Cellular regulation of viscosity

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Viscosity is fundamental to biochemical reactions and hence, life itself. Temperature affects the diffusion rate of molecules and in turn modulates the rate of reactions in non-living systems. For decades it has been assumed that cells in living organisms are subject to the same principles that connect temperature, viscosity, diffusion and reaction rates. Yet it has been a mystery how the incredibly complex diffusion-based interaction networks of a cell are robust to these fluctuations, since perturbation of reaction kinetics in even one pathway has the potential to impact multiple aspects of cellular functioning. The regulation of intracellular viscosity as a strategy to mitigate changes in diffusion due to the environment has been largely unexplored. This proposal addresses how intracellular viscosity is actively regulated, the effects of viscosity on cellular processes, and viscosity dysregulation in disease. We recently discovered that cytosolic diffusion rates and viscosity-controlled reaction rates are held invariant across at least 20° C of steady state temperatures in Saccharomyces cerevisiae. We found that cellular viscosity temporarily increases in response to acute stress. We named this phenomenon “viscoadaptation”. Viscoadaptation is both a homeostatic mechanism for maintaining constant viscosity despite fluctuations in temperature as well as an acute response to a variety of environmental stressors. Viscoadaptation acts via production of the viscous carbohydrate glycogen that is linked to human health and disease, and we hypothesize that low energy levels trigger viscoadaptation. The discovery of viscoadaptation marks a major advance in our understanding of how cells regulate their biophysical properties. Yet many mysteries remain, including 1) how viscodaptation affects the biophysical properties of cells, 2) what signaling pathways regulate viscoadaptation. We propose to (aim 1) study the effect of glycogen on protein mobility and structure (aim 2) investigate how the pathways regulating viscosity in yeast and human cells. The proposed studies will examine regulation of a fundamental yet largely unexplored biophysical feature of cells, viscosity. This will elucidate the long overlooked contribution of viscosity to critical cellular processes and the mechanisms by which this fundamental property is actively regulated in cells. In doing so, this work has the potential to reframe disease conditions from the perspective of viscosity dysregulation and usher in a new conceptual framework of "viscosity-related" pathologies.