bims-ginsta Biomed News
on Genome instability
Issue of 2025–02–09
thirty-six papers selected by
Jinrong Hu, National University of Singapore
  1. Cytoplasmic flow is a cell size sensor that scales anaphase.
  2. Induced Cytokinesis Generates Highly Proliferative Mononuclear Cardiomyocytes at the Expense of Contractility.
  3. Asymmetric partitioning of persistent paternal mitochondria during cell divisions safeguards embryo development and mitochondrial inheritance.
  4. An avoidance segment resolves a lethal nuclear-mitochondrial targeting conflict during ribosome assembly.
  5. Multiomics atlas reveals molecular and genetic drivers of human ovarian aging.
  6. KMT2C/KMT2D-dependent H3K4me1 mediates changes in DNA replication timing and origin activity during a cell fate transition.
  7. RUNX2 promotes fibrosis via an alveolar-to-pathological fibroblast transition.
  8. Liquid-like condensates that bind actin promote assembly and bundling of actin filaments.
  9. Long-term imaging of individual ribosomes reveals ribosome cooperativity in mRNA translation.
  10. Autophagy-dependent changes in alternative splicing bias translation toward inflammation in senescent cells.
  11. Centrioles generate two scaffolds with distinct biophysical properties to build mitotic centrosomes.
  12. The double life of mammalian DNA replication origins.
  13. Cardiac repair using regenerating neonatal heart tissue-derived extracellular vesicles.
  14. A quantitative ultrastructural timeline of nuclear autophagy reveals a role for dynamin-like protein 1 at the nuclear envelope.
  15. The transmembrane protein Syndecan is required for stem cell survival and maintenance of their nuclear properties.
  16. Rhodoquinone carries electrons in the mammalian electron transport chain.
  17. Moesin integrates cortical and lamellar actin networks during Drosophila macrophage migration.
  18. Decaying and expanding Erk gradients process memory of skeletal size during zebrafish fin regeneration.
  19. UV-induced reorganization of 3D genome mediates DNA damage response.
  20. Convergent flow-mediated mesenchymal force drives embryonic foregut constriction and splitting.
  21. Lactate homeostasis is maintained through regulation of glycolysis and lipolysis.
  22. Bilateral cellular flows display asymmetry prior to left-right organizer formation in amniote gastrulation.
  23. Retrograde mitochondrial signaling governs the identity and maturity of metabolic tissues.
  24. Estrogen receptor alpha ablation reverses muscle fibrosis and inguinal hernias.
  25. Multi-omic profiling of sarcopenia identifies disrupted branched-chain amino acid catabolism as a causal mechanism and therapeutic target.
  26. Spatial transcriptomics identifies molecular niche dysregulation associated with distal lung remodeling in pulmonary fibrosis.
  27. Aneuploidy of specific chromosomes is beneficial to cells lacking spindle checkpoint protein Bub3.
  28. Synthetic lethality of mRNA quality control complexes in cancer.
  29. ROS-induced cytosolic release of mitochondrial PGAM5 promotes colorectal cancer progression by interacting with MST3.
  30. Sequence-dependent activity and compartmentalization of foreign DNA in a eukaryotic nucleus.
  31. Protein codes promote selective subcellular compartmentalization.
  32. Mitochondrial heterogeneity: subpopulations with distinct metabolic activities.
  33. Septin assemblies promote the lipid organization of membranes.
  34. Sex-specific and cell-type-specific changes in chaperone-mediated autophagy across tissues during aging.
  35. SLFN11-mediated ribosome biogenesis impairment induces TP53-independent apoptosis.
  36. Quantifying metabolites using structure-switching aptamers coupled to DNA sequencing.
  1. Nat Cell Biol. 2025 Jan 31.
    Cytoplasmic flow is a cell size sensor that scales anaphase.
    Olga Afonso, Ludovic Dumoulin, Karsten Kruse, Marcos Gonzalez-Gaitan.
      During early embryogenesis, fast mitotic cycles without interphase lead to a decrease in cell size, while scaling mechanisms must keep cellular structures proportional to cell size. For instance, as cells become smaller, if the position of nuclear envelope reformation (NER) did not adapt, NER would have to occur beyond the cell boundary. Here we found that NER position in anaphase scales with cell size via changes in chromosome motility, mediated by cytoplasmic flows that themselves scale with cell size. Flows are a consequence of friction between viscous cytoplasm and bulky cargo transported by dynein on astral microtubules. As an emerging property, confinement in cells of different sizes yields scaling of cytoplasmic flows. Thus, flows behave like a cell geometry sensor: astral microtubules approach the boundary causing flow velocity changes, which then affect the velocity of chromosome separation, thus scaling NER.
    DOI:  https://doi.org/10.1038/s41556-024-01605-6
  2. Circulation. 2025 Feb 06.
    Induced Cytokinesis Generates Highly Proliferative Mononuclear Cardiomyocytes at the Expense of Contractility.
    Nicholas T Lam, Ngoc Uyen Nhi Nguyen, Waleed M Elhelaly, Ching-Cheng Hsu, Ivan Menendez-Montes, Feng Xiao, Shah R Ali, Nelson Vo, Nathan Briard, Lobna El-Feky, Qamar M Omari, Alisson C Cardoso, Yan Liu, Mahmoud Salama Ahmed, Shujuan Li, Suwannee Thet, Chao Xing, Lior Zangi, Hesham A Sadek.
       BACKGROUND: Cytokinesis is the last step in the eukaryotic cell cycle, which physically separates a mitotic cell into 2 daughter cells. A few days after birth in mouse cardiomyocytes, DNA synthesis occurs without cytokinesis, leading to the majority of cardiomyocytes becoming binucleated instead of generating 2 daughter cells with 1 nucleus each. This results in cell cycle arrest of cardiomyocytes, and the mouse heart is no longer able to regenerate. A longstanding unanswered question is whether binucleation of cardiomyocytes is a result of cytokinesis failure.
    METHODS: To address this, we generated several transgenic mouse models to determine whether forced induction of cardiomyocyte cytokinesis generates mononucleated cardiomyocytes and restores the endogenous regenerative properties of the myocardium. We focused on 2 complementary regulators of cytokinesis: Plk1 (polo-like kinase 1) and Ect2 (epithelial cell-transformation sequence 2).
    RESULTS: We found that cardiomyocyte-specific transgenic overexpression of constitutively active Plk1(T210D) promotes mitosis and cytokinesis in adult hearts, whereas overexpression of Ect2 alone promotes only cytokinesis. Cardiomyocyte-specific overexpression of both Plk1(T210D) and Ect2 concomitantly (double transgenic) prevents binucleation of cardiomyocytes postnatally and results in widespread cardiomyocyte mitosis, cardiac enlargement, contractile failure, and death before 2 weeks of age. Similarly, doxycycline-inducible cardiomyocyte-specific overexpression of both proteins (inducible double transgenic) in the adult heart results in reversible widespread cardiomyocyte mitosis and contractile failure. Transient induction of both genes in adult mice improves left ventricular systolic function after myocardial infarction.
    CONCLUSIONS: These results collectively demonstrate that cytokinesis failure mediates cardiomyocyte multinucleation and cell cycle exit of postnatal cardiomyocytes, but may be a protective mechanism to preserve the contractile function of the myocardium.
    Keywords:  cytokinesis; myocardium; myocytes, cardiac
    DOI:  https://doi.org/10.1161/CIRCULATIONAHA.124.065763
  3. Dev Cell. 2025 Jan 30. pii: S1534-5807(25)00033-4. [Epub ahead of print]
    Asymmetric partitioning of persistent paternal mitochondria during cell divisions safeguards embryo development and mitochondrial inheritance.
    Songyun Wang, Ding Xue.
      Most eukaryotes inherit only maternal mitochondria. The reasons for paternal mitochondrial elimination and the impacts of persistent paternal mitochondria on animals remain elusive. We show that undegraded paternal mitochondria in autophagy-deficient C. elegans embryos are gradually excluded from germ blastomeres through asymmetric partitioning during cell divisions. The embryonic cortical flow drives anterior-directed movements of paternal mitochondria and contributes to their asymmetric apportioning between two daughter blastomeres. By contrast, autophagosome-enclosed paternal mitochondria cluster around and segregate with centrosomes during mitosis and are rapidly degraded through lysosomes concentrated near centrosomes. Failure to exclude persistent paternal mitochondria from the germ blastomere at first cleavage causes their enrichment in the descendant endomesodermal (EMS) blastomere, leading to elevated reactive oxygen species levels, elongated EMS lineage durations, and increased embryonic lethality, which antioxidant treatments can suppress. Thus, regulated paternal mitochondrial distribution away from germ blastomeres is a fail-safe mechanism, protecting embryo development and maternal mitochondrial inheritance.
    Keywords:  C. elegans; PME; ROS; asymmetric partitioning of mitochondria; autophagy; cortical flow; embryo development; germline blastomere; mitochondrial inheritance; paternal mitochondrial elimination; reactive oxygen species
    DOI:  https://doi.org/10.1016/j.devcel.2025.01.013
  4. Nat Cell Biol. 2025 Jan 31.
    An avoidance segment resolves a lethal nuclear-mitochondrial targeting conflict during ribosome assembly.
    Michaela Oborská-Oplová, Alexander Gregor Geiger, Erich Michel, Purnima Klingauf-Nerurkar, Sven Dennerlein, Yury S Bykov, Simona Amodeo, André Schneider, Maya Schuldiner, Peter Rehling, Vikram Govind Panse.
      The correct sorting of nascent ribosomal proteins from the cytoplasm to the nucleus or to mitochondria for ribosome production poses a logistical challenge for cellular targeting pathways. Here we report the discovery of a conserved mitochondrial avoidance segment (MAS) within the cytosolic ribosomal protein uS5 that resolves an evolutionary lethal conflict between the nuclear and mitochondrial targeting machinery. MAS removal mistargets uS5 to the mitochondrial matrix and disrupts the assembly of the cytosolic ribosome. The resulting lethality can be rescued by impairing mitochondrial import. We show that MAS triages nuclear targeting by disabling a cryptic mitochondrial targeting activity within uS5 and thereby prevents fatal capture by mitochondria. Our findings identify MAS as an essential acquisition by the primordial eukaryote that reinforced organelle targeting fidelity while developing an endosymbiotic relationship with its mitochondrial progenitor.
    DOI:  https://doi.org/10.1038/s41556-024-01588-4
  5. Nat Aging. 2025 Feb 05.
    Multiomics atlas reveals molecular and genetic drivers of human ovarian aging.
      
    DOI:  https://doi.org/10.1038/s43587-025-00821-5
  6. Cell Rep. 2025 Feb 04. pii: S2211-1247(25)00043-9. [Epub ahead of print]44(2): 115272
    KMT2C/KMT2D-dependent H3K4me1 mediates changes in DNA replication timing and origin activity during a cell fate transition.
    Deniz Gökbuget, Liana Goehring, Ryan M Boileau, Kayla Lenshoek, Tony T Huang, Robert Blelloch.
      Mammalian genomes replicate in a cell-type-specific order during the S phase, correlated to transcriptional activity, histone modifications, and chromatin structure. The causal relationships between these features and DNA replication timing (RT), especially during cell fate changes, are largely unknown. Using machine learning, we quantify 21 chromatin features predicting local RT and RT changes during differentiation in embryonic stem cells (ESCs). About one-third of the genome shows RT changes during differentiation. Chromatin features accurately predict both steady-state RT and RT changes. Histone H3 lysine 4 monomethylation (H3K4me1), catalyzed by KMT2C and KMT2D (KMT2C/D), emerges as a top predictor. Loss of KMT2C/D or their enzymatic activities impairs RT changes during differentiation. This correlates with local H3K4me1 loss and reduced replication origin firing, while transcription remains largely unaffected. Our findings reveal KMT2C/D-dependent H3K4me1 as a key regulator of RT and replication initiation, a role that likely impacts diseases associated with KMT2C/D mutations.
    Keywords:  CP: Molecular biology; DNA replication domains; H3K4 monomethylation; KMT2C; KMT2D; MLL3; MLL4; cell cycle; cell fate; chromatin features; epiblast-like cells; epigenetics; formative; genomics; histone modifications; initiation zones; machine learning; naive; pluripotency; predictive modeling; replication origins; replication timing; transcription
    DOI:  https://doi.org/10.1016/j.celrep.2025.115272
  7. Nature. 2025 Feb 05.
    RUNX2 promotes fibrosis via an alveolar-to-pathological fibroblast transition.
    Yinshan Fang, Sanny S W Chung, Le Xu, Chenyi Xue, Xue Liu, Dianhua Jiang, Rongbo Li, Yohei Korogi, Ke Yuan, Anjali Saqi, Hanina Hibshoosh, Yuefeng Huang, Chyuan-Sheng Lin, Tatsuya Tsukui, Dean Sheppard, Xin Sun, Jianwen Que.
      A hallmark of pulmonary fibrosis is the aberrant activation of lung fibroblasts into pathological fibroblasts that produce excessive extracellular matrix1-3. Thus, the identification of key regulators that promote the generation of pathological fibroblasts can inform the development of effective countermeasures against disease progression. Here we use two mouse models of pulmonary fibrosis to show that LEPR+ fibroblasts that arise during alveologenesis include SCUBE2+ alveolar fibroblasts as a major constituent. These alveolar fibroblasts in turn contribute substantially to CTHRC1+POSTN+ pathological fibroblasts. Genetic ablation of POSTN+ pathological fibroblasts attenuates fibrosis. Comprehensive analyses of scRNA-seq and scATAC-seq data reveal that RUNX2 is a key regulator of the expression of fibrotic genes. Consistently, conditional deletion of Runx2 with LeprcreERT2 or Scube2creERT2 reduces the generation of pathological fibroblasts, extracellular matrix deposition and pulmonary fibrosis. Therefore, LEPR+ cells that include SCUBE2+ alveolar fibroblasts are a key source of pathological fibroblasts, and targeting Runx2 provides a potential treatment option for pulmonary fibrosis.
    DOI:  https://doi.org/10.1038/s41586-024-08542-2
  8. Dev Cell. 2025 Feb 04. pii: S1534-5807(25)00032-2. [Epub ahead of print]
    Liquid-like condensates that bind actin promote assembly and bundling of actin filaments.
    Caleb Walker, Aravind Chandrasekaran, Daniel Mansour, Kristin Graham, Andrea Torres, Liping Wang, Eileen M Lafer, Padmini Rangamani, Jeanne C Stachowiak.
      Biomolecular condensates perform diverse physiological functions. Previous work showed that VASP, a processive actin polymerase, forms condensates that assemble and bundle actin. Here, we show that this behavior does not require proteins with specific polymerase activity. Specifically, condensates composed of Lamellipodin, a protein that binds actin but is not an actin polymerase, were also capable of assembling actin filaments. To probe the minimum requirements for condensate-mediated actin bundling, we developed an agent-based computational model. Guided by its predictions, we hypothesized that any condensate-forming protein that binds filamentous actin could bundle filaments through multivalent crosslinking. To test this, we added a filamentous-actin-binding motif to Eps15, a condensate-forming protein that does not normally bind actin. The resulting chimera formed condensates that facilitated efficient assembly and bundling of actin filaments. Collectively, these findings broaden the family of proteins that could organize cytoskeletal filaments to include any filamentous-actin-binding protein that participates in protein condensation.
    Keywords:  Lamellipodin; VASP; actin cytoskeleton; agent-based modeling; biomolecular condensates; multivalent interactions; protein phase separation
    DOI:  https://doi.org/10.1016/j.devcel.2025.01.012
  9. Cell. 2025 Jan 23. pii: S0092-8674(25)00045-5. [Epub ahead of print]
    Long-term imaging of individual ribosomes reveals ribosome cooperativity in mRNA translation.
    Maximilian F Madern, Sora Yang, Olivier Witteveen, Hendrika A Segeren, Marianne Bauer, Marvin E Tanenbaum.
      The genetic information stored in mRNAs is decoded by ribosomes during mRNA translation. mRNAs are typically translated by multiple ribosomes simultaneously, but it is unclear whether and how the activity of different ribosomes on an mRNA is coordinated. Here, we develop an imaging approach based on stopless-ORF circular RNAs (socRNAs) to monitor translation of individual ribosomes in either monosomes or polysomes with very high resolution. Using experiments and simulations, we find that translating ribosomes frequently undergo transient collisions. However, unlike persistent collisions, such transient collisions escape detection by cellular quality control pathways. Rather, transient ribosome collisions promote productive translation by reducing ribosome pausing on problematic sequences, a process we term ribosome cooperativity. Ribosome cooperativity also reduces recycling of ribosomes by quality control pathways, thus enhancing processive translation. Together, our single-ribosome imaging approach reveals that ribosomes cooperate during translation to ensure fast and efficient translation.
    Keywords:  circRNAs; ribosome collision; single-molecule imaging; translation
    DOI:  https://doi.org/10.1016/j.cell.2025.01.016
  10. Dev Cell. 2025 Feb 03. pii: S1534-5807(24)00779-2. [Epub ahead of print]60(3): 337-339
    Autophagy-dependent changes in alternative splicing bias translation toward inflammation in senescent cells.
    Anson Ming Yan Lee, Anne Schreiber.
      Despite limited translational capacity, senescent cells trigger inflammation by upregulating the translation and secretion of proinflammatory factors. In this issue of Developmental Cell, Kim et al. identify that altered autophagy and SFPQ-dependent EIF4H splicing during senescence redirects translation to promote inflammation, informing therapeutic strategies for cancer and other age-related diseases.
    DOI:  https://doi.org/10.1016/j.devcel.2024.12.040
  11. Sci Adv. 2025 Feb 07. 11(6): eadq9549
    Centrioles generate two scaffolds with distinct biophysical properties to build mitotic centrosomes.
    Siu-Shing Wong, Joao M Monteiro, Chia-Chun Chang, Min Peng, Nada Mohamad, Thomas L Steinacker, Bocheng Xiao, Saroj Saurya, Alan Wainman, Jordan W Raff.
      Mitotic centrosomes assemble when centrioles recruit large amounts of pericentriolar material (PCM) around themselves. The PCM comprises hundreds of proteins, and there is much debate about its physical nature. Here, we show that Drosophila Spd-2 (human CEP192) fluxes out from centrioles, recruiting Polo and Aurora A kinases to catalyze the assembly of two distinct mitotic-PCM scaffolds: a Polo-dependent Cnn scaffold, and an Aurora A-dependent TACC scaffold, which exhibit solid- and liquid-like behaviors, respectively. Both scaffolds can independently recruit PCM proteins, but both are required for proper centrosome assembly, with the Cnn scaffold providing mechanical strength, and the TACC scaffold concentrating centriole and centrosome proteins. Recruiting Spd-2 to synthetic beads injected into early embryos reconstitutes key aspects of mitotic centrosome assembly on the bead surface, and this depends on Spd-2's ability to recruit Polo and Aurora A. Thus, Spd-2 orchestrates the assembly of two scaffolds, with distinct biophysical properties, that cooperate to build mitotic centrosomes in flies.
    DOI:  https://doi.org/10.1126/sciadv.adq9549
  12. Genes Dev. 2025 Feb 04.
    The double life of mammalian DNA replication origins.
    Olivier Hyrien, Guillaume Guilbaud, Torsten Krude.
      Mammalian DNA replication origins have been historically difficult to identify and their determinants are still unresolved. Here, we first review methods developed over the last decades to map replication initiation sites either directly via initiation intermediates or indirectly via determining replication fork directionality profiles. We also discuss the factors that may specify these sites as replication initiation sites. Second, we address the controversy that has emerged from these results over whether origins are narrowly defined and localized to specific sites or are more dispersed and organized into broad zones. Ample evidence in favor of both scenarios currently creates an impression of unresolved confusion in the field. We attempt to formulate a synthesis of both models and to reconcile discrepant findings. It is evident that not only one approach is sufficient in isolation but that the combination of several is instrumental toward understanding initiation sites in mammalian genomes. We argue that an aggregation of several individual and often inefficient initiation sites into larger initiation zones and the existence of efficient unidirectional initiation sites and fork stalling at the borders of initiation zones can reconcile the different observations.
    Keywords:  epigenetics and chromatin modification; genome organization; replication fork direction; replication origin; replication timing; replication–transcription interactions
    DOI:  https://doi.org/10.1101/gad.352227.124
  13. Nat Commun. 2025 Feb 03. 16(1): 1292
    Cardiac repair using regenerating neonatal heart tissue-derived extracellular vesicles.
    Hanjing Li, Yining Liu, Yuqing Lin, Sijia Li, Chenlu Liu, Ao Cai, Wei Li, Wanyu Zhang, Xinlu Gao, Zhongyu Ren, Haoyu Ji, Yang Yu, Xiuxiu Wang, Wenya Ma, Ning Wang, Dan Zhao, Tianlong Li, Yu Liu, Benzhi Cai.
      Neonatal mammalian hearts are capable of regenerating by inducing cardiomyocyte proliferation after injury. However, this regenerative capability in adult mammalian hearts almost disappears. Extracellular vesicles (EVs) have been shown to play vital cardioprotective roles in heart repair. Here, we report that EVs from regenerating neonatal heart tissues, after apical resection surgery (AR-Neo-EVs), exhibit stronger pro-proliferative, anti-apoptotic, and pro-angiogenesis activities than EVs from neonatal mouse cardiac tissues (Neo-EVs), effects which are absent in adult mouse heart-derived EVs (Adu-EVs). Proteomic analysis reveals the expression of Wdr75 protein, a regulator of p53, is higher in AR-Neo-EVs than in Neo-EVs. It is shown the regenerative potential of AR-Neo-EVs is abrogated when Wdr75 is knocked down. We further show that delivery of AR-Neo-EVs by sodium alginate hydrogel microspheres is an effective treatment in myocardial infraction. This work shows the potential of using EVs from regenerating tissue to trigger protective and regenerative mechanisms.
    DOI:  https://doi.org/10.1038/s41467-025-56384-x
  14. Nat Cell Biol. 2025 Feb 07.
    A quantitative ultrastructural timeline of nuclear autophagy reveals a role for dynamin-like protein 1 at the nuclear envelope.
    Philip J Mannino, Andrew Perun, Ivan V Surovtsev, Nicholas R Ader, Lin Shao, Elisa C Rodriguez, Thomas J Melia, Megan C King, C Patrick Lusk.
      Autophagic mechanisms that maintain nuclear envelope homoeostasis are bulwarks to ageing and disease. Here we define a quantitative and ultrastructural timeline of nuclear macroautophagy (nucleophagy) in yeast by leveraging four-dimensional lattice light sheet microscopy and correlative light and electron tomography. Nucleophagy begins with a rapid accumulation of the selective autophagy receptor Atg39 at the nuclear envelope and finishes in ~300 s with Atg39-cargo delivery to the vacuole. Although there are several routes to the vacuole, at least one pathway incorporates two consecutive membrane fission steps: inner nuclear membrane (INM) fission to generate an INM-derived vesicle in the perinuclear space and outer nuclear membrane fission to liberate a double-membraned vesicle to the cytosol. Outer nuclear membrane fission occurs independently of phagophore engagement and instead relies surprisingly on dynamin-like protein 1 (Dnm1), which is recruited to sites of Atg39 accumulation by Atg11. Loss of Dnm1 compromises nucleophagic flux by stalling nucleophagy after INM fission. Our findings reveal how nuclear and INM cargo are removed from an intact nucleus without compromising its integrity, achieved in part by a non-canonical role for Dnm1 in nuclear envelope remodelling.
    DOI:  https://doi.org/10.1038/s41556-025-01612-1
  15. PLoS Genet. 2025 Feb 06. 21(2): e1011586
    The transmembrane protein Syndecan is required for stem cell survival and maintenance of their nuclear properties.
    Buffy L Eldridge-Thomas, Jerome G Bohere, Chantal Roubinet, Alexandre Barthelemy, Tamsin J Samuels, Felipe Karam Teixeira, Golnar Kolahgar.
      Tissue maintenance is underpinned by resident stem cells whose activity is modulated by microenvironmental cues. Using Drosophila as a simple model to identify regulators of stem cell behaviour and survival in vivo, we have identified novel connections between the conserved transmembrane proteoglycan Syndecan, nuclear properties and stem cell function. In the Drosophila midgut, Syndecan depletion in intestinal stem cells results in their loss from the tissue, impairing tissue renewal. At the cellular level, Syndecan depletion alters cell and nuclear shape, and causes nuclear lamina invaginations and DNA damage. In a second tissue, the developing Drosophila brain, live imaging revealed that Syndecan depletion in neural stem cells results in nuclear envelope remodelling defects which arise upon cell division. Our findings reveal a new role for Syndecan in the maintenance of nuclear properties in diverse stem cell types.
    DOI:  https://doi.org/10.1371/journal.pgen.1011586
  16. Cell. 2025 Jan 10. pii: S0092-8674(24)01420-X. [Epub ahead of print]
    Rhodoquinone carries electrons in the mammalian electron transport chain.
    Jonathan Valeros, Madison Jerome, Tenzin Tseyang, Paula Vo, Thang Do, Diana Fajardo Palomino, Nils Grotehans, Manisha Kunala, Alexandra E Jerrett, Nicolai R Hathiramani, Michael Mireku, Rayna Y Magesh, Batuhan Yenilmez, Paul C Rosen, Jessica L Mann, Jacob W Myers, Tenzin Kunchok, Tanner L Manning, Lily N Boercker, Paige E Carr, Muhammad Bin Munim, Caroline A Lewis, David M Sabatini, Mark Kelly, Jun Xie, Michael P Czech, Guangping Gao, Jennifer N Shepherd, Amy K Walker, Hahn Kim, Emma V Watson, Jessica B Spinelli.
      Ubiquinone (UQ), the only known electron carrier in the mammalian electron transport chain (ETC), preferentially delivers electrons to the terminal electron acceptor oxygen (O2). In hypoxia, ubiquinol (UQH2) diverts these electrons onto fumarate instead. Here, we identify rhodoquinone (RQ), an electron carrier detected in mitochondria purified from certain mouse and human tissues that preferentially delivers electrons to fumarate through the reversal of succinate dehydrogenase, independent of environmental O2 levels. The RQ/fumarate ETC is strictly present in vivo and is undetectable in cultured mammalian cells. Using genetic and pharmacologic tools that reprogram the ETC from the UQ/O2 to the RQ/fumarate pathway, we establish that these distinct ETCs support unique programs of mitochondrial function and that RQ confers protection upon hypoxia exposure in vitro and in vivo. Thus, in discovering the presence of RQ in mammals, we unveil a tractable therapeutic strategy that exploits flexibility in the ETC to ameliorate hypoxia-related conditions.
    Keywords:  electron transport chain; hypoxia; ischemia; metabolism; mitochondria; rhodoquinone
    DOI:  https://doi.org/10.1016/j.cell.2024.12.007
  17. Nat Commun. 2025 Feb 06. 16(1): 1414
    Moesin integrates cortical and lamellar actin networks during Drosophila macrophage migration.
    Besaiz J Sánchez-Sánchez, Stefania Marcotti, David Salvador-Garcia, María-Del-Carmen Díaz-de-la-Loza, Mubarik Burki, Andrew J Davidson, Will Wood, Brian M Stramer.
      Cells are thought to adopt mechanistically distinct migration modes depending on cell-type and environmental factors. These modes are assumed to be driven by mutually exclusive actin cytoskeletal organizations, which are either lamellar (flat, branched network) or cortical (crosslinked to the plasma membrane). Here we exploit Drosophila macrophage (hemocyte) developmental dispersal to reveal that these cells maintain both a lamellar actin network at their cell front and a cortical actin network at the rear. Loss of classical actin cortex regulators, such as Moesin, perturb hemocyte morphology and cell migration. Furthermore, cortical and lamellipodial actin networks are interregulated. Upon phosphorylation and binding to the plasma membrane, Moesin is advected to the rear by lamellar actin flow. Simultaneously, the cortical actin network feeds back on the lamella to help regulate actin flow speed and leading-edge dynamics. These data reveal that hemocyte motility requires both lamellipodial and cortical actin architectures in homeostatic equilibrium.
    DOI:  https://doi.org/10.1038/s41467-024-55510-5
  18. bioRxiv. 2025 Jan 23. pii: 2025.01.23.634576. [Epub ahead of print]
    Decaying and expanding Erk gradients process memory of skeletal size during zebrafish fin regeneration.
    Ashley Rich, Ziqi Lu, Alessandro De Simone, Lucas Garcia, Jacqueline Janssen, Kazunori Ando, Jianhong Ou, Massimo Vergassola, Kenneth D Poss, Stefano Di Talia.
      Regeneration of an amputated salamander limb or fish fin restores pre-injury size and structure, illustrating the phenomenon of positional memory. Although appreciated for centuries, the identity of position-dependent cues and how they control tissue growth are not resolved. Here, we quantify Erk signaling events in whole populations of osteoblasts during zebrafish fin regeneration. We find that osteoblast Erk activity is dependent on Fgf receptor signaling and organized into millimeter-long gradients that extend from the distal tip to the amputation site. Erk activity scales with the amount of tissue amputated, predicts the likelihood of osteoblast cycling, and predicts the size of regenerated skeletal structures. Mathematical modeling suggests gradients are established by the transient deposition of long-lived ligands that are transported by tissue growth. This concept is supported by the observed scaling of expression of the essential epidermal ligand fgf20a with extents of amputation. Our work provides evidence that localized, scaled expression of pro-regenerative ligands instructs long-range signaling and cycling to control skeletal size in regenerating appendages.
    DOI:  https://doi.org/10.1101/2025.01.23.634576
  19. Nat Commun. 2025 Feb 05. 16(1): 1376
    UV-induced reorganization of 3D genome mediates DNA damage response.
    Veysel Oğulcan Kaya, Ogün Adebali.
      While it is well-established that UV radiation threatens genomic integrity, the precise mechanisms by which cells orchestrate DNA damage response and repair within the context of 3D genome architecture remain unclear. Here, we address this gap by investigating the UV-induced reorganization of the 3D genome and its critical role in mediating damage response. Employing temporal maps of contact matrices and transcriptional profiles, we illustrate the immediate and holistic changes in genome architecture post-irradiation, emphasizing the significance of this reconfiguration for effective DNA repair processes. We demonstrate that UV radiation triggers a comprehensive restructuring of the 3D genome organization at all levels, including loops, topologically associating domains and compartments. Through the analysis of DNA damage and excision repair maps, we uncover a correlation between genome folding, gene regulation, damage formation probability, and repair efficacy. We show that adaptive reorganization of the 3D genome is a key mediator of the damage response, providing new insights into the complex interplay of genomic structure and cellular defense mechanisms against UV-induced damage, thereby advancing our understanding of cellular resilience.
    DOI:  https://doi.org/10.1038/s41467-024-55724-7
  20. bioRxiv. 2025 Jan 23. pii: 2025.01.22.634318. [Epub ahead of print]
    Convergent flow-mediated mesenchymal force drives embryonic foregut constriction and splitting.
    Rui Yan, Ludwig A Hoffmann, Panagiotis Oikonomou, Deng Li, ChangHee Lee, Hasreet Gill, Alessandro Mongera, Nandan L Nerurkar, L Mahadevan, Clifford J Tabin.
      The transformation of a two-dimensional epithelial sheet into various three-dimensional structures is a critical process in generating the diversity of animal forms. Previous studies of epithelial folding have revealed diverse mechanisms driven by epithelium-intrinsic or -extrinsic forces. Yet little is known about the biomechanical basis of epithelial splitting, which involves extreme folding and eventually a topological transition breaking the epithelial tube. Here, we leverage tracheal-esophageal separation (TES), a critical and highly conserved morphogenetic event during tetrapod embryogenesis, as a model system for interrogating epithelial tube splitting both in vivo and ex vivo. Comparing TES in chick and mouse embryos, we identified an evolutionarily conserved, compressive force exerted by the mesenchyme surrounding the epithelium, as being necessary to drive epithelial constriction and splitting. The compressive force is mediated by localized convergent flow of mesenchymal cells towards the epithelium. We further found that Sonic Hedgehog (SHH) secreted by the epithelium functions as an attractive cue for mesenchymal cells. Removal of the mesenchyme, inhibition of cell migration, or loss of SHH signaling all abrogate TES, which can be rescued by externally applied pressure. These results unveil the biomechanical basis of epithelial splitting and suggest a mesenchymal origin of tracheal-esophageal birth defects.
    DOI:  https://doi.org/10.1101/2025.01.22.634318
  21. Cell Metab. 2025 Jan 29. pii: S1550-4131(24)00491-1. [Epub ahead of print]
    Lactate homeostasis is maintained through regulation of glycolysis and lipolysis.
    Won Dong Lee, Daniel R Weilandt, Lingfan Liang, Michael R MacArthur, Natasha Jaiswal, Olivia Ong, Charlotte G Mann, Qingwei Chu, Craig J Hunter, Rolf-Peter Ryseck, Wenyun Lu, Anna M Oschmann, Alexis J Cowan, Tara A TeSlaa, Caroline R Bartman, Cholsoon Jang, Joseph A Baur, Paul M Titchenell, Joshua D Rabinowitz.
      Lactate is among the highest flux circulating metabolites. It is made by glycolysis and cleared by both tricarboxylic acid (TCA) cycle oxidation and gluconeogenesis. Severe lactate elevations are life-threatening, and modest elevations predict future diabetes. How lactate homeostasis is maintained, however, remains poorly understood. Here, we identify, in mice, homeostatic circuits regulating lactate production and consumption. Insulin induces lactate production by upregulating glycolysis. We find that hyperlactatemia inhibits insulin-induced glycolysis, thereby suppressing excess lactate production. Unexpectedly, insulin also promotes lactate TCA cycle oxidation. The mechanism involves lowering circulating fatty acids, which compete with lactate for mitochondrial oxidation. Similarly, lactate can promote its own consumption by lowering circulating fatty acids via the adipocyte-expressed G-protein-coupled receptor hydroxycarboxylic acid receptor 1 (HCAR1). Quantitative modeling suggests that these mechanisms suffice to produce lactate homeostasis, with robustness to noise and perturbation of individual regulatory mechanisms. Thus, through regulation of glycolysis and lipolysis, lactate homeostasis is maintained.
    Keywords:  HCAR1 signaling; TCA cycle; competitive catabolism; diabetes mellitus; insulin resistance; insulin signaling; lactate metabolism; metabolic flux; metabolic homeostasis; quantitative modeling
    DOI:  https://doi.org/10.1016/j.cmet.2024.12.009
  22. Proc Natl Acad Sci U S A. 2025 Feb 11. 122(6): e2414860122
    Bilateral cellular flows display asymmetry prior to left-right organizer formation in amniote gastrulation.
    Rieko Asai, Shubham Sinha, Vivek N Prakash, Takashi Mikawa.
      A bilateral body plan is predominant throughout the animal kingdom. Bilaterality of amniote embryos becomes recognizable as midline morphogenesis begins at gastrulation, bisecting an embryonic field into the left and right sides, and left-right (LR) asymmetry patterning follows. While a series of laterality genes expressed after the LR compartmentalization has been extensively studied, the laterality patterning prior to and at the initiation of midline morphogenesis has remained unclear. Here, through a biophysical quantification in a high spatial and temporal resolution, applied to a chick model system, we show that a large-scale bilateral counterrotating cellular flow, termed "polonaise movements", display LR asymmetries in early gastrulation. This cell movement starts prior to the formation of the primitive streak (PS) (the earliest midline structure) and the subsequent appearance of Hensen's node (the LR organizer). The cellular flow speed and vorticity unravel the location and timing of the LR asymmetries. The bilateral flows displayed a Right dominance after 6 h since the start of cell movements. Mitotic arrest that diminishes PS formation resulted in changes in the bilateral flow pattern, but the Right dominance persisted. Our data indicate that the LR asymmetry in amniote gastrula becomes detectable earlier than suggested by current models, which assume that the asymmetric regulation of the laterality signals at the node leads to the LR patterning. More broadly, our results suggest that physical processes can play an unexpected but significant role in influencing LR laterality during embryonic development.
    Keywords:  L-R asymmetry; bilateral cellular flows; biophysics; gastrulation; particle image velocimetry
    DOI:  https://doi.org/10.1073/pnas.2414860122
  23. Science. 2025 Feb 06. eadf2034
    Retrograde mitochondrial signaling governs the identity and maturity of metabolic tissues.
    Emily M Walker, Gemma L Pearson, Nathan Lawlor, Ava M Stendahl, Anne Lietzke, Vaibhav Sidarala, Jie Zhu, Tracy Stromer, Emma C Reck, Jin Li, Elena Levi-D'Ancona, Mabelle B Pasmooij, Dre L Hubers, Aaron Renberg, Kawthar Mohamed, Vishal S Parekh, Irina X Zhang, Benjamin Thompson, Deqiang Zhang, Sarah A Ware, Leena Haataja, Nathan Qi, Stephen C J Parker, Peter Arvan, Lei Yin, Brett A Kaufman, Leslie S Satin, Lori Sussel, Michael L Stitzel, Scott A Soleimanpour.
      Mitochondrial damage is a hallmark of metabolic diseases, including diabetes, yet the consequences of compromised mitochondria in metabolic tissues are often unclear. Here, we report that dysfunctional mitochondrial quality control engages a retrograde (mitonuclear) signaling program that impairs cellular identity and maturity in β-cells, hepatocytes, and brown adipocytes. Targeted deficiency throughout the mitochondrial quality control pathway, including genome integrity, dynamics, or turnover, impaired the oxidative phosphorylation machinery, activating the mitochondrial integrated stress response, eliciting chromatin remodeling, and promoting cellular immaturity rather than apoptosis to yield metabolic dysfunction. Indeed, pharmacologic blockade of the integrated stress response in vivo restored β-cell identity following loss of mitochondrial quality control. Targeting mitochondrial retrograde signaling may therefore be promising in the treatment or prevention of metabolic disorders.
    DOI:  https://doi.org/10.1126/science.adf2034
  24. J Clin Invest. 2025 Feb 04. pii: e179137. [Epub ahead of print]
    Estrogen receptor alpha ablation reverses muscle fibrosis and inguinal hernias.
    Tanvi Potluri, Tianming You, Ping Yin, John S Coon V, Jonah J Stulberg, Yang Dai, David J Escobar, Richard L Lieber, Hong Zhao, Serdar E Bulun.
      Fibrosis of the lower abdominal muscle (LAM) contributes to muscle weakening and inguinal hernia formation, an ailment affecting a noteworthy fifty percent of men by age 75, necessitating surgical correction as the singular therapy. Despite its prevalence, the mechanisms driving LAM fibrosis and hernia development remain poorly understood. Utilizing a humanized mouse model that replicates elevated skeletal muscle tissue estrogen concentrations akin to aging men, we identified estrogen receptor alpha (ESR1) as a key driver of LAM fibroblast proliferation, extracellular matrix deposition, and hernia formation. Fibroblast-specific ESR1 ablation effectively prevented muscle fibrosis and herniation, while pharmacological ESR1 inhibition with fulvestrant reversed hernias and restored normal muscle architecture. Multiomic analyses on in vitro LAM fibroblasts unveiled an estrogen/ESR1-mediated activation of a distinct profibrotic cistrome and gene expression signature, concordant with observations in inguinal hernia tissues in human males. Our findings hold significant promise for prospective medical interventions targeting fibrotic conditions and presenting non-surgical avenues for addressing inguinal hernias.
    Keywords:  Cell biology; Fibrosis; Muscle biology; Reproductive biology; Sex hormones; Skeletal muscle
    DOI:  https://doi.org/10.1172/JCI179137
  25. Nat Aging. 2025 Feb 05.
    Multi-omic profiling of sarcopenia identifies disrupted branched-chain amino acid catabolism as a causal mechanism and therapeutic target.
    Xinrong Zuo, Rui Zhao, Minming Wu, Yanyan Wang, Shisheng Wang, Kuo Tang, Yang Wang, Jie Chen, Xiaoxiang Yan, Yang Cao, Tao Li.
      Sarcopenia is a geriatric disorder characterized by a gradual loss of muscle mass and function. Despite its prevalence, the underlying mechanisms remain unclear, and there are currently no approved treatments. In this study, we conducted a comprehensive analysis of the molecular and metabolic signatures of skeletal muscle in patients with impaired muscle strength and sarcopenia using multi-omics approaches. Across discovery and replication cohorts, we found that disrupted branched-chain amino acid (BCAA) catabolism is a prominent pathway in sarcopenia, which leads to BCAA accumulation and decreased muscle health. Machine learning analysis further supported the causal role of BCAA catabolic dysfunction in sarcopenia. Using mouse models, we validated that defective BCAA catabolism impairs muscle mass and strength through dysregulated mTOR signaling, and enhancing BCAA catabolism by BT2 protects against sarcopenia in aged mice and in mice lacking Ppm1k, a positive regulator of BCAA catabolism in skeletal muscle. This study highlights improving BCAA catabolism as a potential treatment of sarcopenia.
    DOI:  https://doi.org/10.1038/s43587-024-00797-8
  26. Nat Genet. 2025 Feb 03.
    Spatial transcriptomics identifies molecular niche dysregulation associated with distal lung remodeling in pulmonary fibrosis.
    Annika Vannan, Ruqian Lyu, Arianna L Williams, Nicholas M Negretti, Evan D Mee, Joseph Hirsh, Samuel Hirsh, Niran Hadad, David S Nichols, Carla L Calvi, Chase J Taylor, Vasiliy V Polosukhin, Ana P M Serezani, A Scott McCall, Jason J Gokey, Heejung Shim, Lorraine B Ware, Matthew J Bacchetta, Ciara M Shaver, Timothy S Blackwell, Rajat Walia, Jennifer M S Sucre, Jonathan A Kropski, Davis J McCarthy, Nicholas E Banovich.
      Large-scale changes in the structure and cellular makeup of the distal lung are a hallmark of pulmonary fibrosis (PF), but the spatial contexts that contribute to disease pathogenesis have remained uncertain. Using image-based spatial transcriptomics, we analyzed the gene expression of 1.6 million cells from 35 unique lungs. Through complementary cell-based and innovative cell-agnostic analyses, we characterized the localization of PF-emergent cell types, established the cellular and molecular basis of classical PF histopathologic features and identified a diversity of distinct molecularly defined spatial niches in control and PF lungs. Using machine learning and trajectory analysis to segment and rank airspaces on a gradient of remodeling severity, we identified compositional and molecular changes associated with progressive distal lung pathology, beginning with alveolar epithelial dysregulation and culminating with changes in macrophage polarization. Together, these results provide a unique, spatially resolved view of PF and establish methods that could be applied to other spatial transcriptomic studies.
    DOI:  https://doi.org/10.1038/s41588-025-02080-x
  27. PLoS Genet. 2025 Feb 04. 21(2): e1011576
    Aneuploidy of specific chromosomes is beneficial to cells lacking spindle checkpoint protein Bub3.
    Pallavi Gadgil, Olivia Ballew, Timothy J Sullivan, Soni Lacefield.
      Aneuploidy typically poses challenges for cell survival and growth. However, recent studies have identified exceptions where aneuploidy is beneficial for cells with mutations in certain regulatory genes. Our research reveals that cells lacking the spindle checkpoint gene BUB3 exhibit aneuploidy of select chromosomes. While the spindle checkpoint is not essential in budding yeast, the loss of BUB3 and BUB1 increases the probability of chromosome missegregation compared to wildtype cells. Contrary to the prevailing assumption that the aneuploid cells would be outcompeted due to growth defects, our findings demonstrate that bub3Δ cells consistently maintained aneuploidy of specific chromosomes over many generations. We investigated whether the persistence of these additional chromosomes in bub3Δ cells resulted from the beneficial elevated expression of certain genes, or mere tolerance. We identified several genes involved in chromosome segregation and cell cycle regulation that confer an advantage to Bub3-depleted cells. Overall, our results suggest that the gain of specific genes through aneuploidy may provide a survival advantage to strains with poor chromosome segregation fidelity.
    DOI:  https://doi.org/10.1371/journal.pgen.1011576
  28. Nature. 2025 Feb 05.
    Synthetic lethality of mRNA quality control complexes in cancer.
    Vivian Prindle, Adam E Richardson, Kimberly R Sher, Sarah Kongpachith, Kaitlin Kentala, Sakina Petiwala, Dong Cheng, Deborah Widomski, Phuong Le, Maricel Torrent, Anlu Chen, Stephen Walker, Marianne B Palczewski, Diya Mitra, Vlasios Manaves, Xu Shi, Charles Lu, Stephanie Sandoval, Zoltan Dezso, F Gregory Buchanan, Daniel Verduzco, Brian Bierie, Jonathan A Meulbroek, William N Pappano, Joshua P Plotnik.
      Synthetic lethality exploits the genetic vulnerabilities of cancer cells to enable a targeted, precision approach to treat cancer1. Over the past 15 years, synthetic lethal cancer target discovery approaches have led to clinical successes of PARP inhibitors2 and ushered several next-generation therapeutic targets such as WRN3, USP14, PKMYT15, POLQ6 and PRMT57 into the clinic. Here we identify, in human cancer, a novel synthetic lethal interaction between the PELO-HBS1L and SKI complexes of the mRNA quality control pathway. In distinct genetic contexts, including 9p21.3-deleted and high microsatellite instability (MSI-H) tumours, we found that phenotypically destabilized SKI complex leads to dependence on the PELO-HBS1L ribosomal rescue complex. PELO-HBS1L and SKI complex synthetic lethality alters the normal cell cycle and drives the unfolded protein response through the activation of IRE1, as well as robust tumour growth inhibition. Our results indicate that PELO and HBS1L represent novel therapeutic targets whose dependence converges upon SKI complex destabilization, a common phenotypic biomarker in diverse genetic contexts representing a significant population of patients with cancer.
    DOI:  https://doi.org/10.1038/s41586-024-08398-6
  29. Nat Commun. 2025 Feb 06. 16(1): 1406
    ROS-induced cytosolic release of mitochondrial PGAM5 promotes colorectal cancer progression by interacting with MST3.
    Shiyang Wang, Xi Wu, Wenxin Bi, Jiuzhi Xu, Liyuan Hou, Guilin Li, Yuwei Pan, Hanfu Zhang, Mengzhen Li, Sujuan Du, Mingxin Zhang, Di Liu, Shuiling Jin, Xiaojing Shi, Yuhua Tian, Jianwei Shuai, Maksim V Plikus, Moshi Song, Zhaocai Zhou, Lu Yu, Cong Lv, Zhengquan Yu.
      Aberrant release of mitochondrial reactive oxygen species (mtROS) in response to cellular stress is well known for promoting cancer progression. However, precise molecular mechanism by which mtROS contribute to epithelial cancer progression remains only partially understood. Here, using colorectal cancer (CRC) models, we show that upon sensing excessive mtROS, phosphatase PGAM5, which normally localizes to the mitochondria, undergoes aberrant cleavage by presenilin-associated rhomboid-like protein (PARL), becoming released into the cytoplasm. Cytosolic PGAM5 then directly binds to and dephosphorylates MST3 kinase. This, in turn, prevents STK25-mediated LATS1/2 phosphorylation, leading to YAP activation and CRC progression. Importantly, depletion of MST3 reciprocally promotes accumulation of cytosolic PGAM5 by inducing mitochondrial damage. Taken together, these findings demonstrate how mtROS promotes CRC progression by activating YAP via a post-transcriptional positive feedback loop between PGAM5 and MST3, both of which can serve as potential targets for developing next-generation anti-colon cancer therapeutics.
    DOI:  https://doi.org/10.1038/s41467-025-56444-2
  30. Science. 2025 Feb 07. 387(6734): eadm9466
    Sequence-dependent activity and compartmentalization of foreign DNA in a eukaryotic nucleus.
    Léa Meneu, Christophe Chapard, Jacques Serizay, Alex Westbrook, Etienne Routhier, Myriam Ruault, Manon Perrot, Alexandros Minakakis, Fabien Girard, Amaury Bignaud, Antoine Even, Géraldine Gourgues, Domenico Libri, Carole Lartigue, Aurèle Piazza, Agnès Thierry, Angela Taddei, Frédéric Beckouët, Julien Mozziconacci, Romain Koszul.
      In eukaryotes, DNA-associated protein complexes coevolve with genomic sequences to orchestrate chromatin folding. We investigate the relationship between DNA sequence and the spontaneous loading and activity of chromatin components in the absence of coevolution. Using bacterial genomes integrated into Saccharomyces cerevisiae, which diverged from yeast more than 2 billion years ago, we show that nucleosomes, cohesins, and associated transcriptional machinery can lead to the formation of two different chromatin archetypes, one transcribed and the other silent, independently of heterochromatin formation. These two archetypes also form on eukaryotic exogenous sequences, depend on sequence composition, and can be predicted using neural networks trained on the native genome. They do not mix in the nucleus, leading to a bipartite nuclear compartmentalization, reminiscent of the organization of vertebrate nuclei.
    DOI:  https://doi.org/10.1126/science.adm9466
  31. Science. 2025 Feb 06. eadq2634
    Protein codes promote selective subcellular compartmentalization.
    Henry R Kilgore, Itamar Chinn, Peter G Mikhael, Ilan Mitnikov, Catherine Van Dongen, Guy Zylberberg, Lena Afeyan, Salman F Banani, Susana Wilson-Hawken, Tong Ihn Lee, Regina Barzilay, Richard A Young.
      Cells have evolved mechanisms to distribute ~10 billion protein molecules to subcellular compartments where diverse proteins involved in shared functions must assemble. Here, we demonstrate that proteins with shared functions share amino acid sequence codes that guide them to compartment destinations. A protein language model, ProtGPS, was developed that predicts with high performance the compartment localization of human proteins excluded from the training set. ProtGPS successfully guided generation of novel protein sequences that selectively assemble in the nucleolus. ProtGPS identified pathological mutations that change this code and lead to altered subcellular localization of proteins. Our results indicate that protein sequences contain not only a folding code, but also a previously unrecognized code governing their distribution to diverse subcellular compartments.
    DOI:  https://doi.org/10.1126/science.adq2634
  32. Signal Transduct Target Ther. 2025 Feb 07. 10(1): 36
    Mitochondrial heterogeneity: subpopulations with distinct metabolic activities.
    Fabian den Brave, Swadha Mishra, Thomas Becker.
      
    DOI:  https://doi.org/10.1038/s41392-025-02130-0
  33. Structure. 2025 Jan 24. pii: S0969-2126(25)00005-X. [Epub ahead of print]
    Septin assemblies promote the lipid organization of membranes.
    Fatima El Alaoui, Isabelle Al-Akiki, Sandy Ibanes, Sébastien Lyonnais, David Sanchez-Fuentes, Rudy Desgarceaux, Chantal Cazevieille, Marie-Pierre Blanchard, Andrea Parmeggiani, Adrian Carretero-Genevrier, Simonetta Piatti, Laura Picas.
      Cytoskeletal-mediated membrane compartmentalization is essential to support cellular functions, from signaling to cell division, migration, or phagocytosis. Septins are cytoskeletal proteins that directly interact with membranes, acting as scaffolds to recruit proteins to cellular locations and as structural diffusion barriers. How septins interact with and remodel the lipid organization of membranes is unclear. Here, we combined minimal reconstituted systems and yeast cell imaging to study septin-mediated membrane organization. Our results show that at low concentrations membrane-diffusive septins self-assemble into sub-micrometric patches that co-exist with the septin collar at the division site. We found that patches are made of short septin filaments and that are able to modulate the lipid organization of membranes. Furthermore, we show that the polybasic domain of Cdc11 influences the membrane-organizing and curvature-sensing properties of septins. Collectively, our work provides understanding of the molecular mechanisms by which septins can support cellular functions intimately linked to membranes.
    Keywords:  budding yeast; lipid organization; membranes; septins
    DOI:  https://doi.org/10.1016/j.str.2025.01.005
  34. Nat Aging. 2025 Feb 05.
    Sex-specific and cell-type-specific changes in chaperone-mediated autophagy across tissues during aging.
    Rabia R Khawaja, Adrián Martín-Segura, Olaya Santiago-Fernández, Rebecca Sereda, Kristen Lindenau, Mericka McCabe, Adrián Macho-González, Maryam Jafari, Aurora Scrivo, Raquel Gomez-Sintes, Bhakti Chavda, Ana Rosa Saez-Ibanez, Inmaculada Tasset, Esperanza Arias, Xianhong Xie, Mimi Kim, Susmita Kaushik, Ana Maria Cuervo.
      Aging leads to progressive decline in organ and tissue integrity and function, partly due to loss of proteostasis and autophagy malfunctioning. A decrease with age in chaperone-mediated autophagy (CMA), a selective type of lysosomal degradation, has been reported in various organs and cells from rodents and humans. Disruption of CMA recapitulates features of aging, whereas activating CMA in mice protects against age-related diseases such as Alzheimer's, retinal degeneration and/or atherosclerosis. However, sex-specific and cell-type-specific differences in CMA with aging remain unexplored. Here, using CMA reporter mice and single-cell transcriptomic data, we report that most organs and cell types show CMA decline with age, with males exhibiting a greater decline with aging. Reduced CMA is often associated with fewer lysosomes competent for CMA. Transcriptional downregulation of CMA genes may further contribute to CMA decline, especially in males. These findings suggest that CMA differences may influence organ vulnerability to age-related degeneration.
    DOI:  https://doi.org/10.1038/s43587-024-00799-6
  35. Mol Cell. 2025 Jan 30. pii: S1097-2765(25)00042-5. [Epub ahead of print]
    SLFN11-mediated ribosome biogenesis impairment induces TP53-independent apoptosis.
    Akane Ogawa, Keiichi Izumikawa, Sota Tate, Sho Isoyama, Masaru Mori, Kohei Fujiwara, Soyoka Watanabe, Takayuki Ohga, Ukhyun Jo, Daiki Taniyama, Shojiro Kitajima, Soichiro Tanaka, Hiroshi Onji, Shun-Ichiro Kageyama, Gaku Yamamoto, Hitoshi Saito, Tomoko Yamamori Morita, Masayasu Okada, Manabu Natsumeda, Masami Nagahama, Junya Kobayashi, Akihiro Ohashi, Hiroyuki Sasanuma, Shigeki Higashiyama, Shingo Dan, Yves Pommier, Junko Murai.
      Impairment of ribosome biogenesis (RiBi) triggered by inhibition of ribosomal RNA (rRNA) synthesis and processing leads to various biological effects. We report that Schlafen 11 (SLFN11) induces TP53-independent apoptosis through RiBi impairment. Upon replication stress, SLFN11 inhibits rRNA synthesis with RNA polymerase I accumulation and increased chromatin accessibility in the ribosomal DNA (rDNA) genes. SLFN11-dependent RiBi impairment preferentially depletes short-lived proteins, particularly MCL1, leading to apoptosis in response to replication stress. SLFN11's Walker B motif (E669), DNA-binding site (K652), dephosphorylation site for single-strand DNA binding (S753), and RNase sites (E209/E214) are all required for the SLFN11-mediated RiBi impairment. Comparable effects were obtained with direct RNA polymerase I inhibitors and other RiBi inhibitory conditions regardless of SLFN11. These findings were extended across 34 diverse human cancer cell lines. Thus, we demonstrate that RiBi impairment is a robust inactivator of MCL1 and an additional proapoptotic mechanism by which SLFN11 sensitizes cancer cells to chemotherapeutic agents.
    Keywords:  DNA damage; TP53; apoptosis; cell cycle checkpoint; chromatin; rRNA; replication stress; ribosome biogenesis; stress response; topoisomerase inhibitor
    DOI:  https://doi.org/10.1016/j.molcel.2025.01.008
  36. Nat Biotechnol. 2025 Feb 04.
    Quantifying metabolites using structure-switching aptamers coupled to DNA sequencing.
    June H Tan, Andrew G Fraser.
      Here we report a method, smol-seq (small-molecule sequencing), using structure-switching aptamers (SSAs) and DNA sequencing to quantify metabolites. In smol-seq, each SSA detects a single target molecule and releases a unique DNA barcode on target binding. Sequencing the released barcodes can, thus, read out metabolite levels. We show that SSAs are highly specific and can be multiplexed to detect multiple targets in parallel, bringing the power of DNA sequencing to metabolomics.
    DOI:  https://doi.org/10.1038/s41587-025-02554-7
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