bims-ginsta Biomed News
on Genome instability
Issue of 2025–01–12
thirty-two papers selected by
Jinrong Hu, National University of Singapore
  1. Oversized cells activate global proteasome-mediated protein degradation to maintain cell size homeostasis.
  2. Chromosome mis-segregation triggers cell cycle arrest through a mechanosensitive nuclear envelope checkpoint.
  3. The nuclear matrix stabilizes primed-specific genes in human pluripotent stem cells.
  4. The mechanical state of pre-tumoral epithelia controls subsequent Drosophila tumor aggressiveness.
  5. Cell shape modulates mitotic spindle positioning forces via intracellular hydrodynamics.
  6. Spatially ordered zygotic genome activation fulfills embryo quality control.
  7. Satellite DNA shapes dictate pericentromere packaging in female meiosis.
  8. Mechanism of mammalian transcriptional repression by noncoding RNA.
  9. MDM2 functions as a timer reporting the length of mitosis.
  10. Mitochondria- and ER-associated actin are required for mitochondrial fusion.
  11. Scaling of quantitative cardiomyocyte properties in the left ventricle of different mammalian species.
  12. The cGAS-STING, p38 MAPK, and p53 pathways link genome instability to accelerated cellular senescence in ATM-deficient murine lung fibroblasts.
  13. eIF2α Phosphorylation-ATF4 Axis-Mediated Transcriptional Reprogramming Mitigates Mitochondrial Impairment During ER Stress.
  14. FAT1 alterations contribute to chromosomal instability in cancer cells.
  15. KLF5 loss sensitizes cells to ATR inhibition and is synthetic lethal with ARID1A deficiency.
  16. H3K36 methylation regulates cell plasticity and regeneration in the intestinal epithelium.
  17. Hypoxia-inducible factor 2 regulates alveolar regeneration after repetitive injury in three-dimensional cellular and in vivo models.
  18. RACK1 MARylation regulates translation and stress granules in ovarian cancer cells.
  19. Ectopic expression of DNMT3L in human trophoblast stem cells restores features of the placental methylome.
  20. Crypt density and recruited enhancers underlie intestinal tumour initiation.
  21. Capturing eukaryotic ribosome dynamics in situ at high resolution.
  22. A minimal vertex model explains how the amnioserosa avoids fluidization during Drosophila dorsal closure.
  23. Site-saturation mutagenesis of 500 human protein domains.
  24. Hormonally mediated mechanical remodelling of human haematopoietic stem cells enhances their bone-marrow engraftment.
  25. Nup107 contributes to the maternal to zygotic transition by preventing the premature nuclear export of pri-miRNA 427.
  26. Brain aging and rejuvenation at single-cell resolution.
  27. Phosphorylation of a nuclear condensate regulates cohesion and mRNA retention.
  28. Differential impacts of ribosomal protein haploinsufficiency on mitochondrial function.
  29. NAC regulates metabolism and cell fate in intestinal stem cells.
  30. The galactokinase enzyme of yeast senses metabolic flux to stabilize galactose pathway regulation.
  31. Phase separation of initiation hubs on cargo is a trigger switch for selective autophagy.
  32. Triacylglycerol mobilization underpins mitochondrial stress recovery.
  1. Elife. 2025 Jan 10. pii: e75393. [Epub ahead of print]14
    Oversized cells activate global proteasome-mediated protein degradation to maintain cell size homeostasis.
    Shixuan Liu, Ceryl Tan, Chloe Melo-Gavin, Miriam B Ginzberg, Ron Blutrich, Nish Patel, Michael Rape, Kevin G Mark, Ran Kafri.
      Proliferating animal cells maintain a stable size distribution over generations despite fluctuations in cell growth and division size. Previously, we showed that cell size control involves both cell size checkpoints, which delay cell cycle progression in small cells, and size-dependent regulation of mass accumulation rates (Ginzberg et al., 2018). While we previously identified the p38 MAPK pathway as a key regulator of the mammalian cell size checkpoint (S. Liu et al., 2018), the mechanism of size-dependent growth rate regulation has remained elusive. Here, we quantified global rates of protein synthesis and degradation in cells of varying sizes, both under unperturbed conditions and in response to perturbations that trigger size-dependent compensatory growth slowdown. We found that protein synthesis rates scale proportionally with cell size across cell cycle stages and experimental conditions. In contrast, oversized cells that undergo compensatory growth slowdown exhibit a superlinear increase in proteasome-mediated protein degradation, with accelerated protein turnover per unit mass, suggesting activation of the proteasomal degradation pathway. Both nascent and long-lived proteins contribute to the elevated protein degradation during compensatory growth slowdown, with long-lived proteins playing a crucial role at the G1/S transition. Notably, large G1/S cells exhibit particularly high efficiency in protein degradation, surpassing that of similarly sized or larger cells in S and G2, coinciding with the timing of the most stringent size control in animal cells. These results collectively suggest that oversized cells reduce their growth efficiency by activating global proteasome-mediated protein degradation to promote cell size homeostasis.
    Keywords:  cell biology; human
    DOI:  https://doi.org/10.7554/eLife.75393
  2. Nat Cell Biol. 2025 Jan 08.
    Chromosome mis-segregation triggers cell cycle arrest through a mechanosensitive nuclear envelope checkpoint.
    Solène Hervé, Andrea Scelfo, Gabriele Bersano Marchisio, Marine Grison, Kotryna Vaidžiulytė, Marie Dumont, Annapaola Angrisani, Adib Keikhosravi, Gianluca Pegoraro, Mathieu Deygas, Guilherme P F Nader, Anne-Sophie Macé, Matteo Gentili, Alice Williart, Nicolas Manel, Matthieu Piel, Yekaterina A Miroshnikova, Daniele Fachinetti.
      Errors during cell division lead to aneuploidy, which is associated with genomic instability and cell transformation. In response to aneuploidy, cells activate the tumour suppressor p53 to elicit a surveillance mechanism that halts proliferation and promotes senescence. The molecular sensors that trigger this checkpoint are unclear. Here, using a tunable system of chromosome mis-segregation, we show that mitotic errors trigger nuclear deformation, nuclear softening, and lamin and heterochromatin alterations, leading to rapid p53/p21 activation upon mitotic exit in response to changes in nuclear mechanics. We identify mTORC2 and ATR as nuclear deformation sensors upstream of p53/p21 activation. While triggering mitotic arrest, the chromosome mis-segregation-induced alterations of nuclear envelope mechanics provide a fitness advantage for aneuploid cells by promoting nuclear deformation resilience and enhancing pro-invasive capabilities. Collectively, this work identifies a nuclear mechanical checkpoint triggered by altered chromatin organization that probably plays a critical role in cellular transformation and cancer progression.
    DOI:  https://doi.org/10.1038/s41556-024-01565-x
  3. Nat Cell Biol. 2025 Jan 09.
    The nuclear matrix stabilizes primed-specific genes in human pluripotent stem cells.
    Gang Ma, Xiuling Fu, Lulu Zhou, Isaac A Babarinde, Liyang Shi, Wenting Yang, Jiao Chen, Zhen Xiao, Yu Qiao, Lisha Ma, Yuhao Ou, Yuhao Li, Chen Chang, Boping Deng, Ran Zhang, Li Sun, Guoqing Tong, Dongwei Li, Yiming Li, Andrew P Hutchins.
      The nuclear matrix, a proteinaceous gel composed of proteins and RNA, is an important nuclear structure that supports chromatin architecture, but its role in human pluripotent stem cells (hPSCs) has not been described. Here we show that by disrupting heterogeneous nuclear ribonucleoprotein U (HNRNPU) or the nuclear matrix protein, Matrin-3, primed hPSCs adopted features of the naive pluripotent state, including morphology and upregulation of naive-specific marker genes. We demonstrate that HNRNPU depletion leads to increased chromatin accessibility, reduced DNA contacts and increased nuclear size. Mechanistically, HNRNPU acts as a transcriptional co-factor that anchors promoters of primed-specific genes to the nuclear matrix with POLII to promote their expression and their RNA stability. Overall, HNRNPU promotes cell-type stability and when reduced promotes conversion to earlier embryonic states.
    DOI:  https://doi.org/10.1038/s41556-024-01595-5
  4. Dev Cell. 2024 Dec 30. pii: S1534-5807(24)00728-7. [Epub ahead of print]
    The mechanical state of pre-tumoral epithelia controls subsequent Drosophila tumor aggressiveness.
    Marianne Montemurro, Bruno Monier, Magali Suzanne.
      Tumors evolve through the acquisition of increasingly aggressive traits associated with dysplasia. This progression is accompanied by alterations in tumor mechanical properties, especially through extracellular matrix remodeling. However, the contribution of pre-tumoral tissue mechanics to tumor aggressiveness remains poorly known in vivo. Here, we show that adherens junction tension in pre-tumoral tissues dictates subsequent tumor evolution in Drosophila. Increased cell contractility, observed in aggressive tumors before any sign of tissue overgrowth, proved sufficient to trigger dysplasia in normally hyperplastic tumors. In addition, high contractility precedes any changes in cell polarity and contributes to tumor evolution through cell death induction, which favors cell-cell junction weakening. Overall, our results highlight the need to re-evaluate the roles of tumoral cell death and identify pre-tumoral cell mechanics as an unsuspected early marker and key trigger of tumor aggressiveness.
    Keywords:  Crumbs; Drosophila; JNK; Syx7; Yorkie; aPKC; apoptosis; epithelial-mesenchymal transition; myosin II; tumor mechanics
    DOI:  https://doi.org/10.1016/j.devcel.2024.12.006
  5. Curr Biol. 2024 Dec 28. pii: S0960-9822(24)01622-1. [Epub ahead of print]
    Cell shape modulates mitotic spindle positioning forces via intracellular hydrodynamics.
    Jing Xie, Javad Najafi, Aude Nommick, Luc Lederer, Jeremy Salle, Serge Dmitrieff, Benjamin Lacroix, Julien Dumont, Nicolas Minc.
      The regulation of mitotic spindle positioning and orientation is central to the morphogenesis of developing embryos and tissues.1,2,3,4,5 In many multicellular contexts, cell geometry has been shown to have a major influence on spindle positioning, with spindles that commonly align along the longest cell shape axis.6,7,8,9,10,11,12,13,14 To date, however, we still lack an understanding of how the nature and amplitude of intracellular forces that position, orient, or hold mitotic spindles depend on cell geometry. Here, we used in vivo magnetic tweezers to directly measure the forces that maintain the mitotic spindle in the center of sea urchin cells that adopt different shapes during early embryo development. We found that spindles are held by viscoelastic forces that progressively increase in amplitude as cells become more elongated during early development. By coupling direct cell shape manipulations in microfabricated chambers with in vivo force measurements, we establish how spindle-associated forces increase in dose dependence with cell shape anisotropy. Cytoplasm flow analysis and hydrodynamic simulations suggest that this geometry-dependent mechanical enhancement results from a stronger hydrodynamic coupling between the spindle and cell boundaries, which dampens cytoplasm flows and spindle mobility as cells become more elongated. These findings establish how cell shape affects spindle-associated forces and suggest a novel mechanism for shape sensing and division positioning mediated by intracellular hydrodynamics with functional implications for early embryo morphogenesis.
    Keywords:  cell division; cell shape; cytoplasm; embryogenesis; flows; forces; mitotic spindles
    DOI:  https://doi.org/10.1016/j.cub.2024.11.055
  6. bioRxiv. 2025 Jan 02. pii: 2024.12.22.629969. [Epub ahead of print]
    Spatially ordered zygotic genome activation fulfills embryo quality control.
    Wenchao Qian, Hui Chen, Hongju Lee, Matthew C Good.
      Early embryo development features autonomous, maternally-driven cell divisions that self- organize the multicellular blastula or blastocyst tissue. Maternal control cedes to the zygote starting with the onset of widespread zygotic genome activation (ZGA), which is essential for subsequent cell fate determination and morphogenesis. Intriguingly, although the onset of ZGA is highly regulated at the level of an embryo, it can be non-homogenous and precisely patterned at the single-cell level. We previously demonstrated a stereotyped spatial and temporal ordering of ZGA in a model vertebrate embryo. Unknown, however, was whether this precise ZGA patterning was required for development. To address this fundamental question, we devised a strategy to spatially control cell divisions in the embryo that perturb blastula embryo organization. We demonstrate the feasibility of spatially inverting the cell size pattern of embryos and find that these inverted embryos undergo a flipped pattern of ZGA. Mispatterned ZGA along the animal-vegetal axis causes embryo apoptosis, revealing that gastrula embryos have a built-in quality control system to sense inappropriate ZGA patterning, including regional defects in transcriptional onset. The quality control response is non-autonomous which may depend on anti-apoptotic signals that repress cell death outside of the animal hemisphere. These results reveal the requirement of properly patterned ZGA for normal development and the existence of an embryo quality control response exquisitely tuned to the spatial and temporal ordering of genome activation and zygotic gene expression.
    DOI:  https://doi.org/10.1101/2024.12.22.629969
  7. Nature. 2025 Jan 08.
    Satellite DNA shapes dictate pericentromere packaging in female meiosis.
    Damian Dudka, Jennine M Dawicki-McKenna, Xueqi Sun, Keagan Beeravolu, Takashi Akera, Michael A Lampson, Ben E Black.
      The abundance and sequence of satellite DNA at and around centromeres is evolving rapidly despite the highly conserved and essential process through which the centromere directs chromosome inheritance1-3. The impact of such rapid evolution is unclear. Here we find that sequence-dependent DNA shape dictates packaging of pericentromeric satellites in female meiosis through a conserved DNA-shape-recognizing chromatin architectural protein, high mobility group AT-hook 1 (HMGA1)4,5. Pericentromeric heterochromatin in two closely related mouse species, M. musculus and M. spretus, forms on divergent satellites that differ by both density of narrow DNA minor grooves and HMGA1 recruitment. HMGA1 binds preferentially to M. musculus satellites, and depletion in M. musculus oocytes causes massive stretching of pericentromeric satellites, disruption of kinetochore organization and delays in bipolar spindle assembly. In M. musculus × spretus hybrid oocytes, HMGA1 depletion disproportionately impairs M. musculus pericentromeres and microtubule attachment to their kinetochores. Thus, DNA shape affects both pericentromere packaging and the segregation machinery. We propose that rapid evolution of centromere and pericentromere DNA does not disrupt these essential processes when the satellites adopt DNA shapes recognized by conserved architectural proteins (such as HMGA1). By packaging these satellites, architectural proteins become part of the centromeric and pericentromeric chromatin, suggesting an evolutionary strategy that lowers the cost of megabase-scale satellite expansion.
    DOI:  https://doi.org/10.1038/s41586-024-08374-0
  8. Nat Struct Mol Biol. 2025 Jan 06.
    Mechanism of mammalian transcriptional repression by noncoding RNA.
    Katarína Tlučková, Beata Kaczmarek, Anita Salmazo, Carrie Bernecky.
      Transcription by RNA polymerase II (Pol II) can be repressed by noncoding RNA, including the human RNA Alu. However, the mechanism by which endogenous RNAs repress transcription remains unclear. Here we present cryogenic-electron microscopy structures of Pol II bound to Alu RNA, which reveal that Alu RNA mimics how DNA and RNA bind to Pol II during transcription elongation. Further, we show how distinct domains of the general transcription factor TFIIF control repressive activity. Together, we reveal how a noncoding RNA can regulate mammalian gene expression.
    DOI:  https://doi.org/10.1038/s41594-024-01448-7
  9. Nat Cell Biol. 2025 Jan 09.
    MDM2 functions as a timer reporting the length of mitosis.
    Luke J Fulcher, Tomoaki Sobajima, Caleb Batley, Ian Gibbs-Seymour, Francis A Barr.
      Delays in mitosis trigger p53-dependent arrest in G1 of the next cell cycle, thus preventing repeated cycles of chromosome instability and aneuploidy. Here we show that MDM2, the p53 ubiquitin ligase, is a key component of the timer mechanism triggering G1 arrest in response to prolonged mitosis. This timer function arises due to the attenuation of protein synthesis in mitosis. Because MDM2 has a short half-life and ongoing protein synthesis is therefore necessary to maintain its steady-state concentration, the amount of MDM2 gradually falls during mitosis but normally remains above a critical threshold for p53 regulation at the onset of G1. When mitosis is extended by prolonged spindle assembly checkpoint activation, the amount of MDM2 drops below this threshold, stabilizing p53. Subsequent p53-dependent p21 accumulation then channels G1 cells into a sustained cell-cycle arrest, whereas abrogation of the response in p53-deficient cells allows them to bypass this crucial defence mechanism.
    DOI:  https://doi.org/10.1038/s41556-024-01592-8
  10. Nat Commun. 2025 Jan 07. 16(1): 451
    Mitochondria- and ER-associated actin are required for mitochondrial fusion.
    Priya Gatti, Cara Schiavon, Julien Cicero, Uri Manor, Marc Germain.
      Mitochondria are crucial for cellular metabolism and signalling. Mitochondrial activity is modulated by mitochondrial fission and fusion, which are required to properly balance metabolic functions, transfer material between mitochondria, and remove defective mitochondria. Mitochondrial fission occurs at mitochondria-endoplasmic reticulum (ER) contact sites, and requires the formation of actin filaments that drive mitochondrial constriction and the recruitment of the fission protein DRP1. The role of actin in mitochondrial fusion remains entirely unexplored. Here we show that preventing actin polymerisation on either mitochondria or the ER disrupts both fission and fusion. We show that fusion but not fission is dependent on Arp2/3, whereas both fission and fusion require INF2 formin-dependent actin polymerization. We also show that mitochondria-associated actin marks fusion sites prior to the fusion protein MFN2. Together, our work introduces a method for perturbing organelle-associated actin and demonstrates a previously unknown role for actin in mitochondrial fusion.
    DOI:  https://doi.org/10.1038/s41467-024-55758-x
  11. J Exp Biol. 2025 Jan 01. pii: JEB249489. [Epub ahead of print]228(1):
    Scaling of quantitative cardiomyocyte properties in the left ventricle of different mammalian species.
    Tanja Kloock, David J Jörg, Christian Mühlfeld.
      Small mammals have a higher heart rate and, relative to body mass (Mb), a higher metabolic rate than large mammals. In contrast, heart weight and stroke volume scale linearly with Mb. With mitochondria filling approximately 50% of a shrew cardiomyocyte - space unavailable for myofibrils - it is unclear how small mammals generate enough contractile force to pump blood into circulation. Here, we investigated whether the total number or volume of cardiomyocytes in the left ventricle compensates for allometry-related volume shifts of cardiac mitochondria and myofibrils. Through statistical analysis of data from 25 studies with 19 different mammalian species with Mb spanning seven orders of magnitude (2.2 g to 920 kg), we determined how number, volume density and total volume of cardiomyocytes, mitochondria and myofibrils in the left ventricle depend on Mb. We found that these biological variables follow scaling relationships and are proportional to a power b of Mb. The number [b=1.02 (95% CI: 0.89, 1.14); t-test for b=1: P=0.72] and volume [b=0.95 (95% CI: 0.89, 1.03); t-test for b=1: P=0.18] of cardiomyocytes in the left ventricle increases linearly with increasing Mb. In cardiomyocytes, volume density of mitochondria decreases [b=-0.056 (95% CI: -0.08, -0.04); t-test for b=0: P<0.0001] and that of myofibrils increases [b=0.024 (95%CI: 0.01, 0.04); t-test for b=0: P<0.01] with increasing Mb. Thus, the number or volume of left ventricular cardiomyocytes does not compensate for the higher heart rate and specific metabolic rate of small mammals although a higher mitochondrial and lower myofibrillar volume per cardiomyocyte are present.
    Keywords:  Allometry; Cardiac force; Cardiomyocyte number; Mitochondria; Myofibrils; Stereology
    DOI:  https://doi.org/10.1242/jeb.249489
  12. Proc Natl Acad Sci U S A. 2025 Jan 14. 122(2): e2419196122
    The cGAS-STING, p38 MAPK, and p53 pathways link genome instability to accelerated cellular senescence in ATM-deficient murine lung fibroblasts.
    Majd Haj, Yann Frey, Amit Levon, Avishai Maliah, Tal Ben-Yishay, Rachel Slutsky, Riham Smoom, Yehuda Tzfati, Uri Ben-David, Carmit Levy, Ran Elkon, Yael Ziv, Yosef Shiloh.
      Ataxia-telangiectasia (A-T) is a pleiotropic genome instability syndrome resulting from the loss of the homeostatic protein kinase ATM. The complex phenotype of A-T includes progressive cerebellar degeneration, immunodeficiency, gonadal atrophy, interstitial lung disease, cancer predisposition, endocrine abnormalities, chromosomal instability, radiosensitivity, and segmental premature aging. Cultured skin fibroblasts from A-T patients exhibit premature senescence, highlighting the association between genome instability, cellular senescence, and aging. We found that lung fibroblasts derived from ATM-deficient mice provide a versatile experimental system to explore the mechanisms driving the premature senescence of primary fibroblasts lacking ATM. Atm-/- fibroblasts failed to proliferate under ambient oxygen conditions (21%). Although they initially proliferated under physiological oxygen levels (3%), they rapidly entered senescence. In contrast, wild-type (WT) lung fibroblasts did not senesce under 3% oxygen and eventually underwent immortalization and neoplastic transformation. However, rapid senescence could be induced in WT cells either by Atm gene ablation or persistent chemical inhibition of ATM kinase activity, with senescence induced by ATM inhibition being reversible upon inhibitor removal. Moreover, the concomitant loss of ATM and p53 led to senescence evasion, vigorous growth, rampant genome instability, and subsequent immortalization and transformation. Our findings reveal that the rapid senescence of Atm-/- lung fibroblasts is driven by the collaborative action of the cGAS-STING, p38 MAPK, and p53 pathways in response to persistent DNA damage, ultimately leading to the induction of interferon-α1 and downstream interferon-stimulated genes. We propose that accelerated cellular senescence may exacerbate specific A-T symptoms, particularly contributing to the progressive, life-threatening interstitial lung disease often observed in A-T patients during adulthood.
    Keywords:  ATM; ataxia–telangiectasia; cGAS-STING; p53; senescence
    DOI:  https://doi.org/10.1073/pnas.2419196122
  13. Mol Cells. 2025 Jan 03. pii: S1016-8478(24)00201-2. [Epub ahead of print] 100176
    eIF2α Phosphorylation-ATF4 Axis-Mediated Transcriptional Reprogramming Mitigates Mitochondrial Impairment During ER Stress.
    Hien Thi Le, Jiyoung Yu, Hee Sung Ahn, Mi-Jeong Kim, In Gyeong Chae, Hyun-Nam Cho, Juhee Kim, Hye-Kyung Park, Hyuk Nam Kwon, Han-Jung Chae, Byoung Heon Kang, Jeong Kon Seo, Kyunggon Kim, Sung Hoon Back.
      Eukaryotic translation initiation factor 2α (eIF2α) phosphorylation, which regulates all three unfolded protein response pathways, helps maintain cellular homeostasis and overcome endoplasmic reticulum (ER) stress through transcriptional and translational reprogramming. However, transcriptional regulation of mitochondrial homeostasis by eIF2α phosphorylation during ER stress is not fully understood. Here, we report that the eIF2α phosphorylation-activating transcription factor 4 (ATF4) axis is required for expression of multiple transcription factors (TFs) including nuclear factor erythroid 2-related factor 2 (Nrf2) and their target genes responsible for mitochondrial homeostasis during ER stress. eIF2α phosphorylation-deficient (A/A) cells displayed dysregulated mitochondrial dynamics and mitochondrial DNA replication, decreased expression of oxidative phosphorylation complex proteins, and impaired mitochondrial functions during ER stress. ATF4 overexpression suppressed impairment of mitochondrial homeostasis in A/A cells during ER stress by promoting expression of downstream TFs and their target genes. Our findings underscore the importance of the eIF2α phosphorylation-ATF4 axis for maintaining mitochondrial homeostasis through transcriptional reprogramming during ER stress.
    Keywords:  ATF4; ER stress; Mitochondrial homeostasis; Nrf2; eIF2α phosphorylation
    DOI:  https://doi.org/10.1016/j.mocell.2024.100176
  14. Nat Cell Biol. 2025 Jan 08.
    FAT1 alterations contribute to chromosomal instability in cancer cells.
      
    DOI:  https://doi.org/10.1038/s41556-024-01559-9
  15. Nat Commun. 2025 Jan 08. 16(1): 480
    KLF5 loss sensitizes cells to ATR inhibition and is synthetic lethal with ARID1A deficiency.
    Samah W Awwad, Colm Doyle, Josie Coulthard, Aldo S Bader, Nadia Gueorguieva, Simon Lam, Vipul Gupta, Rimma Belotserkovskaya, Tuan-Anh Tran, Shankar Balasubramanian, Stephen P Jackson.
      ATR plays key roles in cellular responses to DNA damage and replication stress, a pervasive feature of cancer cells. ATR inhibitors (ATRi) are in clinical development for treating various cancers, including those with high replication stress, such as is elicited by ARID1A deficiency, but the cellular mechanisms that determine ATRi efficacy in such backgrounds are unclear. Here, we have conducted unbiased genome-scale CRISPR screens in ARID1A-deficient and proficient cells treated with ATRi. We found that loss of transcription factor KLF5 has severe negative impact on fitness of ARID1A-deficient cells while hypersensitising ARID1A-proficient cells to ATRi. KLF5 loss induced replication stress, DNA damage, increased DNA-RNA hybrid formation, and genomic instability upon ATR inhibition. Mechanistically, we show that KLF5 protects cells from replication stress, at least in part through regulating BRD4 recruitment to chromatin. Overall, our work identifies KLF5 as a potential target for eradicating ARID1A-deficient cancers.
    DOI:  https://doi.org/10.1038/s41467-024-55637-5
  16. Nat Cell Biol. 2025 Jan 08.
    H3K36 methylation regulates cell plasticity and regeneration in the intestinal epithelium.
    Alison R S Pashos, Anne R Meyer, Cameron Bussey-Sutton, Erin S O'Connor, Mariel Coradin, Marilyne Coulombe, Kent A Riemondy, Sanjana Potlapelly, Brian D Strahl, Gunnar C Hansson, Peter J Dempsey, Justin Brumbaugh.
      Plasticity is needed during development and homeostasis to generate diverse cell types from stem and progenitor cells. Following differentiation, plasticity must be restricted in specialized cells to maintain tissue integrity and function. For this reason, specialized cell identity is stable under homeostatic conditions; however, cells in some tissues regain plasticity during injury-induced regeneration. While precise gene expression controls these processes, the regulatory mechanisms that restrict or promote cell plasticity are poorly understood. Here we use the mouse small intestine as a model system to study cell plasticity. We find that H3K36 methylation reinforces expression of cell-type-associated genes to maintain specialized cell identity in intestinal epithelial cells. Depleting H3K36 methylation disrupts lineage commitment and activates regenerative gene expression. Correspondingly, we observe rapid and reversible remodelling of H3K36 methylation following injury-induced regeneration. These data suggest a fundamental role for H3K36 methylation in reinforcing specialized lineages and regulating cell plasticity and regeneration.
    DOI:  https://doi.org/10.1038/s41556-024-01580-y
  17. Sci Transl Med. 2025 Jan 08. 17(780): eadk8623
    Hypoxia-inducible factor 2 regulates alveolar regeneration after repetitive injury in three-dimensional cellular and in vivo models.
    A Scott McCall, Sergey Gutor, Hari Tanjore, Ankita Burman, Taylor Sherrill, Micah Chapman, Carla L Calvi, David Han, Jane Camarata, Raphael P Hunt, David Nichols, Nicholas E Banovich, William E Lawson, Jason J Gokey, Jonathan A Kropski, Timothy S Blackwell.
      Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease in which repetitive epithelial injury and incomplete alveolar repair result in accumulation of profibrotic intermediate/transitional "aberrant" epithelial cell states. The mechanisms leading to the emergence and persistence of aberrant epithelial populations in the distal lung remain incompletely understood. By interrogating single-cell RNA sequencing (scRNA-seq) data from patients with IPF and a mouse model of repeated lung epithelial injury, we identified persistent activation of hypoxia-inducible factor (HIF) signaling in these aberrant epithelial cells. Using mouse genetic lineage-tracing strategies together with scRNA-seq, we found that these disease-emergent aberrant epithelial cells predominantly arose from airway-derived (Scgb1a1-CreER-traced) progenitors and exhibited transcriptional programs of Hif2a activation. In mice treated with repetitive intratracheal bleomycin, deletion of Epas1 (Hif2a) but not Hif1a, from airway-derived progenitors, or administration of the small-molecule HIF2 inhibitor PT-2385, using both prevention and rescue approaches, attenuated experimental lung fibrosis, reduced the appearance of aberrant epithelial cells, and promoted alveolar repair. In mouse alveolar organoids, genetic or pharmacologic inhibition of Hif2 promoted alveolar differentiation of airway-derived epithelial progenitors. In addition, treatment of human distal lung organoids with PT-2385 increased colony-forming efficiency, enhanced protein and transcriptional markers of alveolar type 2 epithelial cell maturation, and prevented the emergence of aberrant epithelial cells. Together, these studies showed that HIF2 activation drives the emergence of aberrant epithelial populations after repetitive injury and that targeted HIF2 inhibition may represent an effective therapeutic strategy to promote functional alveolar repair in IPF and other interstitial lung diseases.
    DOI:  https://doi.org/10.1126/scitranslmed.adk8623
  18. J Cell Biol. 2025 Feb 03. pii: e202401101. [Epub ahead of print]224(2):
    RACK1 MARylation regulates translation and stress granules in ovarian cancer cells.
    Sridevi Challa, Tulip Nandu, Hyung Bum Kim, Xuan Gong, Charles W Renshaw, Wan-Chen Li, Xinrui Tan, Marwa W Aljardali, Cristel V Camacho, Jin Chen, W Lee Kraus.
      Mono(ADP-ribosyl)ation (MARylation) is emerging as a critical regulator of ribosome function and translation. Herein, we demonstrate that RACK1, an integral component of the ribosome, is MARylated by the mono(ADP-ribosyl) transferase (MART) PARP14 in ovarian cancer cells. MARylation of RACK1 is required for stress granule formation and promotes the colocalization of RACK1 in stress granules with G3BP1, eIF3η, and 40S ribosomal proteins. In parallel, we observed reduced translation of a subset of mRNAs, including those encoding key cancer regulators (e.g., AKT). Treatment with a PARP14 inhibitor or mutation of the sites of MARylation on RACK1 blocks these outcomes, as well as the growth of ovarian cancer cells in culture and in vivo. To reset the system after prolonged stress and recovery, the ADP-ribosyl hydrolase TARG1 deMARylates RACK1, leading to the dissociation of the stress granules and the restoration of translation. Collectively, our results demonstrate a therapeutically targetable pathway that controls polysome assembly, translation, and stress granule dynamics in ovarian cancer cells.
    DOI:  https://doi.org/10.1083/jcb.202401101
  19. Cell Stem Cell. 2024 Dec 31. pii: S1934-5909(24)00447-8. [Epub ahead of print]
    Ectopic expression of DNMT3L in human trophoblast stem cells restores features of the placental methylome.
    Georgia Lea, Paula Doria-Borrell, Ana Ferrero-Micó, Anakha Varma, Claire Simon, Holly Anderson, Laura Biggins, Katrien De Clercq, Simon Andrews, Kathy K Niakan, Lenka Gahurova, Naomi McGovern, Vicente Pérez-García, Courtney W Hanna.
      The placental DNA methylation landscape is unique, with widespread partially methylated domains (PMDs). The placental "methylome" is conserved across mammals, a shared feature of many cancers, and extensively studied for links with pregnancy complications. Human trophoblast stem cells (hTSCs) offer exciting potential for functional studies to better understand this epigenetic feature; however, whether the hTSC epigenome recapitulates primary trophoblast remains unclear. We find that hTSCs exhibit an atypical methylome compared with trophectoderm and 1st trimester cytotrophoblast. Regardless of cell origin, oxygen levels, or culture conditions, hTSCs show localized DNA methylation within transcribed gene bodies and a complete loss of PMDs. Unlike early human trophoblasts, hTSCs display a notable absence of DNMT3L expression, which is necessary for PMD establishment in mouse trophoblasts. Remarkably, we demonstrate that ectopic expression of DNMT3L in hTSCs restores placental PMDs, supporting a conserved role for DNMT3L in de novo methylation in trophoblast development in human embryogenesis.
    Keywords:  DNA methylation; DNMT3L; differentiation; epigenetics; histone modifications; human trophoblast stem cells; partially methylated domains; placenta; syncytiotrophoblast
    DOI:  https://doi.org/10.1016/j.stem.2024.12.007
  20. Nature. 2025 Jan 08.
    Crypt density and recruited enhancers underlie intestinal tumour initiation.
    Liam Gaynor, Harshabad Singh, Guodong Tie, Krithika Badarinath, Shariq Madha, Andrew Mancini, Swarnabh Bhattacharya, Mikio Hoshino, Frederic J de Sauvage, Kazutaka Murata, Unmesh Jadhav, Ramesh A Shivdasani.
      Oncogenic mutations that drive colorectal cancer can be present in healthy intestines for long periods without overt consequence1,2. Mutation of Adenomatous polyposis coli (Apc), the most common initiating event in conventional adenomas3, activates Wnt signalling, hence conferring fitness on mutant intestinal stem cells (ISCs)4,5. Apc mutations may occur in ISCs that arose by routine self-renewal or by dedifferentiation of their progeny. Although ISCs of these different origins are fundamentally similar6,7, it is unclear if both generate tumours equally well in uninjured intestines. Also unknown is whether cis-regulatory elements are substantively modulated upon Wnt hyperactivation or as a feature of subsequent tumours. Here, we show in two mouse models that adenomas are not an obligatory outcome of Apc deletion in either ISC source but require proximity of mutant intestinal crypts. Reduced crypt density abrogates, and aggregation of mutant colonic crypts augments, adenoma formation. Moreover, adenoma-resident ISCs open chromatin at thousands of enhancers that are inaccessible in Apc-null ISCs not associated with adenomas. These cis-elements explain adenoma-selective gene activity and persist, with little further expansion of the repertoire, as other oncogenic mutations accumulate. Thus, cooperativity between neighbouring mutant crypts and new accessibility at specific enhancers are key steps early in intestinal tumourigenesis.
    DOI:  https://doi.org/10.1038/s41586-024-08573-9
  21. Nat Struct Mol Biol. 2025 Jan 09.
    Capturing eukaryotic ribosome dynamics in situ at high resolution.
    Jing Cheng, Chunling Wu, Junxi Li, Qi Yang, Mingjie Zhao, Xinzheng Zhang.
      Many protein complexes are highly dynamic in cells; thus, characterizing their conformational changes in cells is crucial for unraveling their functions. Here, using cryo-electron microscopy, 451,700 ribosome particles from Saccharomyces cerevisiae cell lamellae were obtained to solve the 60S region to 2.9-Å resolution by in situ single-particle analysis. Over 20 distinct conformations were identified by three-dimensional classification with resolutions typically higher than 4 Å. These conformations were used to reconstruct a complete elongation cycle of eukaryotic translation with elongation factors (eEFs). We found that compact eEF2 anchors to the partially rotated ribosome after subunit rolling and hypothesize that it stabilizes the local conformation for peptidyl transfer. Moreover, open-eEF3 binding to a fully rotated ribosome was observed, whose conformational change was coupled with head swiveling and body back-rotation of the 40S subunit.
    DOI:  https://doi.org/10.1038/s41594-024-01454-9
  22. Proc Natl Acad Sci U S A. 2025 Jan 07. 122(1): e2322732121
    A minimal vertex model explains how the amnioserosa avoids fluidization during Drosophila dorsal closure.
    Indrajit Tah, Daniel Haertter, Janice M Crawford, Daniel P Kiehart, Christoph F Schmidt, Andrea J Liu.
      Dorsal closure is a process that occurs during embryogenesis of Drosophila melanogaster. During dorsal closure, the amnioserosa (AS), a one-cell thick epithelial tissue that fills the dorsal opening, shrinks as the lateral epidermis sheets converge and eventually merge. During this process, both shape index and aspect ratio of amnioserosa cells increase markedly. The standard 2-dimensional vertex model, which successfully describes tissue sheet mechanics in multiple contexts, would in this case predict that the tissue should fluidize via cell neighbor changes. Surprisingly, however, the amnioserosa remains an elastic solid with no such events. We here present a minimal extension to the vertex model that explains how the amnioserosa can achieve this unexpected behavior. We show that continuous shrinkage of the preferred cell perimeter and cell perimeter polydispersity lead to the retention of the solid state of the amnioserosa. Our model accurately captures measured cell shape and orientation changes and predicts nonmonotonic junction tension that we confirm with laser ablation experiments.
    Keywords:  Drosophila dorsal closure; amnioserosa; epithelial tissue; morphogenesis; vertex model
    DOI:  https://doi.org/10.1073/pnas.2322732121
  23. Nature. 2025 Jan 08.
    Site-saturation mutagenesis of 500 human protein domains.
    Antoni Beltran, Xiang'er Jiang, Yue Shen, Ben Lehner.
      Missense variants that change the amino acid sequences of proteins cause one-third of human genetic diseases1. Tens of millions of missense variants exist in the current human population, and the vast majority of these have unknown functional consequences. Here we present a large-scale experimental analysis of human missense variants across many different proteins. Using DNA synthesis and cellular selection experiments we quantify the effect of more than 500,000 variants on the abundance of more than 500 human protein domains. This dataset reveals that 60% of pathogenic missense variants reduce protein stability. The contribution of stability to protein fitness varies across proteins and diseases and is particularly important in recessive disorders. We combine stability measurements with protein language models to annotate functional sites across proteins. Mutational effects on stability are largely conserved in homologous domains, enabling accurate stability prediction across entire protein families using energy models. Our data demonstrate the feasibility of assaying human protein variants at scale and provides a large consistent reference dataset for clinical variant interpretation and training and benchmarking of computational methods.
    DOI:  https://doi.org/10.1038/s41586-024-08370-4
  24. Nat Biomed Eng. 2025 Jan 07.
    Hormonally mediated mechanical remodelling of human haematopoietic stem cells enhances their bone-marrow engraftment.
      
    DOI:  https://doi.org/10.1038/s41551-024-01310-7
  25. Development. 2025 Jan 10. pii: dev.202865. [Epub ahead of print]
    Nup107 contributes to the maternal to zygotic transition by preventing the premature nuclear export of pri-miRNA 427.
    Valentyna Kostiuk, Rakib Kabir, Kaitlin Levangie, Stefany Empke, Kimberly Morgan, Nick D L Owens, C Patrick Lusk, Mustafa K Khokha.
      Emerging evidence suggests that the nuclear pore complex can have unique compositions and distinct nucleoporin functions in different cells. Here, we show that Nup107, a key component of the NPC scaffold, varies in expression over development: it is expressed at higher levels in the blastula compared to the gastrula suggesting a critical role prior to gastrulation. We find depletion of Nup107 affects the differentiation of the early germ layers leading to an expansion of the ectoderm at the expense of endoderm and mesoderm. By analyzing an RNAseq time course, we observed that depletion of Nup107 affects the maternal-zygotic transition by delaying the degradation of maternal transcripts that occurs as zygotic transcription begins. The transcripts are enriched in miR427 recognition sites, a conserved microRNA that destabilizes maternal transcripts including REST, which encodes a Kruppel-type zinc finger transcription factor that we demonstrate is critical for ectodermal cell fates. Mechanistically, we show that Nup107 is required to prevent the premature export of pri-miR427 transcript before processing. Nup107 depletion leads to the reduced production of mature miR427 and maternal transcript stabilization. We conclude that high levels of Nup107 in the early embryo are critical for the nuclear retention and subsequent processing of pri-miR427 transcripts that is required for timely maternal RNA clearance to enable gastrulation.
    Keywords:  Germ layers patterning; Maternal to zygotic transition; MiR427; MicroRNA; Nuclear transport; Nucleoporins
    DOI:  https://doi.org/10.1242/dev.202865
  26. Neuron. 2025 Jan 08. pii: S0896-6273(24)00885-7. [Epub ahead of print]113(1): 82-108
    Brain aging and rejuvenation at single-cell resolution.
    Eric D Sun, Rahul Nagvekar, Angela N Pogson, Anne Brunet.
      Brain aging leads to a decline in cognitive function and a concomitant increase in the susceptibility to neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. A key question is how changes within individual cells of the brain give rise to age-related dysfunction. Developments in single-cell "omics" technologies, such as single-cell transcriptomics, have facilitated high-dimensional profiling of individual cells. These technologies have led to new and comprehensive characterizations of brain aging at single-cell resolution. Here, we review insights gleaned from single-cell omics studies of brain aging, starting with a cell-type-centric overview of age-associated changes and followed by a discussion of cell-cell interactions during aging. We highlight how single-cell omics studies provide an unbiased view of different rejuvenation interventions and comment on the promise of combinatorial rejuvenation approaches for the brain. Finally, we propose new directions, including models of brain aging and neural stem cells as a focal point for rejuvenation.
    Keywords:  aging; brain; cell-cell interactions; multi-omics; regeneration; rejuvenation; single-cell transcriptomics; spatial transcriptomics
    DOI:  https://doi.org/10.1016/j.neuron.2024.12.007
  27. Nat Commun. 2025 Jan 04. 16(1): 390
    Phosphorylation of a nuclear condensate regulates cohesion and mRNA retention.
    Alexa B R McIntyre, Adrian Beat Tschan, Katrina Meyer, Severin Walser, Arpan Kumar Rai, Keisuke Fujita, Lucas Pelkmans.
      Nuclear speckles are membraneless organelles that associate with active transcription sites and participate in post-transcriptional mRNA processing. During the cell cycle, nuclear speckles dissolve following phosphorylation of their protein components. Here, we identify the PP1 family as the phosphatases that counteract kinase-mediated dissolution. PP1 overexpression increases speckle cohesion and leads to retention of mRNA within speckles and the nucleus. Using APEX2 proximity labeling combined with RNA-sequencing, we characterize the recruitment of specific RNAs. We find that many transcripts are preferentially enriched within nuclear speckles compared to the nucleoplasm, particularly chromatin- and nucleus-associated transcripts. While total polyadenylated RNA retention increases with nuclear speckle cohesion, the ratios of most mRNA species to each other are constant, indicating non-selective retention. We further find that cellular responses to heat shock, oxidative stress, and hypoxia include changes to the phosphorylation and cohesion of nuclear speckles and to mRNA retention. Our results demonstrate that tuning the material properties of nuclear speckles provides a mechanism for the acute control of mRNA localization.
    DOI:  https://doi.org/10.1038/s41467-024-55469-3
  28. J Cell Biol. 2025 Mar 03. pii: e202404084. [Epub ahead of print]224(3):
    Differential impacts of ribosomal protein haploinsufficiency on mitochondrial function.
    Agustian Surya, Blythe Marie Bolton, Reed Rothe, Raquel Mejia-Trujillo, Amanda Leonita, Qiuxia Zhao, Alia Arya, Yue Liu, Rekha Rangan, Yasash Gorusu, Pamela Nguyen, Can Cenik, Elif Sarinay Cenik.
      The interplay between ribosomal protein (RP) composition and mitochondrial function is essential for energy homeostasis. Balanced RP production optimizes protein synthesis while minimizing energy costs, but its impact on mitochondrial functionality remains unclear. Here, we investigated haploinsufficiency for RP genes (rps-10, rpl-5, rpl-33, and rps-23) in Caenorhabditis elegans and corresponding reductions in human lymphoblast cells. Significant mitochondrial morphological differences, upregulation of glutathione transferases, and SKN-1-dependent oxidative stress resistance were observed across mutants. Loss of a Datasingle rps-10 copy reduced mitochondrial activity, energy levels, and oxygen consumption, mirrored by similar reductions in mitochondrial activity and energy levels in lymphoblast cells with 50% lower RPS10 transcripts. Both systems exhibited altered translation efficiency (TE) of mitochondrial electron transport chain components, suggesting a conserved mechanism to adjust mitochondrial protein synthesis under ribosomal stress. Finally, mitochondrial membrane and cytosolic RPs showed significant RNA and TE covariation in lymphoblastoid cells, highlighting the interplay between protein synthesis machinery and mitochondrial energy production.
    DOI:  https://doi.org/10.1083/jcb.202404084
  29. Sci Adv. 2025 Jan 10. 11(2): eadn9750
    NAC regulates metabolism and cell fate in intestinal stem cells.
    Sofia Ramalho, Ferhat Alkan, Stefan Prekovic, Katarzyna Jastrzebski, Eric Pintó Barberà, Liesbeth Hoekman, Maarten Altelaar, Cecilia de Heus, Nalan Liv, Maria J Rodríguez-Colman, Mehmet Yilmaz, Rob van der Kammen, Juliette Fedry, Mark C de Gooijer, Saskia Jacoba Elisabeth Suijkerbuijk, William J Faller, Joana Silva.
      Intestinal stem cells (ISCs) face the challenge of integrating metabolic demands with unique regenerative functions. Studies have shown an intricate interplay between metabolism and stem cell capacity; however, it is still not understood how this process is regulated. Combining ribosome profiling and CRISPR screening in intestinal organoids, we identify the nascent polypeptide-associated complex (NAC) as a key mediator of this process. Our findings suggest that NAC is responsible for relocalizing ribosomes to the mitochondria and regulating ISC metabolism. Upon NAC inhibition, intestinal cells show decreased import of mitochondrial proteins, which are needed for oxidative phosphorylation, and, consequently, enable the cell to maintain a stem cell identity. Furthermore, we show that overexpression of NACα is sufficient to drive mitochondrial respiration and promote ISC identity. Ultimately, our results reveal the pivotal role of NAC in regulating ribosome localization, mitochondrial metabolism, and ISC function, providing insights into the potential mechanism behind it.
    DOI:  https://doi.org/10.1126/sciadv.adn9750
  30. Nat Metab. 2025 Jan 06.
    The galactokinase enzyme of yeast senses metabolic flux to stabilize galactose pathway regulation.
    Julius Palme, Ang Li, Michael Springer.
      Nutrient sensors allow cells to adapt their metabolisms to match nutrient availability by regulating metabolic pathway expression. Many such sensors are cytosolic receptors that measure intracellular nutrient concentrations. One might expect that inducing the metabolic pathway that degrades a nutrient would reduce intracellular nutrient levels, destabilizing induction. However, in the galactose-responsive (GAL) pathway of Saccharomyces cerevisiae, we find that induction is stabilized by flux sensing. Previously proposed mechanisms for flux sensing postulate the existence of metabolites whose concentrations correlate with flux. The GAL pathway flux sensor uses a different principle: the galactokinase Gal1p both performs the first step in GAL metabolism and reports on flux by signalling to the GAL repressor, Gal80p. Both Gal1p catalysis and Gal1p signalling depend on the concentration of the Gal1p-GAL complex and are therefore directly correlated. Given the simplicity of this mechanism, flux sensing is probably a general feature throughout metabolic regulation.
    DOI:  https://doi.org/10.1038/s42255-024-01181-x
  31. Nat Cell Biol. 2025 Jan 07.
    Phase separation of initiation hubs on cargo is a trigger switch for selective autophagy.
    Mariya Licheva, Jeremy Pflaum, Riccardo Babic, Hector Mancilla, Jana Elsässer, Emily Boyle, David M Hollenstein, Jorge Jimenez-Niebla, Jonas Pleyer, Mio Heinrich, Franz-Georg Wieland, Joachim Brenneisen, Christopher Eickhorst, Johann Brenner, Shan Jiang, Markus Hartl, Sonja Welsch, Carola Hunte, Jens Timmer, Florian Wilfling, Claudine Kraft.
      Autophagy is a key cellular quality control mechanism. Nutrient stress triggers bulk autophagy, which nonselectively degrades cytoplasmic material upon formation and liquid-liquid phase separation of the autophagy-related gene 1 (Atg1) complex. In contrast, selective autophagy eliminates protein aggregates, damaged organelles and other cargoes that are targeted by an autophagy receptor. Phase separation of cargo has been observed, but its regulation and impact on selective autophagy are poorly understood. Here, we find that key autophagy biogenesis factors phase separate into initiation hubs at cargo surfaces in yeast, subsequently maturing into sites that drive phagophore nucleation. This phase separation is dependent on multivalent, low-affinity interactions between autophagy receptors and cargo, creating a dynamic cargo surface. Notably, high-affinity interactions between autophagy receptors and cargo complexes block initiation hub formation and autophagy progression. Using these principles, we converted the mammalian reovirus nonstructural protein µNS, which accumulates as particles in the yeast cytoplasm that are not degraded, into a neo-cargo that is degraded by selective autophagy. We show that initiation hubs also form on the surface of different cargoes in human cells and are key to establish the connection to the endoplasmic reticulum, where the phagophore assembly site is formed to initiate phagophore biogenesis. Overall, our findings suggest that regulated phase separation underscores the initiation of both bulk and selective autophagy in evolutionarily diverse organisms.
    DOI:  https://doi.org/10.1038/s41556-024-01572-y
  32. Nat Cell Biol. 2025 Jan 08.
    Triacylglycerol mobilization underpins mitochondrial stress recovery.
    Zakery N Baker, Yunyun Zhu, Rachel M Guerra, Andrew J Smith, Aline Arra, Lia R Serrano, Katherine A Overmyer, Shankar Mukherji, Elizabeth A Craig, Joshua J Coon, David J Pagliarini.
      Mitochondria are central to myriad biochemical processes, and thus even their moderate impairment could have drastic cellular consequences if not rectified. Here, to explore cellular strategies for surmounting mitochondrial stress, we conducted a series of chemical and genetic perturbations to Saccharomyces cerevisiae and analysed the cellular responses using deep multiomic mass spectrometry profiling. We discovered that mobilization of lipid droplet triacylglycerol stores was necessary for strains to mount a successful recovery response. In particular, acyl chains from these stores were liberated by triacylglycerol lipases and used to fuel biosynthesis of the quintessential mitochondrial membrane lipid cardiolipin to support new mitochondrial biogenesis. We demonstrate that a comparable recovery pathway exists in mammalian cells, which fail to recover from doxycycline treatment when lacking the ATGL lipase. Collectively, our work reveals a key component of mitochondrial stress recovery and offers a rich resource for further exploration of the broad cellular responses to mitochondrial dysfunction.
    DOI:  https://doi.org/10.1038/s41556-024-01586-6
This page is being maintained by Thomas Krichel. It was last updated on 2025‒01‒31 at 6:05.