Macromolecular crowding A novel player in mitochondrial physiology and disease

In a recent EMBO Journal study, researchers from the Radboudumc and the University of Twente collaborated with the University of Amsterdam and King’s college London to demonstrate that the mitochondrial matrix displays macromolecular crowding-associated phenomena.

Macromolecules of various size induce crowding of the cellular environment. This crowding impacts on biochemical reactions by increasing solvent viscosity, decreasing the water-accessible volume and altering protein shape, function and interactions. Although mitochondria represent highly protein-rich organelles, most of these proteins are somehow immobilized. Therefore, it is still unclear whether the mitochondrial matrix solvent exhibits macromolecular crowding. It has been shown that fluorescent protein fusion peptides (AcGFP1 concatemers) in the mitochondrial matrix of HeLa cells display an elongated molecular structure and that their diffusion constant decreases with increasing molecular weight in a manner typical of macromolecular crowding. Chloramphenicol treatment impaired mitochondrial function and reduced the number of cristae without triggering mitochondrial orthodox-to-condensed transition or a mitochondrial unfolded protein response. Chloramphenicol-treated cells displayed progressive concatemer immobilization with increasing molecular weight and an eight-fold matrix viscosity increase, compatible with increased macromolecular crowding. These results establish that the matrix solvent exhibits macromolecular crowding in functional and dysfunctional mitochondria. Therefore, changes in matrix crowding likely affect matrix biochemical reactions in a manner depending on the molecular weight of the involved crowders and reactants. This makes macromolecular crowding a potential target for manipulation of mitochondrial function in human disease.

Publication

Bulthuis EP, Dieteren CEJ, Bergmans J, Berkhout J, Wagenaars JA, van de Westerlo EMA, Podhumljak E, Hink MA, Hesp LFB, Rosa HS, Malik AN, Lindert MK, Willems PHGM, Gardeniers HJGE, den Otter WK, Adjobo-Hermans MJW, Koopman WJH. Stress-dependent macromolecular crowding in the mitochondrial matrix. EMBO J. 2023 Feb 24:e108533. doi: 10.15252/embj.2021108533. Epub ahead of print. PMID: 36825437.