The chemistry and physics of dormancy

How does the cytoplasm change under starvation conditions and how do cells survive and recover from starvation? Our recent findings suggest that the eukaryotic cytoplasm undergoes drastic changes during starvation. We found that in energy-depleted yeast, metabolic enzymes assemble into filaments and that filament formation leads to enzyme inactivation (Petrovska et al., 2014). We could further show that enzyme assembly is triggered by a starvation-induced drop in the cytosolic pH and that enzymes contained in filaments can be reused when starved cells resume growth, suggesting that these filaments are storage depots for enzymes (Figure 1).

In a related line of research, we discovered that acidification of the cytoplasm promotes entry into a dormant state (Munder et al., submitted). We found that dormancy is associated with a drastic decrease in the mobility of organelles and foreign tracer particles, a phenomenon, which we call cytoplasmic arrest. We could show that cytoplasmic arrest is triggered by pH-induced assembly of many cytosolic proteins into higher order structures, thus promoting a transition of the cytoplasm from a fluid to a solid-like state with increased mechanical stability. These findings have important implications for understanding alternative physiological states, such as quiescence and dormancy, and create a new view of the eukaryotic cytoplasm as an adaptable fluid that can reversibly transition into a protective glass state.

<b>Figure 1:</b> A simple physicochemical parameter—the cytosolic pH—triggers the assembly of metabolic enzymes into enzymatically inactive filaments, suggesting a pathway for entry into a dormant state. Transitions between unassembled enzyme decamers (left), filaments (middle), and fibrils (right) are driven by pH changes and excluded volume effects. Blue spheres denote inert macromolecules that are excluded from the space occupied by the enzyme (indicated by the dotted lines). The bottom diagram illustrates the cumulative excluded volume effect that entropically drives assembly.

Future Plans:

In the future, we aim to firmly establish that changes in the cytosolic pH regulate a liquid to solid phase transition of the cytoplasm. We further aim to determine the structure of several pH-induced assemblies in collaboration with Gaia Pigino at the MPI-CBG. In addition, we will investigate the functional role of cytosolic pH changes in other organisms such as C. elegans and Drosophila. We expect that phase transitions play an important role during dormancy and are used more broadly to promote adaption to unfavorable environmental conditions.