bims-ginsta Biomed News
on Genome instability
Issue of 2025–12–07
38 papers selected by
Jinrong Hu, National University of Singapore
  1. Fertilization triggers early proteomic symmetry breaking in mammalian embryos.
  2. Dual role of Oct4 and Sox2 in controlling the developmental capacity and timing of tissue morphogenesis in the embryonic lineage.
  3. Membrane potential mediates the cellular response to mechanical pressure.
  4. Cohesin guides homology search during DNA repair using loops and sister chromatid linkages.
  5. Nuclear actin and DNA replication stress regulate telomere maintenance by telomerase.
  6. A human epiblast model reveals dynamic TGFβ-mediated control of epithelial identity during mammalian epiblast development.
  7. CIP2A mediates mitotic recruitment of SLX4/MUS81/XPF to resolve replication stress-induced DNA lesions.
  8. Nucleosome stability safeguards cell identity, stress resilience and healthy aging.
  9. Protein codes and mobility together shape cellular function and disease.
  10. Cohesin drives chromatin scanning during the RAD51-mediated homology search.
  11. Intercellular diffusion of cyclic nucleotides followed by gap junction closure restarts meiosis in mouse preovulatory follicles.
  12. Design of de novo nucleolar surface proteins.
  13. Drosophila and mouse intestinal stem cells are spatiotemporally specified by Notch suppression and Wnt activation.
  14. High-resolution mapping of the actin fusion focus reveals myosin V-dependent formin transport for aster formation.
  15. Karyopherins remodel the dynamic organization of the nuclear pore complex transport barrier.
  16. High-fidelity human chromosome transfer and elimination.
  17. Structural mechanism of mRNA decoding by mammalian GTPase GTPBP1.
  18. Modelling late gastrulation in stem cell-derived monkey embryo models.
  19. Regulation of cell dynamics by rapid integrin transport through the biosynthetic pathway.
  20. Innate immune and metabolic signals induce mitochondria-dependent membrane lysis via mitoxyperiosis.
  21. Platelet-mediated activation of perivascular mast cells triggers progression of sepsis to septic shock in mice.
  22. Human Hearts Intrinsically Increase Cardiomyocyte Mitosis After Myocardial Infarction.
  23. Viral RNA blocks circularization to evade host codon usage control.
  24. Sprint interval exercise disrupts mitochondrial ultrastructure driving a unique mitochondrial stress response and remodelling in men.
  25. Phosphatidylserine exposure and annexin A5 weaken the actin cortex in osteoclast fusion.
  26. Dynamic Organellar Mapping in yeast reveals extensive protein localization changes during ER stress.
  27. Single-cell transcriptomics reveals stepwise transformation of epithelial cells into Non-Professional Phagocytes.
  28. Rbfox2 selectively governs hematopoietic stem cell self-renewal by regulating proteostasis.
  29. Rate-limiting enzymes in nucleotide metabolism synchronize nucleotide biosynthesis and chromatin formation.
  30. Multiscale structure of chromatin condensates explains phase separation and material properties.
  31. Mitochondrial components secretion in extracellular vesicles promotes alveolar epithelial mitochondrial quality control.
  32. Phosphorylation remodels the mitotic centrosome matrix to generate bipartite γ-tubulin complex docking sites.
  33. Artificial cells evidence apical compressive forces building up during neuroepithelial organoid early development.
  34. DDX6 undergoes phase separation to modulate metabolic plasticity and chemoresistance.
  35. Analyses of bent spindles reveal the mechanics of anaphase B in fission yeast.
  36. A fin-loop-like structure in GPX4 underlies neuroprotection from ferroptosis.
  37. Epigenome-wide association study of nuclear DNA methylation in relation to mitochondrial heteroplasmy.
  38. Chaperone-mediated autophagy sustains muscle stem cell regenerative functions but declines with age.
  1. Cell. 2025 Dec 03. pii: S0092-8674(25)01255-3. [Epub ahead of print]
    Fertilization triggers early proteomic symmetry breaking in mammalian embryos.
    Lisa K Iwamoto-Stohl, Aleksandra A Petelski, Baiyi Quan, Maciej Meglicki, Audrey Fu, Shoma Nakagawa, Breanna McMahon, Ting-Yu Wang, Saad Khan, Harrison Specht, Gray Huffman, Jason Derks, Sergi Junyent, Bailey A T Weatherbee, Antonia Weberling, Carlos W Gantner, Rachel S Mandelbaum, Richard J Paulson, Lisa Lam, Tsui-Fen Chou, Nikolai Slavov, Magdalena Zernicka-Goetz.
      While non-mammalian embryos often rely on spatial pre-patterning, mammalian development has long been thought to begin with equivalent blastomeres. However, emerging evidence challenges this. Here, using multiplexed and label-free single-cell proteomics, we identify over 300 asymmetrically abundant proteins-many involved in protein degradation and transport-dividing mouse 2-cell-stage blastomeres into two distinct clusters, which we term alpha and beta. These proteomic asymmetries are detectable as early as the zygote stage, intensify by the 4-cell stage, and correlate with the sperm entry site, implicating fertilization as a symmetry-breaking event. Splitting 2-cell-stage embryos into halves reveals that beta blastomeres possess greater developmental potential than alpha blastomeres. Similar clustering and protein enrichment patterns found in human 2-cell embryos suggest this early asymmetry might be conserved. These findings uncover a previously unrecognized proteomic pre-patterning triggered by fertilization in mammalian embryos, with important implications for understanding totipotency and early lineage bias.
    Keywords:  2-cell blastomere asymmetries; developmental biology; embryonic patterning; epiblast; human development; lineage specification; mammalian embryonic development; pre-implantation development; single-cell proteomics by mass spectrometry; totipotency
    DOI:  https://doi.org/10.1016/j.cell.2025.11.006
  2. Dev Cell. 2025 Dec 02. pii: S1534-5807(25)00695-1. [Epub ahead of print]
    Dual role of Oct4 and Sox2 in controlling the developmental capacity and timing of tissue morphogenesis in the embryonic lineage.
    Deepthi Chandramohan, Rongge Yan, Kai Kruse, Heike Brinkmann, Hyun-Woo Jeong, Yanlin Hou, Kenjiro Adachi, Hans R Schöler, Ivan Bedzhov.
      The fundamental processes of cell fate specification, differentiation, and morphogenesis must be finely synchronized to enable proper developmental progression, yet the molecular factors coordinating these processes are not well understood. A key driver of embryonic morphogenesis is the establishment of epithelial polarity, which organizes and structures the early cell layers. Here, we investigated factors controlling the epithelialization in epiblast cells and implemented sequential loss-of-function approaches in mouse embryos to define the timing of developmental significance. We found that the expression wave of the core pluripotency factors Oct4 and Sox2 following the 8-cell stage plays a critical role in this process. In this context, one of the key shared functions of these factors is to prevent premature activation of the epithelial program until the completion of the second lineage segregation. Thus, Oct4 and Sox2 simultaneously govern developmental capacity and regulate the developmental timing of tissue morphogenesis of the embryonic lineage.
    Keywords:  ICM; Oct4; Sox2; blastocyst; core pluripotency factors; embryo; epiblast; epithelial polarity; morphogenesis; mouse
    DOI:  https://doi.org/10.1016/j.devcel.2025.11.003
  3. Cell. 2025 Dec 02. pii: S0092-8674(25)01253-X. [Epub ahead of print]
    Membrane potential mediates the cellular response to mechanical pressure.
    Avik Mukherjee, Yanqing Huang, Jens Elgeti, Seungeun Oh, Jose G Abreu, Leander Ammar, Anjali R Neliat, Janik Schüttler, Dan-Dan Su, Christophe Dupre, Nina Catherine Benites, Xili Liu, Leonid Peshkin, Mihail Barboiu, Hugo Stocker, Marc W Kirschner, Markus Basan.
      Mechanical forces influence cellular decisions to grow, die, or differentiate, through largely mysterious mechanisms. Separately, changes in resting membrane potential have been observed in development, differentiation, regeneration, and cancer. We demonstrate that membrane potential is an important mediator of cellular response to mechanical pressure. We show that mechanical forces acting on the cell change cellular biomass density, which, in turn, alters membrane potential. Membrane potential then regulates cell number density in epithelia by controlling cell growth, proliferation, and cell elimination. Mechanistically, we show that changes in membrane potential control signaling through the Hippo and mitogen-activated protein kinase (MAPK) pathways and potentially other signaling pathways that originate at the cell membrane. While many molecular interactions are known to affect Hippo signaling, the upstream signal that activates the canonical Hippo pathway at the membrane has previously been elusive. Our results establish membrane potential as an important regulator of growth and tissue homeostasis.
    Keywords:  Hippo; YAP; biomass density; growth control; mapk; mechanotransduction; membrane potential; tissue homeostasis
    DOI:  https://doi.org/10.1016/j.cell.2025.11.004
  4. Science. 2025 Dec 04. 390(6777): eadw0566
    Cohesin guides homology search during DNA repair using loops and sister chromatid linkages.
    Federico Teloni, Zsuzsanna Takacs, Michael Mitter, Christoph C H Langer, Inès Prlesi, Thomas L Steinacker, Vincent P Reuter, Dmitry Mylarshchikov, Daniel W Gerlich.
      Accurate repair of DNA double-strand breaks (DSBs) is essential for genome stability, and defective repair underlies diseases such as cancer. Homologous recombination uses an intact homologous sequence to faithfully restore damaged DNA, yet how broken DNA ends find homologous sites in a genome containing billions of bases remains unclear. Here, we introduce sister-pore-C, a high-resolution method to map intra- and intermolecular interactions in replicated chromosomes. We show how DSBs remodel chromosome architecture using two functionally distinct pools of cohesin. Loop-extruding cohesin accumulates across megabase-scale domains surrounding DSBs to control local homology sampling, whereas cohesive cohesin concentrates at break sites to tether DNA ends to the sister chromatid. This mechanism restricts the homology-sampling space, highlighting how chromosome conformation helps to preserve genomic integrity.
    DOI:  https://doi.org/10.1126/science.adw0566
  5. Nat Commun. 2025 Dec 02. 16(1): 10193
    Nuclear actin and DNA replication stress regulate telomere maintenance by telomerase.
    Ashley Harman, Melissa Kartawinata, Nohad M Maroun, Darren R Nguyen, Shabita Rahman, William E Hughes, Kevin Winardi, Scott B Cohen, Anthony J Cesare, Noa Lamm, Tracy M Bryan.
      The recruitment of telomerase to telomeres is a tightly regulated process which is stimulated by replication stress and the DNA damage response regulatory kinase ATR, via an unknown mechanism. Here, we demonstrate that nuclear filamentous actin is important for the stable interaction of telomerase with telomeres in immortal human cells, resulting in productive telomere elongation by telomerase in an actin-dependent manner. This process is regulated by both ATR and mTOR kinases, and employs other regulators of actin structure and function, such as WASP, ARP2/3 and myosin. Nuclear filamentous actin serves as a site for telomerase recruitment, which is mediated by telomere tethering on actin fibers in response to replication stress, allowing telomerase to localize to telomeres containing stalled replication forks. Overall, these data demonstrate that, in human cells which express telomerase, telomeric replication stress triggers the recruitment of telomerase to telomeres via a nuclear actin network, enabling telomere length maintenance.
    DOI:  https://doi.org/10.1038/s41467-025-66506-0
  6. Nat Cell Biol. 2025 Dec 03.
    A human epiblast model reveals dynamic TGFβ-mediated control of epithelial identity during mammalian epiblast development.
    Irene Zorzan, Elena Carbognin, Andrea Lauria, Valentina Proserpio, Davide Benvegnù, Federica Bertelli, Susana De Juambelz Urías, Caterina Dalrio, Giorgia Panebianco, Rebecca Scarfò, Eleonora Pensabene, Mattia Arboit, Irene Paolucci, Andrea Drusin, Dario Bizzotto, Monika Sledziowska, Paola Braghetta, Andrea Ditadi, Gianluca Amadei, Salvatore Oliviero, Graziano Martello.
      Pluripotency, the ability to generate all body cell types, emerges in a disorganized embryonic cell mass. After implantation, these cells form a columnar epithelium and initiate lumenogenesis. During gastrulation, some undergo epithelial-to-mesenchymal transition to form the primitive streak (PS). The signals controlling these events in humans are largely unknown. Here, to study them, we developed a chemically defined 3D model where conventional pluripotent stem cells self-organize into a columnar epithelium with a lumen, from which PS-like cells emerge. We show that early TGFβ family inhibition prevents epithelial identity, also in murine 3D embryo models and in embryos. ZNF398 acts downstream of TGFβ1, activating the epithelial master regulator ESRP1 while repressing mesenchymal factors CDH2 and ZEB2. After epithelium formation, TGFβ1 stimulation is dispensable for its maintenance. However, treatment via ACTIVIN-a distinct TGFβ family ligand-induces PS efficiently. Thus, signalling of the TGFβ family dynamically governs pluripotent epiblast epithelial identity.
    DOI:  https://doi.org/10.1038/s41556-025-01831-6
  7. Nat Commun. 2025 Dec 02.
    CIP2A mediates mitotic recruitment of SLX4/MUS81/XPF to resolve replication stress-induced DNA lesions.
    Lauren de Haan, Sietse J Dijt, Alejandro García-López, Dan Ruan, Panagiotis Martzios, Femke J Bakker, Marieke Everts, Harry Warner, Frank N Mol, J Ross Chapman, H Rudolf de Boer, Bert van de Kooij, Pim J Huis In 't Veld, Rifka Vlijm, Marcel A T M van Vugt.
      Perturbed DNA replication can lead to incompletely replicated DNA when cells enter mitosis and can interfere with chromosome segregation. Cells therefore require mechanisms to resolve these lesions during mitosis. The CIP2A-TOPBP1 complex is described to tether fragmented DNA molecules during mitosis. Whether CIP2A also functions in processing of incompletely replicated DNA remained unclear. We show that CIP2A-TOPBP1 form large filamentous structures at sites of incomplete DNA replication during mitosis, and that CIP2A-TOPBP1 facilitate the recruitment of SMX tri-nuclease complex members SLX4, MUS81 and XPF-ERCC1. These structures form in proximity to sites of mitotic DNA synthesis, although CIP2A is not required for mitotic DNA synthesis. In addition to its globular and coiled-coil domain, the unstructured C-terminal domain of CIP2A is essential for CIP2A-TOPBP1 filamentous structure formation and recruitment of the SMX complex. BRCA1-/- and BRCA2-/- cells have increased mitotic DNA lesions that recruit CIP2A and SLX4. We show that the C-terminal part of CIP2A is required for survival of BRCA2-/- cells. Moreover, SLX4 is crucial for genome stability in BRCA2-/- cells. Combined, we demonstrate that CIP2A-TOPBP1 recruits the SMX complex during mitosis, which is required to resolve mitotic DNA lesions, allows faithful chromosome segregation and maintain viability of BRCA2-/- cells.
    DOI:  https://doi.org/10.1038/s41467-025-66549-3
  8. Res Sq. 2025 Nov 18. pii: rs.3.rs-7913970. [Epub ahead of print]
    Nucleosome stability safeguards cell identity, stress resilience and healthy aging.
    Peter Adams, Hiroshi Tanaka, Brenna McCauley, Clara Guida, Xue Lei, Sha Li, Tatiana Moreno, K'leigh Guillotte, Zong Chua, Adrianna Abele, Aashna Lamba, Rouven Arnold, Adarsh Rajesh, Marcos Teneche, Laurence Haddadin, Anagha Deshpande, Aniruddha Deshpande, Alexandre Colas, Caroline Kumsta, Michael Petrascheck, Rolf Bodmer, Weiwei Dang.
      The Information Theory of Aging (ITOA) proposes that aging results from the progressive loss of epigenetic information. As the repeating units of the epigenome, nucleosomes are considered pivotal for its stability. Accordingly, the ITOA predicts that destabilization of nucleosomes will accelerate aging. However, this causal link has not been directly tested. Here, we addressed this through histone mutants that weaken histone-histone interactions. Without broadly perturbing steady-state chromatin accessibility, DNA damage, cell proliferation or viability, nucleosome instability compromised cell identity maintenance, altered lineage specification and activated intrinsic inflammatory and stress pathways in a manner reminiscent of aging in mouse tissues and human cells. Consistently, nucleosome instability accelerated age-associated transcriptional alterations and functional decline in Caenorhabditis elegans and Drosophila melanogaster, and reduced cellular resilience to exogenous perturbations-including environmental, epigenetic and mitotic stress-in human cells and Saccharomyces cerevisiae. These cross-species findings establish nucleosome stability as a fundamental requirement for preserving cell identity and stress resilience, thereby safeguarding organismal longevity.
    DOI:  https://doi.org/10.21203/rs.3.rs-7913970/v1
  9. Trends Biochem Sci. 2025 Nov 28. pii: S0968-0004(25)00250-6. [Epub ahead of print]
    Protein codes and mobility together shape cellular function and disease.
    Henry R Kilgore, Shannon Moreno, Richard A Young.
      Cells organize their biochemical activities by assembling proteins into both membrane-bound organelles and membrane-less condensates. These compartments enable specialized chemical environments that support unique biochemical functions. Recent evidence indicates that proteins carry encoded instructions for not only protein folding, but also selective distribution into condensate compartments. The dynamic movement of proteins into and within compartments is essential for normal function, while disruptions that reduce protein mobility can impair biochemical rates and cause dysfunction and disease. Here, we review these principles of condensate compartmentalization, emphasizing how encoded protein properties, chemical environments, and dynamic movement shape both cellular health and disease pathology.
    Keywords:  biomolecular condensates; collision-limited reactions; macromolecular crowding; oxidative stress; protein solvation environments; proteolethargy
    DOI:  https://doi.org/10.1016/j.tibs.2025.10.009
  10. Science. 2025 Dec 04. 390(6777): eadw1928
    Cohesin drives chromatin scanning during the RAD51-mediated homology search.
    Alberto Marin-Gonzalez, Adam T Rybczynski, Namrata M Nilavar, Daniel Nguyen, Andrew G Li, Violetta Karwacki-Neisius, Roger S Zou, Franklin J Avilés-Vázquez, Masato T Kanemaki, Ralph Scully, Taekjip Ha.
      Cohesin folds genomes into chromatin loops, the roles of which are under debate. We found that double-strand breaks (DSBs) induce de novo formation of chromatin loops in human cells, with the loop base positioned at the DSB site. These loops form in the S and G2 phases of the cell cycle during homologous recombination repair, concomitantly with DNA end resection and radiation-sensitive protein 51 (RAD51) recruitment. RAD51 shows a broad (megabase-sized) chromatin domain reflective of the homology search. This domain is regulated by cohesin unloader and overlaps with chromatin regions reeled through the break-anchored loop, suggesting that loop extrusion regulates the homology search. Indeed, depletion of the loop-extruding cohesin subunit NIPBL lowers homologous recombination in mouse embryonic stem cells, and this effect is more pronounced when the homologous recombination donor is hundreds of kilobases from the DSB. Our data indicate that loop-extruding cohesin promotes the mammalian homology search by facilitating break-chromatin interactions.
    DOI:  https://doi.org/10.1126/science.adw1928
  11. Proc Natl Acad Sci U S A. 2025 Dec 09. 122(49): e2524136122
    Intercellular diffusion of cyclic nucleotides followed by gap junction closure restarts meiosis in mouse preovulatory follicles.
    Iris F Nakashima, Haining Zhong, Viacheslav O Nikolaev, Corie M Owen, Siu-Pok Yee, Laurinda A Jaffe, Jeremy R Egbert.
      Signaling by luteinizing hormone (LH) in the outer granulosa cells of mammalian ovarian follicles causes meiosis to resume in the oocyte, located ~10 cell layers away, preparing the oocyte for ovulation and fertilization. This long-distance communication is accomplished by cAMP and cGMP diffusion through gap junctions, but knowledge of cAMP dynamics in the oocyte is based on static measurements, and information about cAMP changes in the granulosa cells has not been integrated with information about cAMP changes in the oocyte. By simultaneous multihour imaging of both compartments of live ovarian follicles, using mice expressing an improved cAMP sensor, we elucidate how the meiosis-activating signal is transmitted. In response to LH, cAMP generated in the granulosa cells diffuses within ~10 min to the oocyte. cAMP in the granulosa cells then remains high for at least 5 h, but over a 3-h period, cAMP in the oocyte decreases to a new plateau level below the original baseline. We show that the cAMP decrease in the oocyte depends not only on the established mechanism of LH lowering cGMP in the oocyte, which relieves inhibition of the PDE3A phosphodiesterase in the oocyte, but also on the subsequent LH-induced closure of gap junctions between the granulosa cells. This closure prevents cAMP from diffusing into the oocyte from the granulosa cells, a concept that has been proposed but not previously tested. We conclude that LH coordinates changes in both cGMP and gap junctions to lower cAMP in the oocyte, reinitiating meiotic progression.
    Keywords:  cyclic nucleotides; gap junctions; luteinizing hormone; oocyte meiosis; ovarian follicle
    DOI:  https://doi.org/10.1073/pnas.2524136122
  12. Biophys J. 2025 Dec 03. pii: S0006-3495(25)03457-5. [Epub ahead of print]
    Design of de novo nucleolar surface proteins.
    Amal Narayanan, Clifford P Brangwynne.
      Biomolecular condensates are membraneless intracellular structures formed from the phase separation of proteins and nucleic acids. Although biomolecular condensates do not have a phospholipid membrane at their surface, recent studies reveal conspicuous assemblies of proteins at the interface between the dense and dilute phases of nucleoli, P granules, and other condensates. The molecular and biophysical rules that govern the surfactant-like localization of these proteins are only beginning to be understood. Here, we created de novo nucleolar surface proteins (NoLSurfers) by fusing diverse synthetic nucleoli-philic and nucleoli-phobic protein segments. By quantitatively analyzing the spatial distribution of different combinations of nucleoli-philic and nucleoli-phobic protein segments, we find that the nucleolar surface localization of NoLSurfers is largely determined by the oligomerization state of nucleoli-philic proteins and their immiscibility with the underlying condensate structure. While nucleoli-philic proteins with low oligomerization are miscible in the dense phase of nucleoli, nucleoli-philic proteins with high oligomerization become immiscible and show surface localization, and in some cases form de novo condensates in the nucleoplasm. These engineered NoLSurfers are useful as a tool to both elucidate central aspects of the biophysics of condensate interfaces and to potentially modulate condensate properties and function.
    DOI:  https://doi.org/10.1016/j.bpj.2025.12.001
  13. Sci Adv. 2025 Dec 05. 11(49): eady7272
    Drosophila and mouse intestinal stem cells are spatiotemporally specified by Notch suppression and Wnt activation.
    You Wu, Lingxiao Yu, Yuxin Yu, Song Wu, Qili Yuan, Weicheng Duan, Sicheng Cai, Bo Xiong, Rong Lin, Zheng Guo.
      The specification of intestinal stem cells (ISCs) during development is critical for maintaining intestinal homeostasis. However, the mechanisms underlying this process remain elusive. Here, by counting and tracing ISC in Drosophila pupal midgut, we show that ISCs are specified within a narrow 12-hour developmental window, with ~150 ISCs emerging from a pool of ~6000 intestinal epithelial cells. Single-cell sequencing revealed the involvement of Notch and Wnt signaling, with genetic experiments demonstrating that ISC specification requires both Notch suppression and Wnt activation. Furthermore, we showed that Wnt signaling is activated in discrete spatial domains, and Notch-mediated lateral inhibition specifies ISCs in these Wnt-active zones, achieving a ratio of ~1/40. Notably, Notch suppression also promoted the specification of Lgr5+ progenitors in the mouse embryonic intestine. Together, our data show that Wnt activation defines niches permissive for ISC fate, whereas Notch suppression licenses fate commitment, a spatiotemporal coordination conserved from insects to mammals.
    DOI:  https://doi.org/10.1126/sciadv.ady7272
  14. J Cell Biol. 2026 Feb 02. pii: e202510018. [Epub ahead of print]225(2):
    High-resolution mapping of the actin fusion focus reveals myosin V-dependent formin transport for aster formation.
    Valentine Thomas, Hikari Mase, Laetitia Michon, Andrea Picco, Marko Kaksonen, Sophie G Martin.
      Many processes such as polarized growth and secretion require specific actin networks. In fungi, cell-cell fusion requires cell wall digestion mediated by local secretion of lytic enzymes. In Schizosaccharomyces pombe, the myosin V Myo52 transports enzyme-containing secretory vesicles on the actin fusion focus, an aster-like actin network assembled by the condensate-forming formin Fus1. The fusion focus also concentrates proteins regulating cell polarity, communication, cytoskeleton, exocytosis, and membrane merging. Here, using centroid tracking and averaging, we present a spatiotemporal map of the fusion site with 8-nm precision. We show that a pool of vesicles remains at constant distance from the membrane as the actin structure condenses. Unexpectedly, Myo52 detaches from this pool and colocalizes with Fus1 closer to the membrane. We show that Myo52 binds Fus1 and transports it along actin filaments, and that Myo52 and Fus1 actin assembly activity contribute to focus compaction. Thus, myosin V-driven transport of formin Fus1 along Fus1-nucleated actin filaments underlies positive feedback for actin aster formation.
    DOI:  https://doi.org/10.1083/jcb.202510018
  15. Nat Cell Biol. 2025 Dec 02.
    Karyopherins remodel the dynamic organization of the nuclear pore complex transport barrier.
    Toshiya Kozai, Javier Fernandez-Martinez, Larisa E Kapinos, Paola Gallardo, Trevor van Eeuwen, Martin Saladin, Roi Eliasian, Adam Mazur, Wenzhu Zhang, Jeremy Tempkin, Radhakrishnan Panatala, Maria Delgado-Izquierdo, Raul Escribano-Marin, Qingzhou Feng, Chenxiang Lin, Andrej Sali, Brian T Chait, Barak Raveh, Liesbeth M Veenhoff, Michael P Rout, Roderick Y H Lim.
      Nuclear pore complexes (NPCs) mediate selective exchange of macromolecules between the nucleus and cytoplasm, but the organization of their transport barrier has been a matter of debate. Here we used high-speed atomic force microscopy, complemented with orthogonal in vitro and in vivo approaches, to probe the dynamic behaviour of the NPC central channel at millisecond resolution. We found that nuclear transport factors dynamically remodel intrinsically disordered phenylalanine-glycine (FG) domains tethered within the NPC channel, partitioning the barrier into two zones: a rapidly fluctuating annular region and a highly mobile central plug. Increased FG-repeat density in mutant NPCs dampened barrier dynamics and impaired transport. Notably, NPC-like behaviour was recapitulated in DNA origami nanopores bearing transport factors and correctly tethered FG domains but not in in vitro FG hydrogels. Thus, the rotationally symmetric architecture of NPCs supports a nanoscopic barrier organization that contrasts with many of the bulk properties of in vitro FG-domain assemblies.
    DOI:  https://doi.org/10.1038/s41556-025-01812-9
  16. Science. 2025 Dec 04. 390(6777): 1038-1043
    High-fidelity human chromosome transfer and elimination.
    Gianluca Petris, Simona Grazioli, Linda van Bijsterveldt, Pierre Murat, Kim C Liu, Jakob Birnbaum, Julian E Sale, Jason W Chin.
      The synthesis of human genomes and other gigabase-scale genomes will require new strategies. Here, we realized key steps in our pipeline for building synthetic human chromosomes. We established: (i) the facile transfer of human chromosomes from human cells to mouse embryonic stem cells (assembly cells), where they are haploid, are nonessential, and may be operated on; (ii) the transfer of these human chromosomes from monochromosomal hybrids back into human cells to generate defined, synthetic aneuploidies; and (iii) the elimination of the corresponding endogenous human chromosomes to regenerate diploid cells containing a transferred chromosome. All steps were performed in nontransformed cells without chromothripsis and generated minimal structural variants, insertions, deletions, or single-nucleotide variants.
    DOI:  https://doi.org/10.1126/science.adv9797
  17. Nat Commun. 2025 Dec 05.
    Structural mechanism of mRNA decoding by mammalian GTPase GTPBP1.
    Denis Susorov, Anna Miścicka, Dmitrij Golovenko, Anna B Loveland, Alexandra Zinoviev, Tatyana V Pestova, Andrei A Korostelev.
      GTP-binding protein 1 (GTPBP1) is a widespread translational GTPase closely related to elongation factor eEF1A. The loss of GTPBP1 leads to neurodevelopmental and neurodegenerative disorders in animals. Although linked to translation and quality control mechanisms, GTPBP1 molecular functions remain largely obscure. Similarly to eEF1A, GTPBP1 delivers aminoacyl-tRNA to the ribosome, but the ensuing GTPBP1-mediated elongation is slow. Here, using cryo-EM of mammalian 80S ribosomal complexes bound to GTPBP1 and aa-tRNA with GTP or the non-hydrolysable analog GDPCP, we show that the distinct GTPBP1 architecture and interactions with tRNA underlie slow GTPBP1 dissociation after GTP hydrolysis, resulting in delayed tRNA accommodation. Slow dissociation correlates with an extended proofreading stage and higher accuracy of GTPBP1-mediated decoding, potentially allowing GTPBP1 to elicit its putative quality control functions. GTPBP1 visualization provides the foundation for mapping and elucidating GTPBP1 mutations associated with human diseases.
    DOI:  https://doi.org/10.1038/s41467-025-66833-2
  18. Nature. 2025 Dec 03.
    Modelling late gastrulation in stem cell-derived monkey embryo models.
    Jie Li, Jie Li, Jing Cao, ShenShen Shang, Liansheng Zhang, Fei Gao, Jiqiang Fu, Hongyu Chen, Guizhong Cui, Haoyuan Wu, Xiaolong Wang, Alfonso Martinez-Arias, Qiang Sun, Zhen Liu.
      Stem cell-derived embryo models could greatly facilitate our understanding of embryonic development. Although human and monkey embryo models have reached early gastrulation stage1-7, the development of robust models beyond this time remains to be accomplished8. Here, using an optimized 3D suspension culture system, we have successfully advanced the in vitro culture of a stem cell-derived monkey blastoid to day 25. Morphological and histological analyses showed that these monkey embryoids underwent gastrulation and largely recapitulated key developmental events of the late gastrulation stage observed in vivo, with the appearance of a neural plate, haematopoietic system, allantois, primitive gut, primordial germ cells, yolk sac structures and progenitors of other organs, excluding trophoblast derivatives. Single-cell transcriptomic analyses revealed that the lineage composition and differentiation trajectories of cells in these monkey embryoids were similar to those found in natural embryos during gastrulation. Thus, this primate stem cell-derived embryo model provides a valuable platform for dissecting the mechanisms of primate embryonic development from blastocyst to late gastrulation stage.
    DOI:  https://doi.org/10.1038/s41586-025-09831-0
  19. J Cell Biol. 2026 Feb 02. pii: e202508155. [Epub ahead of print]225(2):
    Regulation of cell dynamics by rapid integrin transport through the biosynthetic pathway.
    Martina Lerche, Mathilde Mathieu, Hellyeh Hamidi, Megan Chastney, Guillaume Jacquemet, Bart Marlon Herwig Bruininks, Shreyas Kaptan, Lene Malerød, Nina Marie Pedersen, Andreas Brech, Nobuyuki Matoba, Yuichiro Sato, Ilpo Vattulainen, Pere Roca-Cusachs, Franck Perez, Gaelle Boncompain, Stéphanie Miserey, Johanna Ivaska.
      Constitutive integrin endocytosis and recycling control cell movement and morphology. In contrast, the role of newly synthesized integrins delivered via the biosynthetic pathway has been largely overlooked. We used the retention using selective hooks system to monitor the localization of new integrins exiting the endoplasmic reticulum in space and time. We discovered that new integrin delivery to the plasma membrane is polarized and enhances cell protrusion and focal adhesion growth in an extracellular matrix-ligand-dependent manner. Motor-clutch modeling explained the increased adhesion as higher integrin availability driving recruitment of additional receptors. Unexpectedly, live-cell imaging revealed a small subset of fast-emerging integrin vesicles rapidly transported to the cell surface to facilitate localized spreading. This unconventional secretion depended on cell adhesion and correlated with increased surface levels of immature, high-mannose glycosylated integrin, indicating bypass of the canonical Golgi-dependent secretory pathway. Thus, spatial plasma membrane-targeting of new integrins rapidly alters adhesion receptor availability, providing cells with added plasticity to respond to their environment.
    DOI:  https://doi.org/10.1083/jcb.202508155
  20. Cell. 2025 Nov 28. pii: S0092-8674(25)01251-6. [Epub ahead of print]
    Innate immune and metabolic signals induce mitochondria-dependent membrane lysis via mitoxyperiosis.
    Yaqiu Wang, Jianlin Lu, Alexandre F Carisey, Sangappa B Chadchan, Ha Won Lee, R K Subbarao Malireddi, Bhesh Raj Sharma, Nagakannan Pandian, Rebecca E Tweedell, Gustavo Palacios, Nathalie Becerra Mora, Camenzind G Robinson, Aaron Pitre, Peter Vogel, Taosheng Chen, Michael P Murphy, Thirumala-Devi Kanneganti.
      The combination of innate immune activation and metabolic disruption plays critical roles in many diseases, often leading to mitochondrial dysfunction and oxidative stress that drive pathogenesis. However, mechanistic regulation under these conditions remains poorly defined. Here, we report a distinct lytic cell death mechanism induced by innate immune signaling and metabolic disruption, independent of caspase activity and previously described pyroptosis, PANoptosis, necroptosis, ferroptosis, and oxeiptosis. Instead, mitochondria undergoing BAX/BAK1/BID-dependent oxidative stress maintained prolonged plasma membrane contact, leading to local oxidative damage, a process we termed mitoxyperiosis. This process then caused membrane lysis and cell death, termed mitoxyperilysis. mTORC2 regulated the cell death, and mTOR inhibition restored cytoskeletal activity for lamellipodia to retract and mobilize mitochondria away from the membrane, preserving integrity. Activating this pathway in vivo regressed tumors in an mTORC2-dependent manner. Overall, our results identify a lytic cell death modality in response to the synergism of innate immune signaling and metabolic disruption.
    Keywords:  carbon starvation; cytokine; inflammasome; inflammatory cell death; innate immunity; mTOR; metabolism; mitochondria; oxidative damage; tumor
    DOI:  https://doi.org/10.1016/j.cell.2025.11.002
  21. Nat Commun. 2025 Dec 03.
    Platelet-mediated activation of perivascular mast cells triggers progression of sepsis to septic shock in mice.
    Hae Woong Choi, Joo Hwan Noh, Jason Iskarpatyoti, Xiaoyi Zhu, Chunjing Bao, Mathew Abraham, Ulrike Hoffmann, Jamie R Privratsky, Robert H Lee, Wolfgang Bergmeier, Ephraim L Tsalik, Cassandra Fiorino, Junjie Yao, Soman N Abraham, Jörn Karhausen.
      The critical events that trigger sepsis progression into life-threatening septic shock remain unclear. In agreement with reports that link a drop in platelet count to a complicated clinical course in sepsis patients, here we report that, during sepsis, mouse platelets become activated, deposit systemically on vascular walls, and stimulate perivascular mast cells (MC) by releasing platelet activating factor (PAF). In mouse models and patient samples, MC activation correlates with the development of shock in sepsis and is mechanistically linked to shock by inducing systemic hypotension, vascular leakage and microvascular perfusion abnormalities. Preventing platelet or MC activation, or inhibiting the activity of the major MC granule constituent chymase, averts progression from sepsis to shock and reduces mortality of septic mice. Thus, our work establishes that, during sepsis progression, platelet microvascular adhesion leads to MC-mediated vascular changes to culminate in septic shock and septic shock-associated mortality.
    DOI:  https://doi.org/10.1038/s41467-025-66978-0
  22. Circ Res. 2025 Dec 04.
    Human Hearts Intrinsically Increase Cardiomyocyte Mitosis After Myocardial Infarction.
    Robert D Hume, Jessica Warwick, Woo Jun Shim, Cassandra Malecki, Mengbo Li, Lakshay Seth, Dylan Harney, Julien Dagher, Trina Lum, Geraldine Tierney, Wendy Cooper, Eugene Slaughter, Xiaosuo Wang, Lisa Nguyen, Louise Cole, James Edelman, Fairooj Rashid, Callum Houlahan, Antony Gao, Angela L Ferguson, James J H Chong, Mark Larance, John O'Sullivan, Nathan J Palpant, Paul Bannon, Sean Lal.
       BACKGROUND: Myocardial infarction (MI) is a leading cause of death worldwide and can eliminate up to a third of the cardiomyocytes within the human heart. Although cardiomyocytes undergo mitosis during early development, most cardiomyocytes cease cell cycling soon after birth. In contrast, rodent MI models have shown that cardiomyocytes increase mitosis in response to ischemia; however, this has not been shown in humans.
    METHODS: Using a unique premortem post-MI human heart, immunostaining, bulk RNA sequencing, proteomics, metabolomics, single-nucleus RNA sequencing and a novel post-MI human biopsy method, we investigated human cardiomyocyte mitosis post-MI.
    RESULTS: We show that adult human cardiomyocytes exhibit increased mitosis and cytokinesis in response to ischemia.
    CONCLUSIONS: Future development of therapeutics to enhance this intrinsic mitotic potential could lead to new treatments that reverse heart failure via cardiac regeneration.
    Keywords:  cause of death; heart; mitosis; myocardial infarction; myocytes, cardiac
    DOI:  https://doi.org/10.1161/CIRCRESAHA.125.327486
  23. Nature. 2025 Dec 03.
    Viral RNA blocks circularization to evade host codon usage control.
    Huan Liu, Jiabin Duan, Renu Garg, Pancheng Xie, Yi Liu.
      Codon usage bias-the preferential use of certain synonymous codons-is a fundamental feature of all genomes. Codon usage has a key role in determining gene-expression levels in all organisms that have so far been studied1-3. Nearly all human-infecting viruses show patterns of codon usage that are distinct from those of human genes-yet they express their proteins efficiently in host cells to cause diseases and pandemics. The mechanism behind this evasion of codon usage control by viral RNA translation is unknown. Here we show that viral proteins are subject to strong codon usage control when they are translated like human genes, but that they can evade this control when translated from viral replicons. This evasion is mediated by viral 5' untranslated regions (UTRs) in diverse human viruses, which support codon-usage-insensitive translation. Canonical mRNA translation depends on codon usage, requiring the 5' cap, 3' polyA tail and their associated proteins, which suggests that mRNA looping has a role in the effect of codon usage on translation. Notably, RNA circularization for mRNAs with viral 5' UTRs restores codon-usage-dependent translation, owing mainly to non-optimal codon-usage-mediated repression. These results suggest that mRNA circularization is crucial for initiating codon-usage-dependent translation, and that viral RNAs bypass this mechanism by blocking circularization, allowing efficient translation despite their poor codon usage profiles.
    DOI:  https://doi.org/10.1038/s41586-025-09809-y
  24. Nat Commun. 2025 Dec 01.
    Sprint interval exercise disrupts mitochondrial ultrastructure driving a unique mitochondrial stress response and remodelling in men.
    J Botella, E Perri, N J Caruana, S López-Calcerrada, M Brischigliaro, N A Jamnick, V Oorschot, N J Saner, J Díaz-Lara, D F Taylor, A Garnham, E Fernández-Vizarra, C Ugalde, G Ramm, D A Stroud, M Lazarou, D J Bishop.
      Exercise is a key lifestyle intervention for mitochondrial health, yet the molecular mechanisms by which different exercise prescriptions regulate mitochondrial remodeling remain unclear. We conducted an open-label counterbalanced randomized controlled trial (ACTRN12617001105336) and observed that sprint-interval exercise (SIE; n = 14), compared to moderate-intensity continuous exercise (MICE; n = 14), induces a mitochondrial stress signature and unfolded protein response (UPRmt). SIE triggers morphological and structural mitochondrial alterations along with activation of the integrated stress response (ISR) and mitochondrial quality control (MQC) pathways. Following eight weeks of training, moderate-intensity continuous training (MICT) increases mitochondrial content, complex I activity, and displays an enrichment of tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS) proteins, while sprint-interval training (SIT) improves respiratory function and upregulates pathways involved in 1-carbon metabolism and protein quality control. We identify COX7A2L accumulating in III2 + IV1 supercomplexes only after SIT. These findings elucidate how exercise intensity shapes mitochondrial remodeling, informing tailored exercise prescriptions.
    DOI:  https://doi.org/10.1038/s41467-025-66625-8
  25. J Cell Biol. 2026 Feb 02. pii: e202508055. [Epub ahead of print]225(2):
    Phosphatidylserine exposure and annexin A5 weaken the actin cortex in osteoclast fusion.
    Evgenia Leikina, Andrey K Tsaturyan, Kamran Melikov, Jarred M Whitlock, Jared Cunanan, Morgan Roegner, Griffin Katz, Michael M Kozlov, Leonid V Chernomordik.
      Diverse cell-cell fusions involve Ca2+ signaling, exposure of phosphatidylserine (PS) at the cell surface and binding of extracellular annexin A5 (Anx A5). Here we report that in the fusion stage of osteoclast formation, each of these shared hallmarks of cell fusion represents a step in a novel signaling pathway. A rise in intracellular Ca2+ activates a lipid scramblase that translocates PS from the inner to the outer leaflet of the plasma membrane. This redistribution is enhanced by binding of extracellular Anx A5 to PS. Depletion of PS in the inner leaflet weakens actin cortex-plasma membrane attachment, as evidenced by the preferential localization of the cortex detachment areas within PS-enriched regions at the cell surface. Weakening of the cortex attachment promotes osteoclast fusion. Based on these findings and theoretical analysis, we propose that PS exposure-to-cortex detachment pathway facilitates pre-fusion membrane contacts and fusion pore expansion in osteoclast fusion and other cell-cell fusions by promoting outward membrane deformations with locally elevated tension.
    DOI:  https://doi.org/10.1083/jcb.202508055
  26. Nat Commun. 2025 Dec 02. 16(1): 10842
    Dynamic Organellar Mapping in yeast reveals extensive protein localization changes during ER stress.
    Anna Platzek, Klára Odehnalová, Julia P Schessner, Georg H H Borner, Sebastian Schuck.
      Sophisticated techniques are available for systematic studies of yeast cell biology. However, it remains challenging to investigate protein subcellular localization changes on a proteome-wide scale. Here, we apply Dynamic Organellar Mapping by label-free mass spectrometry to detect localization changes of native, untagged proteins during endoplasmic reticulum (ER) stress. We find that hundreds of proteins shift between cellular compartments. For example, we show that numerous secretory pathway proteins accumulate in the ER, thus defining the extent and selectivity of ER retention of misfolded proteins. Furthermore, we identify candidate cargo proteins of the ER reflux pathway, determine constituents of reticulon clusters that segregate from the remainder of the ER and provide evidence for altered nuclear pore complex composition and nuclear import. These findings uncover protein relocalization as a major aspect of cellular reorganization during ER stress and establish Dynamic Organellar Maps as a powerful discovery tool in yeast.
    DOI:  https://doi.org/10.1038/s41467-025-66946-8
  27. PLoS Genet. 2025 Dec;21(12): e1011953
    Single-cell transcriptomics reveals stepwise transformation of epithelial cells into Non-Professional Phagocytes.
    Caique Almeida Machado Costa, Cristian Alejandro Santiago-Santiago, Yi-Chun Huang, Wu-Min Deng.
      The differentiation of epithelial cells into Non-Professional Phagocytes (NPPs) is essential for maintaining tissue homeostasis and clearing apoptotic debris. In the Drosophila ovary, epithelial follicle cells transform into NPPs following germline cell death, but the genetic mechanisms controlling this transition are not well defined. To investigate these mechanisms, we used a model in which overexpression of the active form of Notch, the Notch Intracellular Domain (NICD), induces a robust epithelial-to-NPP transition. Using single-cell RNA sequencing and trajectory analysis, we identified three transcriptional phases of NPP maturation: an early stage of metabolic activation, an intermediate stage enriched in genes related to migration and cytoskeletal remodeling, and a late stage marked by autophagy-related gene expression. These transcriptomic patterns were validated by immunostaining. SCENIC and ChiP-seq analyses identified the JNK effector Jun-related antigen (Jra) and its predicted targets, Arp2 and Arp3, which encode components of the Arp2/3 complex, as regulators of cytoskeletal remodeling. Functional assays confirmed that the JNK-Jra-Arp2/3 axis is required for cytoplasmic expansion and debris clearance during NPP differentiation.
    DOI:  https://doi.org/10.1371/journal.pgen.1011953
  28. Sci Adv. 2025 Dec 05. 11(49): eaea7451
    Rbfox2 selectively governs hematopoietic stem cell self-renewal by regulating proteostasis.
    Longfei Gao, Desmond Dickson, Huijuan Feng, Chaolin Zhang, Lei Ding.
      Self-renewing hematopoietic stem cells (HSCs) generate all blood cells and give rise to long-term reconstitution of the hematopoietic system after transplantation, but the molecular mechanisms that specifically regulate HSCs remain poorly defined. Here, we found that HSCs displayed a distinct messenger RNA alternative splicing pattern and preferentially expressed Rbfox2, an alternative splicing regulator, compared with multipotent progenitors (MPPs). Deletion of Rbfox2 from the hematopoietic compartment specifically depleted HSCs, but not progenitors in the adult bone marrow. Rbfox1 did not function redundantly with Rbfox2 in HSCs. Mechanistically, Rbfox2 loss led to proteostasis stress, including increased protein synthesis rate and accumulated misfolded/unfolded protein contents, in HSCs, but not in progenitors. Small molecules that restore proteostasis rescued HSC defects in Rbfox2-deficient mice. Our work thus reveals that HSCs, but not progenitors, selectively rely on Rbfox2 for their self-renewal and maintenance.
    DOI:  https://doi.org/10.1126/sciadv.aea7451
  29. Mol Cell. 2025 Dec 03. pii: S1097-2765(25)00905-0. [Epub ahead of print]
    Rate-limiting enzymes in nucleotide metabolism synchronize nucleotide biosynthesis and chromatin formation.
    Shashank Srivastava, Daniela Samaniego-Castruita, Shubhi Srivastava, Sakshi Khurana, Jalees Rehman, Vipul Shukla, Issam Ben-Sahra, Daniel R Foltz.
      Chromatin formation requires both an adequate nucleotide supply and histone availability. Newly synthesized histones are escorted by histone chaperones that mediate their orderly transfer from ribosomes to DNA. While nucleotide and histone synthesis are the two major biosynthetic processes required for chromatin assembly, how these processes are coordinated remains unknown. Phosphoribosyl pyrophosphate synthetases (PRPSs), which catalyze the first and rate-limiting step in nucleotide biosynthesis, form a complex with PRPS-associated proteins (PRPSAPs). Using a rapid degron system in multiple human cell lines, we show that PRPS enzymes, together with PRPSAPs, play a key role in early histone maturation independent of their nucleotide biosynthetic function. Depletion of either PRPS1 or PRPSAP1 limits histone availability and disrupts chromatin assembly. These findings reveal a previously unrecognized synchrony between nucleotide metabolism and chromatin regulation, providing insight into how nucleotide production and histone deposition are coordinated.
    Keywords:  PRPS; PRPSAP; chromatin; chromatin assembly; histone chaperone; histone deposition; histone supply; metabolism; nucleotide metabolism
    DOI:  https://doi.org/10.1016/j.molcel.2025.11.009
  30. Science. 2025 Dec 04. 390(6777): eadv6588
    Multiscale structure of chromatin condensates explains phase separation and material properties.
    Huabin Zhou, Jan Huertas, M Julia Maristany, Kieran Russell, June Ho Hwang, Run-Wen Yao, Nirnay Samanta, Joshua Hutchings, Ramya Billur, Momoko Shiozaki, Xiaowei Zhao, Lynda K Doolittle, Bryan A Gibson, Andrea Soranno, Margot Riggi, Jorge R Espinosa, Zhiheng Yu, Elizabeth Villa, Rosana Collepardo-Guevara, Michael K Rosen.
      The structure and interaction networks of molecules within biomolecular condensates are poorly understood. Using cryo-electron tomography and molecular dynamics simulations, we elucidated the structure of phase-separated chromatin condensates across scales, from individual amino acids to network architecture. We found that internucleosomal DNA linker length controls nucleosome arrangement and histone tail interactions, shaping the structure of individual chromatin molecules within and outside condensates. This structural modulation determines the balance between intra- and intermolecular interactions, which governs the molecular network, thermodynamic stability, and material properties of chromatin condensates. Mammalian nuclei contain dense clusters of nucleosomes whose nonrandom organization is mirrored by the reconstituted condensates. Our work explains how the structure of individual chromatin molecules determines physical properties of chromatin condensates and cellular chromatin organization.
    DOI:  https://doi.org/10.1126/science.adv6588
  31. Nat Commun. 2025 Dec 05.
    Mitochondrial components secretion in extracellular vesicles promotes alveolar epithelial mitochondrial quality control.
    Bowen Liu, Yue Han, Yuan Jin, Meng Ye, Zeliang Yang, Jingyi Yang, Minglu Zhu, Xuyang Zhao, Yan Jin, Yuxin Yin.
      The quality control network in type 2 alveolar epithelial cells (AEC2s) is essential to respond to intrinsic and extrinsic challenges. However, the mechanisms that regulate AEC2 mitochondrial homeostasis remain unclear understood. Here, we report a role of G protein-coupled receptor class C group 5 member A (GPRC5A) in mitochondrial quality control in AEC2s through promoting mitochondrial secretion in extracellular vesicles (EVs). Utilizing mice models, we demonstrate that the disruption of GPRC5A specifically in AEC2s aggravates lung injuries. We further observe that GPRC5A deficiency in AEC2s reduces secretion of mitochondrial components in small-EVs and disrupts mitochondrial functions both in vitro and in vivo. Mechanistically, we determine that the GPRC5A-MIRO2 pathway facilitates the transfer of mitochondrial fragments into late endosomes. Collectively, our findings provide evidence of the shedding of mitochondrial components dependent on GPRC5A as a pathway of mitochondrial quality control in AEC2s, which is crucial in the maintenance of epithelial physiological activities and lung tissue homeostasis.
    DOI:  https://doi.org/10.1038/s41467-025-66901-7
  32. bioRxiv. 2025 Nov 21. pii: 2025.11.20.689565. [Epub ahead of print]
    Phosphorylation remodels the mitotic centrosome matrix to generate bipartite γ-tubulin complex docking sites.
    Midori Ohta, Orie Arakawa, Yajie Gu, Wanying Tian, Kevin D Corbett, Arshad Desai, Karen Oegema.
      Mitotic centrosomes consist of centrioles surrounded by a proteinaceous matrix that docks and activates γ-tubulin complexes (γTuCs) to nucleate microtubules for spindle assembly. During mitotic entry, phosphorylation at centrosomes remodels CDK5RAP2 family matrix proteins to generate γTuC docking sites. We address the mechanism of this conversion using C. elegans SPD-5 as a model. We show that SPD-5 contains two regions, PRGB1 and PRGB2, that are each sufficient for Polo-Like Kinase 1 (PLK1) phosphorylation-regulated γTuC binding. We define key phosphosites in each region and uncover autoinhibition mediated by interactions within and between them. PRGB2 is dimeric and requires γTuCs containing the Mozart family microprotein MZT-1 for binding, whereas PRGB1 is monomeric and binds independently of MZT-1. Our results support PLK1 phosphorylation inducing a conformational change that enables MZT-1-dependent PRGB2 binding, which in turn relieves PRGB1 inhibition. Such a multi-step mechanism would ensure robust spindle assembly by restricting microtubule nucleation in space and time.
    DOI:  https://doi.org/10.1101/2025.11.20.689565
  33. Biomaterials. 2025 Nov 24. pii: S0142-9612(25)00790-2. [Epub ahead of print]328 123870
    Artificial cells evidence apical compressive forces building up during neuroepithelial organoid early development.
    Hassan Kanso, Stefania Di Cio, Ruth Rose, Isabel M Palacios, Julien E Gautrot.
      During early stages of development of cerebral organoids, budding neuroepithelia display striking changes in size and morphology, occurring very rapidly. Whilst mechanical forces mediated by cadherin-cadherin junctions are known to control the assembly, maturation and stability of epithelia, little is known of the mechanical context associated with neuroepithelial organoid development. In this report, we demonstrate a rapid translocation of YAP to budding neuroepithelial apical junctions, suggesting the build-up of strong compressive forces early on in their development. To study the mechanics of budding rosettes, we designed oil microdroplets stabilised by protein nanosheets displaying cadherin receptors, able to engage with receptors presented by neighbouring neuroepithelial cells, to integrate into embryoid bodies and developing organoids. The resulting artificial cells are able to sustain the formation of mature junctions with neighbouring cells and lead to the recruitment of tight junction maturation proteins such as ZO1. During early budding of neuroepithelial rosettes, artificial cells are found to be rapidly expelled from the developing organoids, further evidencing apical compressive forces. These forces are not opposed by sufficiently strong shear forces from neighbouring cells, or adhesive forces maintaining anchorage to the apical junction, to induce deformation of artificial cells.
    Keywords:  Artificial cells; Mechanosensing; Neuroepithelial; Organoid; Protein engineering; Protein nanosheet
    DOI:  https://doi.org/10.1016/j.biomaterials.2025.123870
  34. Nat Commun. 2025 Dec 02.
    DDX6 undergoes phase separation to modulate metabolic plasticity and chemoresistance.
    Hongjie Bi, Wei Li, Lili Ren, Honghai Zhang, Lei Dong, Anthony Chan, Xueer Wang, Lu Yang, Xiaoxu Zhang, Meilin Xue, Hanjun Qin, Xiwei Wu, Johanna Ten Hoeve-Scott, Bin Zhang, Ling Li, Mark Wunderlich, James C Mulloy, Steven T Rosen, Jianjun Chen, Xiaobo Li, Chun-Wei Chen, Rui Su.
      Stress granules (SGs) and processing bodies (PBs), assembled via liquid-liquid phase separation (LLPS), are critical for spatial regulation of gene expression in the cytoplasm. However, their roles in tumorigenesis remain poorly understood. Here, we show DEAD-box helicase 6 (DDX6) as the most promising vulnerability in acute myeloid leukemia (AML) through in vitro and in vivo CRISPR screenings using a specialized library targeting RNA-binding proteins enriched in SGs and PBs. Knockout (KO) of DDX6 significantly delays leukemogenesis with minimal impact on normal hematopoiesis. Importantly, the functions of DDX6 in AML depend largely on its ability to trigger LLPS and PB assembly. Mechanistically, PBs serve as "reservoirs" for the mRNAs interacting directly with DDX6 and having low GC content. DDX6 KO leads to rapid PB dissolution and release of PB-enriched mRNAs, such as BCAT1, into the cytosol, where these transcripts undergo degradation. By reducing BCAT1 levels, DDX6 KO reprograms amino acid metabolism and sensitizes AML cells to cytarabine chemotherapy.
    DOI:  https://doi.org/10.1038/s41467-025-66966-4
  35. bioRxiv. 2025 Nov 20. pii: 2025.11.20.689516. [Epub ahead of print]
    Analyses of bent spindles reveal the mechanics of anaphase B in fission yeast.
    Paula Real-Calderón, Thomas G Fai, Rafael R Daga, Joël Lemière, Fred Chang.
      The mitotic spindle in the fission yeast Schizosaccharomyces pombe is a single bundle of microtubules which elongates to segregate the chromosomes during anaphase B. The mechanical properties of the spindle and the forces driving its elongation remain poorly defined. Here, we analyzed how spindles react to mechanical and genetic perturbations to uncover their mechanical properties. Treatment of cells with osmotic oscillations and blue light led to a consistent phenotype of spindle buckling and breakage in mid-anaphase. The stalling of pole separation and reduced rates of spindle elongation indicated that spindles elongate and buckle under increased mechanical load. The structural integrity of the bent spindles was dependent on Ase1 (PRC1), while the spindle elongation rate was dependent on motor proteins Klp9 (kinesin-6) and Cut7 (kinesin-5). Modeling of bent spindle shapes revealed that most spindles behave mechanically as a beam with a two-fold increase in rigidity in the midzone. Upon reaching a threshold size, bent spindles broke at a specific fragile site near the edge of the spindle midzone. Our findings in this simple fission yeast spindle are relevant to the mechanics of more complex metazoan spindles.
    Significance statement: The anaphase B spindle in S. pombe consists of a microtubule bundle that elongates to move the chromosomes apart. The various forces and mechanical properties of the spindle remain poorly quantified. The authors establish a method to induce spindle buckling in mid-anaphase. Time-lapse imaging shows that these spindles elongate at reduced rates, buckle as a non-homogeneous beam under mechanical load, and break at a fragile site adjacent to the midzone.These results provide quantitative and molecular insights into spindle force regulation and structural integrity that are relevant to mitosis in other cell types.
    DOI:  https://doi.org/10.1101/2025.11.20.689516
  36. Cell. 2025 Dec 04. pii: S0092-8674(25)01310-8. [Epub ahead of print]
    A fin-loop-like structure in GPX4 underlies neuroprotection from ferroptosis.
    Svenja M Lorenz, Adam Wahida, Mark J Bostock, Tobias Seibt, André Santos Dias Mourão, Anastasia Levkina, Dietrich Trümbach, Mohamed Soudy, David Emler, Nicola Rothammer, Marcel S Woo, Jana K Sonner, Mariia Novikova, Bernhard Henkelmann, Maceler Aldrovandi, Daniel F Kaemena, Eikan Mishima, Perrine Vermonden, Zhi Zong, Deng Cheng, Toshitaka Nakamura, Junya Ito, Sebastian Doll, Bettina Proneth, Erika Bürkle, Francesca Rizzollo, Abril Escamilla Ayala, Valeria Napolitano, Marta Kolonko-Adamska, Stefan Gaussmann, Juliane Merl-Pham, Stefanie Hauck, Anna Pertek, Tanja Orschmann, Emily van San, Tom Vanden Berghe, Daniela Hass, Adriano Maida, Joris M Frenz, Lohans Pedrera, Amalia Dolga, Markus Kraiger, Martin Hrabé de Angelis, Helmut Fuchs, Gregor Ebert, Jerica Lenberg, Jennifer Friedman, Carolin Scale, Patrizia Agostinis, Annemarie Zimprich, Daniela Vogt-Weisenhorn, Lillian Garrett, Sabine M Hölter, Wolfgang Wurst, Enrico Glaab, Jan Lewerenz, Bastian Popper, Christian Sieben, Petra Steinacker, Hans Zischka, Ana J Garcia-Saez, Anna Tietze, Sanath Kumar Ramesh, Scott Ayton, Michelle Vincendeau, Manuel A Friese, Kristen Wigby, Michael Sattler, Matthias Mann, Irina Ingold, Ashok Kumar Jayavelu, Grzegorz M Popowicz, Marcus Conrad.
      Ferroptosis, driven by uncontrolled peroxidation of membrane phospholipids, is distinct from other cell death modalities because it lacks an initiating signal and is surveilled by endogenous antioxidant defenses. Glutathione peroxidase 4 (GPX4) is the guardian of ferroptosis, although its membrane-protective function remains poorly understood. Here, structural and functional analyses of a missense mutation in GPX4 (p.R152H), which causes early-onset neurodegeneration, revealed that this variant disrupts membrane anchoring without considerably impairing its catalytic activity. Spatiotemporal Gpx4 deletion or neuron-specific GPX4R152H expression in mice induced degeneration of cortical and cerebellar neurons, accompanied by progressive neuroinflammation. Patient induced pluripotent stem cell (iPSC)-derived cortical neurons and forebrain organoids displayed increased ferroptotic vulnerability, mirroring key pathological features, and were sensitive to ferroptosis inhibition. Neuroproteomics revealed Alzheimer's-like signatures in affected brains. These findings highlight the necessity of proper GPX4 membrane anchoring, establish ferroptosis as a key driver of neurodegeneration, and provide the rationale for targeting ferroptosis as a therapeutic strategy in neurodegenerative disease.
    Keywords:  Alzheimer’s disease; GPX4; SSMD; Sedaghatian type; cell death; ferroptosis; neurodegeneration; neuroinflammation; spondylometaphyseal dysplasia
    DOI:  https://doi.org/10.1016/j.cell.2025.11.014
  37. Nat Commun. 2025 Dec 02.
    Epigenome-wide association study of nuclear DNA methylation in relation to mitochondrial heteroplasmy.
    NHLBI Trans-Omics for Precision Medicine (TOPMed) mtDNA Working Group
      We analyze 10,986 participants (mean age 77; 63% women; 54% non-White) across seven U.S. cohorts to study the relationship between mitochondrial DNA (mtDNA) heteroplasmy and nuclear DNA methylation. We identify 597 CpGs associated with heteroplasmy burden, generally showing lower methylation. These CpGs are enriched in dynamically regulated island shores and depleted in CpG islands, indicating involvement in context-specific rather than constitutive gene regulation. In HEK293T cells, we introduce a truncating mtDNA mutation (MT-COX3, mt.9979) and observe a positive correlation between variant allele fraction and methylation at cg04569152, supporting a direct mtDNA-nDNA epigenetic link. Many heteroplasmy-associated CpGs overlap with known methylation-trait associations for metabolic and behavioral traits. Composite CpG scores predict all-cause mortality and incident CVD, with one-unit increases associated with 1.27-fold and 1.12-fold higher hazards, respectively. These findings suggest an mtDNA-nDNA epigenetic connection in aging and disease, though its direction and mechanisms remain to be studied.
    DOI:  https://doi.org/10.1038/s41467-025-65845-2
  38. Nat Metab. 2025 Dec 03.
    Chaperone-mediated autophagy sustains muscle stem cell regenerative functions but declines with age.
    Ignacio Ramírez-Pardo, Silvia Campanario, Bhakti Chavda, Olaya Santiago-Fernández, Marta Flández, Mercedes Grima-Terrén, Andrés Cisneros, Aina Calls-Cobos, Daniel N Itzhak, Bryan Ngo, Sudha Janaki-Raman, Edward D Kantz, Laura Ortet, Antonio Diaz, Kristen Lindenau, Julio Doménech-Fernández, Mari Carmen Gómez-Cabrera, Emilio Camafeita, Jesús Vázquez, Marta Martinez-Vicente, Antonio L Serrano, Eusebio Perdiguero, Joan Isern, Ana Maria Cuervo, Pura Muñoz-Cánoves.
      Proteostasis supports stemness, and its loss correlates with the functional decline of diverse stem cell types. Chaperone-mediated autophagy (CMA) is a selective autophagy pathway implicated in proteostasis, but whether it plays a role in muscle stem cell (MuSC) function is unclear. Here we show that CMA is necessary for MuSC regenerative capacity throughout life. Genetic loss of CMA in young MuSCs, or failure of CMA in aged MuSCs, causes proliferative impairment resulting in defective skeletal muscle regeneration. Using comparative proteomics to identify CMA substrates, we find that actin cytoskeleton organization and glycolytic metabolism are key processes altered in aged murine and human MuSCs. CMA reactivation and glycolysis enhancement restore the proliferative capacity of aged mouse and human MuSCs, and improve their regenerative ability. Overall, our results show that CMA is a decisive stem cell-fate regulator, with implications in fostering muscle regeneration in old age.
    DOI:  https://doi.org/10.1038/s42255-025-01411-w
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