution.
    Josephine Deleuran Hendriksen, Alessio Locallo, Balthasar Clemens Schlotmann, Francisco Germán Rodríguez González, Jane Skjøth-Rasmussen, Christina Westmose Yde, Dorte Schou Nørøxe, Hans Skovgaard Poulsen, Ulrik Lassen, Joachim Weischenfeldt.
       BACKGROUND: Genomic alterations are a hallmark of cancer, and extrachromosomal DNA (ecDNA) has emerged as a key source of oncogene selection, tumor growth, and drug resistance. The intratumor heterogeneity and clonal selection of ecDNA is, however, poorly understood.
    RESULTS: In this study, we pursue a computational approach that leverages allelic imbalance and outlier expression from standard single-cell RNA sequencing (scRNA-seq) to deconvolve the tumor heterogeneity of ecDNA at the single-cell level (ecSingle). Using this approach, we identify oncogene-carrying ecDNAs in tumor samples at the single-cell level, which we validate using genome sequencing. Moreover, we show the superiority of using single-molecule long-read sequencing in resolving ecDNA. ecDNAs displayed extensive intratumor heterogeneity, including subclonal oncogene-carrying ecDNA in primary tumor cells that segregate with distinct transcriptional cell states. Importantly, we show that a rare ecDNA+ clone in the primary tumor can expand to form dominant clones in relapse tumors.
    CONCLUSIONS: Our study introduces a novel approach to studying ecDNA at the single-cell level, enabling both clonal evolution and transcription cell state analysis. We apply this approach to cancer samples to gain deeper insights into the role of ecDNA in intratumor heterogeneity and cellular plasticity.
    Keywords:  Cancer; Clonal evolution; Extrachromosomal DNA; Long-read sequencing; Oncogene amplification; Single cell
    DOI:  https://doi.org/10.1186/s13059-026-03933-2
  47. Int J Mol Sci. 2026 Jan 14. pii: 834. [Epub ahead of print]27(2):
    Altered Magnesium Environments Restrict Colorectal HT-29 Spheroid Growth by Disturbing Cellular Mg2+ Homeostasis.
    Nattida Kampuang, Pongsakorn Lapchock, Tanida Treerattanakulporn, Phossawee Kongkaew, Siriporn Chamniansawat, Narongrit Thongon.
      Dysregulated magnesium (Mg2+) homeostasis contributes to colorectal cancer (CRC), yet its context-dependent function within the tumor microenvironment remains unresolved. This study aimed to determine how sustained low and high extracellular Mg2+ environments affect CRC spheroid (SP) growth and Mg2+ homeostasis using HT-29 SPs. We analyzed Mg2+ flux, the expression of Mg2+ transporters (e.g., Transient Receptor Potential Melastatin (TRPM) 6), viability, apoptotic and autophagic markers, and phospho-/oxidoproteomic alterations. Both Mg2+ extremes destabilized SP architecture, reduced viability, and induced apoptosis and autophagy, with SPs displaying heightened vulnerability relative to 2D cultures. Mg2+ stress impaired Mg2+ influx and eliminated adaptive transporter regulation in SPs. Loss of membrane TRPM6/7 heterodimers, driven by altered phosphorylation (e.g., TRPM6 Serine 141, Serine 1252, Threonine 1851) and elevated oxidation (e.g., Methionine 1755), suppressed channel activity. High Mg2+ caused profound metabolic failure despite increased total Mg2+, reflecting functional Mg2+ deficiency. CRC spheroids are acutely susceptible to Mg2+ imbalance due to collapsed transporter homeostasis and post-translational inhibition of Mg2+ channels. These findings reveal a targetable metabolic vulnerability and support the therapeutic potential of localized Mg2+ modulation in CRC.
    Keywords:  Mg2+ transport mechanisms; TRPM6/7 channel regulation; colorectal tumor spheroids; high extracellular Mg2+ environment; low extracellular Mg2+ environment; magnesium imbalance; tumor microenvironment
    DOI:  https://doi.org/10.3390/ijms27020834
  48. EMBO J. 2026 Jan 26.
    TORC1-dependent translation drives chromatin remodeling during the germ-cell-to-maternal transition in Drosophila.
    Noor M Kotb, Gulay Ulukaya, Anupriya Ramamoorthy, Lina Seojin Park, Julia Tang, Dan Hasson, Prashanth Rangan.
      Proper oogenesis requires a programmed transition from an undifferentiated germ-cell gene expression program to a maternal gene-expression state. While this process depends on the heterochromatin-mediated silencing of germ-cell genes, the upstream mechanisms that enforce this transcriptional shift remain unclear. Here, we uncover a translation-driven chromatin remodeling program that promotes oocyte fate in Drosophila. Through a loss of function screen, we identify TORC1 activity (Mio, Raptor), ribosome biogenesis (Zfrp8, Bystin, Aramis), and a translation factor (eEF1α1) as essential for silencing the germ-cell program. We show that TORC1 activity increases during oocyte specification, and that disruption of TORC1 activity, translation, or ribosome biogenesis during this window impairs heterochromatin maintenance at germ-cell gene loci. Polysome profiling reveals that Zfrp8 promotes translation of the nuclear pore component Nucleoporin 44A (Nup44A), whose function is independently required for chromatin organization and repression of a cohort of germ-cell genes. Taken together, our findings reveal that a transient increase in translation orchestrates chromatin remodeling to ensure commitment to oocyte fate.
    Keywords:  Chromatin; Oocyte; Ribosome; TORC1; Translation
    DOI:  https://doi.org/10.1038/s44318-026-00697-0
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