Understanding protein diffusion in confined cell compartments

Dieteren, Cindy

Inside cells, most chemical reactions are spatially restricted in compartments like the cytosol, nucleus, endoplasmic reticulum and mitochondrion. However, diffusion of intracellular solutes like metabolites and proteins is still an area of deep controversies because the intracellular medium is not simply a diluted solution as mistakenly accepted in still many works. Although it is recognized that the kinetics of reaction-diffusion systems greatly depend on the physicochemical properties of the compartment, progress in this field has been held back by the lack of quantitative information. This is a hot topic in cell and systems biology.

In this study a team of Nijmegen scientists from the Departments of Biochemistry, Biophysics and Pediatrics joined forces to develop a novel strategy that allows determination of the 'real' (i.e. purely solvent-dependent) diffusion constant of proteins inside cell compartments with an experimentally accessible nanostructure. In essence, the method consists of quantitatively matching synthetic fluorescence recovery after photobleaching (FRAP) curves, generated by a realistic 3D mathematical model, with experimental FRAP data of fluorescent proteins (FPs). Our hybrid in silico and experimental approach revealed that, in sharp contrast to the current biological dogma, FP diffusion in the mitochondrial matrix is severely hindered by diffusion barriers (cristae). Therefore, we propose that regulated alterations in compartment nanostructure allow the cell to control solute diffusion inside cellular compartments. This implies that alterations in mitochondrial nanostructure, as observed during numerous (patho)physiological conditions, can affect the properties of intra-matrix reaction-diffusion systems and thereby mitochondrial and cellular function.

Reference: Cindy E.J. Dieteren, Stan C.A.M. Gielen, Leo G.J. Nijtmans, Jan A.M. Smeitink, Herman G. Swarts, Roland Brock, Peter H.G.M. Willems & Werner J.H. Koopman (2011). Solute diffusion is hindered in the mitochondrial matrix. Proc. Natl. Acad. Sci. USA (in press).


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