Conserved nucleocytoplasmic density homeostasis drives cellular organization across eukaryotes

Abin Biswas, Omar Muñoz, Kyoohyun Kim, Carsten Hoege, Benjamin M. Lorton, Rainer Nikolay, Matthew L. Kraushar, David Shechter, Jochen Guck (), Vasily Zaburdaev () and Simone Reber ()
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Abin Biswas: Max Planck Institute for Infection Biology
Omar Muñoz: Max-Planck-Zentrum für Physik und Medizin
Kyoohyun Kim: Max Planck Institute for the Science of Light
Carsten Hoege: Max Planck Institute of Molecular Cell Biology & Genetics
Benjamin M. Lorton: Albert Einstein College of Medicine
Rainer Nikolay: Max Planck Institute for Molecular Genetics
Matthew L. Kraushar: Max Planck Institute for Molecular Genetics
David Shechter: Albert Einstein College of Medicine
Jochen Guck: Max Planck Institute for the Science of Light
Vasily Zaburdaev: Max-Planck-Zentrum für Physik und Medizin
Simone Reber: Max Planck Institute for Infection Biology

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract The confinement of macromolecules has profound implications for cellular biochemistry. It generates environments with specific physical properties affecting diffusion, macromolecular crowding, and reaction rates. Yet, it remains unknown how intracellular density distributions emerge and affect cellular physiology. Here, we show that the nucleus is less dense than the cytoplasm and that living systems establish a conserved density ratio between these compartments due to a pressure balance across the nuclear envelope. Nuclear transport establishes a specific nuclear proteome that exerts a colloid osmotic pressure, which, assisted by chromatin pressure, increases nuclear volume. During C. elegans development, the nuclear-to-cytoplasmic density ratio is robustly maintained even when nuclear-to-cytoplasmic volume ratios change. We show that loss of density homeostasis correlates with altered cell functions like senescence and propose density distributions as key markers in pathophysiology. In summary, this study reveals a homeostatic coupling of macromolecular densities that drives cellular organization and function.

Date: 2025
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DOI: 10.1038/s41467-025-62605-0

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