The chemistry and physics of cellular shutdown: unraveling how and why cells enter into a hypometabolic state

• Applicant: Professor Dr. Simon Alberti
• Subject Area: Cell Biology ; Biophysics
• Term: from 2015 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 268449510

A hallmark of living matter is its highly dynamic and yet exquisitely organized state. Maintenance of this delicate state requires a constant input of energy and a metabolism that is far from thermodynamic equilibrium. However, organisms typically live in unpredictable environments and frequently experience conditions that are not optimal for growth and reproduction. Under such conditions, cells can protect themselves by entering into a non-dividing state with reduced metabolic activity (hypometabolic state). However, how cells enter into and recover from this state is a largely unresolved question.Recent findings in budding yeast suggest that starvation and other stress conditions induce an extensive rearrangement of the cytoplasm and the assembly of key metabolic enzymes into higher order structures. The hypothesis to be tested in this grant proposal is that these changes are induced by a drop in cytosolic pH and that the pH-induced alterations in cytoplasmic organization promote entry into a protective hypometabolic state. To prove this hypothesis, we will investigate how starvation-induced enzyme assemblies form (their mechanism of assembly) and how assembly formation affects the activity of these enzymes (their molecular and cellular function). Our preliminary findings suggest that assembly of the translation initiation factor eIF2B into filamentous structures plays a key role in shutting down protein synthesis. Hence, we will particularly focus on the question of how eIF2B assembly promotes entry into a hypometabolic state. We will further investigate whether the cytoplasm changes its physical properties in response to stress. We already have strong evidence that the cytoplasm transitions from a dynamic to a frozen state upon energy depletion, and we aim to identify the molecular and structural causes of cytoplasmic freezing. Finally, we aim to demonstrate that these molecular changes improve the survival and longevity of yeast cells in response to energy depletion and other types of stresses.Our studies will have broad implications for understanding alternative physiological states, such as cellular dormancy and quiescence. They will also reveal how a eukaryotic cell can deal with severe environmental perturbations. We also predict that our studies provide important clues about potential causes and consequences of metabolic diseases and aging, and will reveal critical molecular changes that an organism undergoes when it dies.

• DFG Programme: Research Grants