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Hiroyuki Uechi, Sindhuja Sridharan, Jik Nijssen, Jessica Bilstein, Juan M Iglesias-Artola, Satoshi Kishigami, Virginia Casablancas-Antras, Ina Poser, Eduardo J Martinez, Edgar Boczek, Michael Wagner, Nadine Tomschke, Antonio Domingues, Arun Pal, Thom Doeleman, Sukhleen Kour, Eric D Anderson, Frank Stein, Hyun O. Lee, Xiaojie Zhang, Anatol Fritsch, Marcus Jahnel, Julius Fürsch, Anastasia C Murthy, Simon Alberti, Marc Bickle, Nicolas L Fawzi, André Nadler, Della C David, Udai Pandey, Andreas Hermann, Florian Stengel, Benjamin G Davis, Andrew J Baldwin, Mikhail M Savitski, Anthony Hyman#, Richard Wheeler#
Small-molecule dissolution of stress granules by redox modulation benefits ALS models.
Nat Chem Biol, 21(10) 1577-1588 (2025)
Open Access PubMed Source   

Neurodegenerative diseases, such as amyotrophic lateral sclerosis, are often associated with mutations in stress granule proteins. Aberrant stress granule condensate formation is associated with disease, making it a potential target for pharmacological intervention. Here, we identified lipoamide, a small molecule that specifically prevents cytoplasmic condensation of stress granule proteins. Thermal proteome profiling showed that lipoamide stabilizes intrinsically disordered domain-containing proteins, including SRSF1 and SFPQ, which are stress granule proteins necessary for lipoamide activity. SFPQ has redox-state-specific condensate dissolving behavior, which is modulated by the redox-active lipoamide dithiolane ring. In animals, lipoamide ameliorates aging-associated aggregation of a stress granule reporter protein, improves neuronal morphology and recovers motor defects caused by amyotrophic lateral sclerosis-associated FUS and TDP-43 mutants. Thus, lipoamide is a well-tolerated small-molecule modulator of stress granule condensation, and dissection of its molecular mechanism identified a cellular pathway for redox regulation of stress granule formation.
@article{Uechi9000,
author={Hiroyuki Uechi, Sindhuja Sridharan, Jik Nijssen, Jessica Bilstein, Juan M Iglesias-Artola, Satoshi Kishigami, Virginia Casablancas-Antras, Ina Poser, Eduardo J Martinez, Edgar Boczek, Michael Wagner, Nadine Tomschke, Antonio Domingues, Arun Pal, Thom Doeleman, Sukhleen Kour, Eric D Anderson, Frank Stein, Hyun O. Lee, Xiaojie Zhang, Anatol Fritsch, Marcus Jahnel, Julius Fürsch, Anastasia C Murthy, Simon Alberti, Marc Bickle, Nicolas L Fawzi, André Nadler, Della C David, Udai Pandey, Andreas Hermann, Florian Stengel, Benjamin G Davis, Andrew J Baldwin, Mikhail M Savitski, Anthony Hyman, Richard Wheeler},
title={Small-molecule dissolution of stress granules by redox modulation benefits ALS models.},
journal ={Nature chemical biology},
volume={21},
issue ={10},
pages={1577--1588},
year=2025
}

Daniel S Alber*, Shiheng Zhao*, Alexandre O Jacinto, Eric F Wieschaus, Stanislav Y. Shvartsman#, Pierre A. Haas#
A model for boundary-driven tissue morphogenesis.
Proc Natl Acad Sci U.S.A., 122(38) Art. No. e2505160122 (2025)
Open Access PubMed Source   

Tissue deformations during morphogenesis can be active, driven by internal processes, or passive, resulting from stresses applied at their boundaries. Here, we introduce the Drosophila hindgut primordium as a model for studying boundary-driven tissue morphogenesis. We characterize its deformations and show that its complex shape changes can be a passive consequence of the deformations of the active regions of the embryo that surround it. First, we find an intermediate characteristic "triangular keyhole" shape in the 3D deformations of the hindgut. We construct a minimal model of the hindgut primordium as an elastic ring deformed by active midgut invagination and germ band extension on an ellipsoidal surface, which robustly captures the symmetry-breaking into this triangular keyhole shape. We then quantify the 3D kinematics of the tissue by a set of contours and find that the hindgut deforms in two stages: An initial translation on the curved embryo surface followed by a rapid breaking of shape symmetry. We extend our model to show that the contour kinematics in both stages are consistent with our passive picture. Our results suggest that the role of in-plane deformations during hindgut morphogenesis is to translate the tissue to a region with anisotropic embryonic curvature and show that uniform boundary conditions are sufficient to generate the observed nonuniform shape change. Our work thus provides a possible explanation for the various characteristic shapes of blastopore-equivalents in different organisms and a framework for the mechanical emergence of global morphologies in complex developmental systems.
@article{Alber9060,
author={Daniel S Alber, Shiheng Zhao, Alexandre O Jacinto, Eric F Wieschaus, Stanislav Y. Shvartsman, Pierre A. Haas},
title={A model for boundary-driven tissue morphogenesis.},
journal ={Proceedings of the National Academy of Sciences of the United States of America},
volume={122},
issue ={38},
pages={null--null},
year=2025
}

Kristin Böhlig, Juan M Iglesias-Artola, Antonino Asaro, H Mathilda Lennartz, Anna C Link, Björn Drobot, André Nadler
Bifunctional Probes Reveal the Rules of Intracellular Ether Lipid Transport.
Angew Chem Int Ed Engl, Art. No. doi: 10.1002/anie.202513360 (2025)
Open Access PubMed Source   

Ether glycerophospholipids bear a long chain alcohol attached via an alkyl or vinyl ether bond at the sn1 position of the glycerol backbone. Ether lipids play a significant role in physiology and human health. However, their cellular functions remain largely unknown due to a lack of tools for identifying their subcellular localization and interacting proteins. Here, we address this methodological gap by synthesizing minimally modified bifunctional ether lipid probes by introducing diazirine and alkyne groups. To interrogate the subcellular kinetics of intracellular ether lipid transport in mammalian cells, we used a combination of fluorescence imaging, machine learning-assisted image analysis, and mathematical modelling. We find that alkyl-linked ether lipids are transported up to twofold faster than vinyl-linked species (plasmalogens), pointing to yet undiscovered cellular lipid transport machinery able to distinguish between linkage types differing by as little as two hydrogen atoms. We find that ether lipid transport predominantly occurs via non-vesicular pathways, with varying contributions from vesicular mechanisms between cell types. Altogether, our results suggest that differential recognition of alkyl- and vinyl ether lipids by lipid transfer proteins contributes to their distinct biological functions. In the future, the probes reported here will enable studying ether lipid biology in much greater detail through identification of interacting proteins and in-depth characterization of intracellular ether lipid dynamics.
@article{Böhlig9058,
author={Kristin Böhlig, Juan M Iglesias-Artola, Antonino Asaro, H Mathilda Lennartz, Anna C Link, Björn Drobot, André Nadler},
title={Bifunctional Probes Reveal the Rules of Intracellular Ether Lipid Transport.},
journal ={Angewandte Chemie (International ed. in English)},
volume={},
pages={1--1},
year=2025
}

Camilo A. S. Afanador*, Stéphane Urcun*, Ivo F. Sbalzarini, Stéphane P. A. Bordas, Olga Barrera, Mohammad Mahdi Rajabi, Romain Seil, Anas Obeidat
Mechanics of knee meniscus results from precise balance between material microstructure and synovial fluid viscosity.
PLoS ONE, 20(9) Art. No. e0304440 (2025)
Open Access   PubMed Source   

The meniscus plays a crucial role in the biomechanics of the knee, serving as load transmitter and reducing friction between joints. Understanding the biomechanics of the meniscus is essential to effective treatment of knee injuries and degenerative conditions. This study aims to elucidate the relationship between the porous microstructure of the human knee meniscus and its biomechanical function, specifically focusing on fluid dynamics at the pore scale. Here, we use two central-meniscus samples extracted from a human knee and reconstruct high-resolution geometry models from [Formula: see text]-CT scans. By eroding the channels of the original meniscus geometry, we simulate perturbed microstructures with varying porosities ( 53% to 80%), whilst preserving the connectivity of the porous structure. We numerically solve for the fluid dynamics in the meniscus using a mesh-free particle method, considering various inlet pressure conditions, characterising the fluid flow within the microstructures. The results of the original microstructure associated with a physiological dynamic viscosity of synovial fluid are in accordance with biophysical experiments on menisci. Furthermore, the eroded microstructure with a 33% increase in porosity exhibited a remarkable 120% increase in flow velocity. This emphasises the sensitivity of meniscus physiology to the porous microstructure, showing that detailed computational models can explore physiological and pathological conditions, advancing further knee biomechanics research.
@article{Afanador9041,
author={Camilo A. S. Afanador, Stéphane Urcun, Ivo F. Sbalzarini, Stéphane P. A. Bordas, Olga Barrera, Mohammad Mahdi Rajabi, Romain Seil, Anas Obeidat},
title={Mechanics of knee meniscus results from precise balance between material microstructure and synovial fluid viscosity.},
journal ={PloS one},
volume={20},
issue ={9},
pages={null--null},
year=2025
}

Subham Biswas, Rahul Grover, Cordula Reuther, Chetan Poojari, Reza Shaebani, Shweta Nandakumar, Mona Gruenewald, Amir Zablotsky, Jochen S Hub, Stefan Diez, Karin John#, Laura Schaedel#
Tau accelerates tubulin exchange in the microtubule lattice.
Nat Phys, Art. No. doi: 10.1038/s41567-025-03003-7 (2025)
Open Access Source   

Microtubules are cytoskeletal filaments characterized by dynamic instability at their tips and a dynamic lattice that undergoes continuous tubulin loss and incorporation. Tau, a neuronal microtubule-associated protein, is well known for its role in stabilizing microtubule tips and promoting microtubule bundling. Here we demonstrate that tau also modulates microtubule lattice dynamics. Although tau lacks enzymatic activity, it significantly accelerates tubulin exchange within the lattice, particularly at topological defect sites. Our findings indicate that tau enhances lattice anisotropy by stabilizing longitudinal tubulin-tubulin interactions while destabilizing lateral ones, thereby enhancing the mobility and annihilation of lattice defects. These results challenge the traditional view of tau as merely a passive stabilizer, revealing its active role in dynamically remodelling the microtubule lattice structure.
@article{Biswas9064,
author={Subham Biswas, Rahul Grover, Cordula Reuther, Chetan Poojari, Reza Shaebani, Shweta Nandakumar, Mona Gruenewald, Amir Zablotsky, Jochen S Hub, Stefan Diez, Karin John, Laura Schaedel},
title={Tau accelerates tubulin exchange in the microtubule lattice.},
journal ={Nature physics},
volume={},
pages={1--1},
year=2025
}

Julia Vorhauser, Theodoros I Roumeliotis, David Coupe, Jacky K Leung, Lu Yu, Kristin Böhlig, Thomas Zerjatke, Ingmar Glauche, André Nadler, Jyoti S Choudhary, Jorg Mansfeld
A redox switch in p21-CDK feedback during G2 phase controls the proliferation-cell cycle exit decision.
Mol Cell, 85(17) 3241-3255 (2025)
Open Access PubMed Source   

Reactive oxygen species (ROS) influence cell proliferation and fate decisions by oxidizing cysteine residues (S-sulfenylation) of proteins, but specific targets and underlying regulatory mechanisms remain poorly defined. Here, we employ redox proteomics to identify cell-cycle-coordinated S-sulfenylation events and investigate their functional role in proliferation control. Although ROS levels rise during cell cycle progression, the overall oxidation of the proteome remains constant, with dynamic S-sulfenylation restricted to a subset of cysteines. Among these, we identify a critical redox-sensitive cysteine residue (C41) in the cyclin-dependent kinase (CDK) inhibitor p21. C41 oxidation regulates the interaction of p21 with CDK2 and CDK4, controlling a double-negative feedback loop that determines p21 stability. When C41 remains reduced, p21's half-life increases in the G2 phase, resulting in more p21 inheritance to daughter cells, suppressing proliferation and promoting senescence after irradiation. Notably, we identify dynamic S-sulfenylation on further cell cycle regulators, implying coordination of cell cycle and redox control.
@article{Vorhauser9054,
author={Julia Vorhauser, Theodoros I Roumeliotis, David Coupe, Jacky K Leung, Lu Yu, Kristin Böhlig, Thomas Zerjatke, Ingmar Glauche, André Nadler, Jyoti S Choudhary, Jorg Mansfeld},
title={A redox switch in p21-CDK feedback during G2 phase controls the proliferation-cell cycle exit decision.},
journal ={Molecular cell},
volume={85},
issue ={17},
pages={3241--3255},
year=2025
}

Patrick M McCall#, Kyoohyun Kim, Anna Shevchenko, Martine Ruer-Gruß, Jan Peychl, Jochen Guck, Andrej Shevchenko, Anthony Hyman, Jan Brugués#
A label-free method for measuring the composition of multicomponent biomolecular condensates.
Nat Chem, Art. No. doi: 10.1038/s41557-025-01928-3 (2025)
Open Access PubMed Source   

Many subcellular compartments are biomolecular condensates made of multiple components, often including several distinct proteins and nucleic acids. However, current tools to measure condensate composition are limited and cannot capture this complexity quantitatively because they either require fluorescent labels, which can perturb composition, or can distinguish only one or two components. Here we describe a label-free method based on quantitative phase imaging and analysis of tie-lines and refractive index to measure the composition of reconstituted condensates with multiple components. We first validate the method empirically in binary mixtures, revealing sequence-encoded density variation and complex ageing dynamics for condensates composed of full-length proteins. We then use analysis of tie-lines and refractive index to simultaneously resolve the concentrations of five macromolecular solutes in multicomponent condensates containing RNA and constructs of multiple RNA-binding proteins. Our measurements reveal an unexpected decoupling of density and composition, highlighting the need to determine molecular stoichiometry in multicomponent condensates. We foresee this approach enabling the study of compositional regulation of condensate properties and function.
@article{McCall9055,
author={Patrick M McCall, Kyoohyun Kim, Anna Shevchenko, Martine Ruer-Gruß, Jan Peychl, Jochen Guck, Andrej Shevchenko, Anthony Hyman, Jan Brugués},
title={A label-free method for measuring the composition of multicomponent biomolecular condensates.},
journal ={Nature chemistry},
volume={},
pages={1--1},
year=2025
}

Bruno C Vellutini#, Marina B Cuenca, Abhijeet Krishna, Alicja Szałapak, Carl D. Modes, Pavel Tomancak#
Patterned invagination prevents mechanical instability during gastrulation.
Nature, Art. No. doi: 10.1038/s41586-025-09480-3 (2025)
Open Access PubMed Source   

Mechanical forces are crucial for driving and shaping tissue morphogenesis during embryonic development1-3. However, their relevance for the evolution of development remains poorly understood4. Here we show that an evolutionary novelty of fly embryos-the patterned embryonic invagination known as the cephalic furrow5-7-has a mechanical role during Drosophila gastrulation. By integrating in vivo experiments and in silico simulations, we demonstrate that the head-trunk boundary of the embryo is under increased compressive stress due to the concurrent formation of mitotic domains and germ band extension and that the cephalic furrow counteracts these stresses, preventing mechanical instabilities during gastrulation. Then, by comparing the genetic patterning of species with and without the cephalic furrow, we find evidence that changes in the expression of the transcription factor buttonhead are associated with the evolution of the cephalic furrow. These results suggest that the cephalic furrow may have evolved through the genetic stabilization of morphogenesis in response to the mechanical challenges of dipteran gastrulation. Together, our findings uncover empirical evidence for how mechanical forces can influence the evolution of morphogenetic innovations in early development.
@article{Vellutini9040,
author={Bruno C Vellutini, Marina B Cuenca, Abhijeet Krishna, Alicja Szałapak, Carl D. Modes, Pavel Tomancak},
title={Patterned invagination prevents mechanical instability during gastrulation.},
journal ={Nature},
volume={},
pages={1--1},
year=2025
}

Jannik Rothkegel, Sylvia Kaufmann, Michaela Wilsch-Bräuninger, Catarina Lopes, Rita Mateus
Purine Molecular Interactions Determine Anisotropic Shape of Zebrafish Biogenic Crystals.
Small Methods, 9(9) Art. No. e01956 (2025)
Open Access PubMed Source   

Across phyla, many organisms self-organize crystals, for functions like vision, pigmentation, and metabolite storage. In zebrafish, a vertebrate known for its crystal-based color patterns, iridophores concentrate purines in membrane-bound organelles, the iridosomes. Inside these vesicles, crystals assemble into large, flat, and thin hexagons following unknown mechanisms that defy typical thermodynamic interactions. Here, we investigate the development of zebrafish iridosomal crystals by using live imaging, cryoFIB-SEM, and novel morphometric analysis pipelines. In doing so, we find that crystal growth predominantly occurs along the b-crystallographic axis, producing their characteristic anisotropic shape. By performing comparative genetic analyses in vivo and reproducing such conditions in silico, we uncover that the zebrafish crystals' in-plane hydrogen bond molecular structure is the main determinant for the observed crystal anisotropy. Macroscopically, the b-axis anisotropy is controlled by the ratio of guanine-to-hypoxanthine in the iridosome, without affecting the other axes. At the atomic level, the extent of the (100) facet anisotropy depends entirely on the type, number, and strength of molecular H-bonds within the crystal lattice. Mechanistically, our work shows that purine diversity and availability inside the zebrafish iridosome is key to form an anisotropic crystal lattice, leading to the observed functional crystal shapes.
@article{Rothkegel9038,
author={Jannik Rothkegel, Sylvia Kaufmann, Michaela Wilsch-Bräuninger, Catarina Lopes, Rita Mateus},
title={Purine Molecular Interactions Determine Anisotropic Shape of Zebrafish Biogenic Crystals.},
journal ={Small methods},
volume={9},
issue ={9},
pages={null--null},
year=2025
}

Wulf Tonnus, Francesca Maremonti, Shubhangi Gavali, Marlena Nastassja Schlecht, Florian Gembardt, Alexia Belavgeni, Nadja Leinung, Karolin Flade, Natalie Bethe, Sofia Traikov, Anne Haag, Danny Schilling, Sider Penkov, Melodie Mallais, Christine Gaillet, Claudia Meyer, Melika Katebi, Anushka Ray, Louisa M S Gerhardt, Anne Brucker, Jorunn Naila Becker, Mirela Tmava, Lisa Schlicker, Almut Schulze, Nina Himmerkus, Andrej Shevchenko, M Peitzsch, Uladzimir Barayeu, Sonia Nasi, Juliane Putz, Kenneth S Korach, Joel Neugarten, Ladan Golestaneh, Christian Hugo, Jan Ulrich Becker, Joel M Weinberg, Svenja Lorenz, Bettina Proneth, Marcus Conrad, Eckhard Wolf, Bernd Plietker, Raphaël Rodriguez, Derek A Pratt, Tobias P Dick, Maria Fedorova, Stefan R. Bornstein, Andreas Linkermann
Multiple oestradiol functions inhibit ferroptosis and acute kidney injury.
Nature, 645(8082) 1011-1019 (2025)
Open Access PubMed Source   

Acute tubular necrosis mediates acute kidney injury (AKI) and nephron loss1, the hallmark of end-stage renal disease2-4. For decades, it has been known that female kidneys are less sensitive to AKI5,6. Acute tubular necrosis involves dynamic cell death propagation by ferroptosis along the tubular compartment7,8. Here we demonstrate abrogated ferroptotic cell death propagation in female kidney tubules. 17β-oestradiol establishes an anti-ferroptotic state through non-genomic and genomic mechanisms. These include the potent direct inhibition of ferroptosis by hydroxyoestradiol derivatives, which function as radical trapping antioxidants, are present at high concentrations in kidney tubules and, when exogenously applied, protect male mice from AKI. In cells, the oxidized hydroxyoestradiols are recycled by FSP19,10, but FSP1-deficient female mice were not sensitive to AKI. At the genomic level, female ESR1-deficient kidney tubules partially lose their anti-ferroptotic capacity, similar to ovariectomized mice. While ESR1 promotes the anti-ferroptotic hydropersulfide system, male tubules express pro-ferroptotic proteins of the ether lipid pathway which are suppressed by ESR1 in female tissues until menopause. In summary, we identified non-genomic and genomic mechanisms that collectively explain ferroptosis resistance in female tubules and may function as therapeutic targets for male and postmenopausal female individuals.
@article{Tonnus9048,
author={Wulf Tonnus, Francesca Maremonti, Shubhangi Gavali, Marlena Nastassja Schlecht, Florian Gembardt, Alexia Belavgeni, Nadja Leinung, Karolin Flade, Natalie Bethe, Sofia Traikov, Anne Haag, Danny Schilling, Sider Penkov, Melodie Mallais, Christine Gaillet, Claudia Meyer, Melika Katebi, Anushka Ray, Louisa M S Gerhardt, Anne Brucker, Jorunn Naila Becker, Mirela Tmava, Lisa Schlicker, Almut Schulze, Nina Himmerkus, Andrej Shevchenko, M Peitzsch, Uladzimir Barayeu, Sonia Nasi, Juliane Putz, Kenneth S Korach, Joel Neugarten, Ladan Golestaneh, Christian Hugo, Jan Ulrich Becker, Joel M Weinberg, Svenja Lorenz, Bettina Proneth, Marcus Conrad, Eckhard Wolf, Bernd Plietker, Raphaël Rodriguez, Derek A Pratt, Tobias P Dick, Maria Fedorova, Stefan R. Bornstein, Andreas Linkermann},
title={Multiple oestradiol functions inhibit ferroptosis and acute kidney injury.},
journal ={Nature},
volume={645},
issue ={8082},
pages={1011--1019},
year=2025
}
* joint first authors, # joint corresponding authors