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Basusree Ghosh*, Patrick M McCall*, Kristian Le Vay, Archishman Ghosh, Lars Hubatsch, David Thomas Gonzales, Jan Brugués, Hannes Mutschler#, T-Y Dora Tang#
RNA-peptide interactions tune the ribozyme activity within coacervate microdroplet dispersions.
Nat Commun, 16(1) Art. No. 8765 (2025)
Open Access PubMed Source Full Text   

Membrane-free complex coacervate microdroplets are compelling models for primitive compartmentalisation with the ability to form from biological molecules. However, understanding how molecular interactions can influence physicochemical properties and catalytic activity of membrane-free compartments is still in its infancy. This is important for defining the function of membrane-free compartments during the origin of life as well as in modern biology. Here, we use RNA-peptide coacervate microdroplets prepared with prebiotically relevant amino acids and a minimal hammerhead ribozyme. This is a model system to probe the relationship between coacervate composition, its properties and ribozyme activity. We show that ribozyme catalytic activity is inhibited within the coacervate compared to buffer solution, whilst variations in peptide sequence can modulate rates and yield of the ribozyme within the coacervate droplet by up to 15-fold. The apparent ribozyme rate constant is anti-correlated with its concentration and correlated to its diffusion coefficient within the coacervates. Our results provide a relationship between the physicochemical properties of the coacervate microenvironment and the catalytic activity of the ribozyme where membrane-free compartments could provide a selection pressure to drive molecular evolution on prebiotic earth.
@article{Ghosh9066,
author={Basusree Ghosh, Patrick M McCall, Kristian Le Vay, Archishman Ghosh, Lars Hubatsch, David Thomas Gonzales, Jan Brugués, Hannes Mutschler, T-Y Dora Tang},
title={RNA-peptide interactions tune the ribozyme activity within coacervate microdroplet dispersions.},
journal ={Nature communications},
volume={16},
issue ={1},
pages={null--null},
year=2025
}

Anna Hadarovich, David Kuster, Maria Luisa Romero Romero, Agnes Toth-Petroczy
On the Evolution of Biomolecular Condensates: From Prebiotic Origins to Subcellular Diversity.
Annu Rev Cell Dev Biol, 41(1) 403-432 (2025)
Open Access PubMed Source   

Biomolecular condensates provide a way to compartmentalize subcellular components with high temporal and spatial resolution, enabling rapid responses to signals and environmental changes. While the formation, components, and function of some condensates are well-characterized, their presence across organisms, their evolutionary history, and their origin are less well-understood. Here, we review the diversity of condensate components and highlight that not only disordered but also fully structured proteins are capable of driving condensate formation. We compare how proteomes of condensates overlap within and across species, and we present functionally analogous condensates across organisms. Additionally, we discuss the potential role of condensation in early life, suggesting that phase separation could have facilitated the selection and concentration of prebiotic molecules, promoting essential biochemical processes. We conclude that condensate-related organization principles are ubiquitously used across organisms from bacteria to mammals, and they potentially played a key role in prebiotic evolution, serving as primitive compartments for early biochemical processes.
@article{Hadarovich9033,
author={Anna Hadarovich, David Kuster, Maria Luisa Romero Romero, Agnes Toth-Petroczy},
title={On the Evolution of Biomolecular Condensates: From Prebiotic Origins to Subcellular Diversity.},
journal ={Annual review of cell and developmental biology},
volume={41},
issue ={1},
pages={403--432},
year=2025
}

Juan M Iglesias-Artola, Kristin Böhlig, Kai Schuhmann, Katelyn C Cook, H Mathilda Lennartz, Milena Schuhmacher, Pavel Barahtjan, Cristina Jiménez López, Radek Šachl, Vannuruswamy Garikapati, Karina Pombo-Garcia, Annett Lohmann, Petra Riegerová, Martin Hof, Björn Drobot, Andrej Shevchenko, Alf Honigmann#, André Nadler#
Quantitative imaging of lipid transport in mammalian cells.
Nature, 646(8084) 474-482 (2025)
Open Access PubMed Source   

Eukaryotic cells produce over 1,000 different lipid species that tune organelle membrane properties, control signalling and store energy1,2. How lipid species are selectively sorted between organelles to maintain specific membrane identities is largely unclear, owing to the difficulty of imaging lipid transport in cells3. Here we measured the retrograde transport and metabolism of individual lipid species in mammalian cells using time-resolved fluorescence imaging of bifunctional lipid probes in combination with ultra-high-resolution mass spectrometry and mathematical modelling. Quantification of lipid flux between organelles revealed that directional, non-vesicular lipid transport is responsible for fast, species-selective lipid sorting, in contrast to the slow, unspecific vesicular membrane trafficking. Using genetic perturbations, we found that coupling between energy-dependent lipid flipping and non-vesicular transport is a mechanism for directional lipid transport. Comparison of metabolic conversion and transport rates showed that non-vesicular transport dominates the organelle distribution of lipids, while species-specific phospholipid metabolism controls neutral lipid accumulation. Our results provide the first quantitative map of retrograde lipid flux in cells4. We anticipate that our pipeline for mapping of lipid flux through physical and chemical space in cells will boost our understanding of lipids in cell biology and disease.
@article{Iglesias-Artola9051,
author={Juan M Iglesias-Artola, Kristin Böhlig, Kai Schuhmann, Katelyn C Cook, H Mathilda Lennartz, Milena Schuhmacher, Pavel Barahtjan, Cristina Jiménez López, Radek Šachl, Vannuruswamy Garikapati, Karina Pombo-Garcia, Annett Lohmann, Petra Riegerová, Martin Hof, Björn Drobot, Andrej Shevchenko, Alf Honigmann, André Nadler},
title={Quantitative imaging of lipid transport in mammalian cells.},
journal ={Nature},
volume={646},
issue ={8084},
pages={474--482},
year=2025
}

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
}

Tommaso Cossetto, Jonathan Rodenfels#, Pablo Sartori#
Thermodynamic dissipation constrains metabolic versatility of unicellular growth.
Nat Commun, 16(1) Art. No. 8543 (2025)
Open Access PubMed Source Full Text   

Metabolic versatility enables unicellular organisms to grow in vastly different environments. Since growth occurs far from thermodynamic equilibrium, the second law of thermodynamics has long been believed to pose key constraints to life. Yet, such constraints remain largely unknown. Here, we integrate published data spanning decades of experiments on unicellular chemotrophic growth and compute the corresponding thermodynamic dissipation. Due to its span in chemical substrates and microbial species, this dataset samples the versatility of metabolism. We find two empirical thermodynamic rules: first, the amount of energy dissipation per unit of biomass grown is largely conserved across metabolic types and domains of life; second, aerobic respiration exhibits a trade-off between dissipation and growth, reflecting in its high thermodynamic efficiency. By relating these rules to the fundamental thermodynamic forces that drive and oppose growth, our results show that dissipation imposes tight constraints on metabolic versatility.
@article{Cossetto9067,
author={Tommaso Cossetto, Jonathan Rodenfels, Pablo Sartori},
title={Thermodynamic dissipation constrains metabolic versatility of unicellular growth.},
journal ={Nature communications},
volume={16},
issue ={1},
pages={null--null},
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
}
* joint first authors, # joint corresponding authors