Mechano-dependent sorbitol accumulation supports biomolecular condensate

S Torrino and WM Oldham and AR Tejedor and IS Burgos and L Nasr and N Rachedi and K Fraissard and C Chauvet and C Sbai and BP O'Hara and S Abélanet and F Brau and C Favard and S Clavel and R Collepardo-Guevara and JR Espinosa and I Ben-Sahra and T Bertero, CELL, 188, 447-464 (2025).

DOI: 10.1016/j.cell.2024.10.048

Condensed droplets of protein regulate many cellular functions, yet the physiological conditions regulatingtheir formation remain largely unexplored. Increasing our understanding of these mechanisms is paramount,as failure to control condensate formation and dynamics can lead to many diseases. Here, we provide evi-dence that matrix stiffening promotes biomolecular condensationin vivo. We demonstrate that the extracel-lular matrix links mechanical cues with the control of glucose metabolism to sorbitol. In turn, sorbitol acts as anatural crowding agent to promote biomolecular condensation. Usingin silicosimulations andin vitroas-says, we establish that variations in the physiological range of sorbitol concentrations, but not glucose con-centrations, are sufficient to regulate biomolecular condensates. Accordingly, pharmacological and geneticmanipulation of intracellular sorbitol concentration modulates biomolecular condensates in breast cancer- amechano-dependent disease. We propose that sorbitol is a mechanosensitive metabolite enabling proteincondensation to control mechano-regulated cellular functions.

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