Srivastava, N.; Calabrese, L.; Plancke, C.; Rollin, R.; Venkova, L.; Havas, K.; Cosentino Lagomarsino, M.; Piel, M.

The concentration of macromolecules, especially proteins, is vital for cellular function and is influenced not only by synthesis and degradation but also by the total cell volume. While we understand various growth regulation mechanisms, the coupling of dry mass and volume in growing mammalian cells remains unclear. Here we show that two independent mechanisms acting in single cells, one regulating volume through biophysical modulation and the other controlling protein biosynthesis, work together to maintain macromolecular dry mass density and restore it following perturbations. These mechanisms ensure that proliferating cells remain within a specific range around a target density, providing density homeostasis at the population level. Although the target density appears consistent across different cell types, it is disrupted around cell division, upon perturbations of growth pathways and in senescent cells. It may represent an optimal value for cellular processes, ensuring the efficiency of essential intracellular functions.