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Just as life pulsates in big vibrant cities, it also prospers in crowded environments inside cells. The interior of cells is densely packed with biomolecules like proteins and nucleic acids. How is all this material distributed within a cell and what regulates its distribution? In a recent study published in “Nature Communications” researchers measure subcellular densities across a wide range of organisms. Their aim is to better understand biomolecular processes ranging from yeast cells to human cells.
Not what most scientists would think
Conventional scientific textbooks describe the cell nucleus as a compartment packed with an impressive amount of DNA wrapped around histone proteins. Now, an international team of researchers with the participation of the Max-Planck-Zentrum für Physik und Medizin, Erlangen (MPZPM), the Max Planck Institutes for Infection Biology, Berlin (MPIIB) and the Science of Light, Erlangen (MPL) has discovered that – contrary to expectations – the nucleus is less dense than the surrounding cytoplasm. Despite their rich biomolecular composition, nuclei contain less dry mass than the same volume of the surrounding cytoplasm.
Prof. Simone Reber, MPIIB and University of Applied Sciences, Berlin explains why it is important to understand how crowded cellular environments are: “It is essential to understand the ‘real’ environment inside cells as it affects biomolecular structure, dynamics, and function. The main discovery of our study is that although different species broadly vary in their absolute intracellular density, they maintain the same nuclear-to-cytoplasmic (NC) density ratio.”
“While every organism is unique in its biomolecular composition, it is likely that the fundamental physical principles of pressure balance set the density and the volume of the nucleus,” explains Prof. Vasily Zaburdaev, MPZPM and Friedrich-Alexander-Universität Erlangen-Nürnberg.
Using light to probe density at microscales
How can density be measured in microscopic objects such as individual cell compartments? Scientists use light for this purpose. Not only does light allow cells to be examined, it also enables them to be manipulated. Light can exert forces, enabling laser beams to “pull” on cells and measure their mechanical properties using an “optical stretcher”. “We had previously tried to use our optical stretcher on nuclei, but were not successful. The physically plausible – but back then biologically counterintuitive – explanation was that the nucleus had a lower density than its surrounding material,” adds Prof. Jochen Guck, MPZPM and Director at MPL, Erlangen. Therefore, the researchers developed an optical setup which allowed them to obtain three-dimensional density distributions inside cells at high resolution by combining optical diffraction tomography and confocal fluorescence microscopy.
Density as a fundamental property and diagnostic indicator
“While NC density ratios are maintained from yeast to human cells, we do start seeing deviations in disease. During stressed cellular states such as ageing, the so-called senescence, cell nuclei become denser than the cytoplasm. Thus, the study points to the fundamental importance of density as a variable that determines healthy cellular processes,” says Reber. The scientists now want to understand how cells establish and maintain a specific intracellular density distribution in order to decipher further biophysical mechanisms that regulate cell function in both healthy and pathological states.
An international and interdisciplinary effort
“Apart from being an exciting question to tackle, what stood out for me was how we were able to synergize the expertise of scientists at different locations to achieve a common goal,” says Abin Biswas, postdoc at MPZPM and MPIIB and first author. Indeed, this work was the result of close collaborative cooperation with international colleagues from the MPI for Molecular Genetics, MPI for Cell Biology and the Albert Einstein College of Medicine in New York.
Prof. Jochen Guck
Max-Planck-Zentrum für Physik und Medizin /
Max Planck Institute for the Science of Light
“Cell Physics”
https://mpzpm.mpg.de | jochen.guck@mpzpm.mpg.de
Prof. Simone Reber
Max Planck Institute for Infection Biology
“Quantitative Biology”
University of Applied Sciences Berlin
https://www.mpiib-berlin.mpg.de | reber@mpiib-berlin.mpg.de
Prof. Vasily Zaburdaev
Max-Planck-Zentrum für Physik und Medizin
“Immunophysics”
FAU Erlangen-Nürnberg
https://mpzpm.mpg.de | vasily.zaburdaev@mpzpm.mpg.de
Biswas, A., Muñoz, O., Kim, K. et al. Conserved nucleocytoplasmic density homeostasis drives cellular organization across eukaryotes. Nat Commun 16, 7597 (2025).
DOI: https://doi.org/10.1038/s41467-025-62605-0
A cell nucleus reconstituted in vitro in Xenopus laevis (African clawed frog) egg extract. Left imag ...
Copyright: Abin Biswas
Top: Illustration of the complex interior within the nucleus and cytoplasm (Illustration by David Go ...
Copyright: Abin Biswas, Illustration by David S. Goodsell
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