Between life and death – cellular strategies for coping with acute metabolic stress during suspended animation

A PhD project for the 2022 doctoral clinical fellows programme with Nathan Goehring (primary supervisor, Crick), Guillaume Charras (UCL) and Rickie Patani (Crick/UCL).

Project description

Guillaume Charras

Professor in Cell and Tissue Biophysics, UCL

Life for many organisms is characterised by encounters with unreliable environments that pose existential threats to their survival. Organisms have therefore evolved numerous mechanisms to adapt to changing environments. One strategy used by many organisms to cope with extreme stress such as oxygen deprivation is to enter states of suspended animation or dormancy that minimise energy consumption while maintaining long term viability [1]. Induced suspended animation is also used clinically to extend organ viability, for example, in trauma patients to extend time available for transport and treatment.

Suspended animation often involves wholesale alterations in physicochemical properties of cells. For example, in some organisms, the fluid-like interior of the cell transitions into a protective solid or glass-like state [2,3]. Arrest can also trigger reversible phase separation of protein complexes within clusters and or droplets, potentially to sequester molecules in a protective conformation [4].  While such processes have been studied in unicellular organisms, we have much less understanding of how physicochemical changes in animal cells help them achieve viable, but suspended states. In particular, acute changes to cellular architecture have not been explored extensively.

Our labs are particularly interested in how self-organizing processes that establish cell architecture are affected by entry into suspended states. Under normal circumstances cells constantly consume ATP to drive processes responsible for maintaining their internal organization. This includes assembly of the cytoskeleton and patterning of the cell membrane into functional domains, but also numerous homeostatic pathways such as regulation of membrane identity and cell cycle status that depend on ATP-consuming cycles of phosphorylation and/or GTP hydrolysis. This raises the question of how such processes respond to conditions of restricted energy expenditure and whether cells have evolved general strategies to allow them to avoid the collapse of internal architecture in suspended states.

To address these questions, this project will explore the cellular response to suspended animation using mammalian tissue culture cells and the C. elegans embryo.  Preliminary data obtained by our labs and others are consistent with large scale organizational changes to these cells.  Building on these observations, we aim to characterize changes to the phospho-proteome, cellular metabolites, rheology and mechanics of arrested cells.  At the same time, we have also identified organizational changes to specific cellular structures.  Thus, in a second line of work, we will ask how such changes are induced upon the transition into suspended animation, how they may be influenced by global changes to the state of the cell, and whether they reflect specific adaptations to promote the ability of cells to recover upon reanimation.

We envision that this work will reveal general principles of the cellular response to entry into suspended animation. These principles will help inform our understanding of clinically-relevant examples of cellular dormancy, from arrested mammalian oocytes, embryos and stem cells to long term persisting cancer cells, improve our understanding of how stress influences cellular behaviours such as when cancer cells encounter oxygen-depleted micro-environments, and guide strategies for organ and tissue preservation.

The partner institution for this project is UCL.
 

References

  1.  Bickler, P.E., and Buck, L.T. (2007). Hypoxia Tolerance in Reptiles, Amphibians, and Fishes: Life with Variable Oxygen Availability. Annu. Rev. Physiol. 69, 145–170.
  2. Munder, M.C., Midtvedt, D., Franzmann, T., Nüske, E., Otto, O., Herbig, M., Ulbricht, E., Müller, P., Taubenberger, A., Maharana, S., et al. (2016). A pH-driven transition of the cytoplasm from a fluid- to a solid-like state promotes entry into dormancy. Elife 5.
  3. Parry, B.R., Surovtsev, I. V., Cabeen, M.T., O’Hern, C.S., Dufresne, E.R., and Jacobs-Wagner, C. (2014). The Bacterial Cytoplasm Has Glass-like Properties and Is Fluidized by Metabolic Activity. Cell 156, 183–194.
  4. Pu, Y., Li, Y., Jin, X., Tian, T., Ma, Q., Zhao, Z., Lin, S., Chen, Z., Li, B., Yao, G., et al. (2018). ATP-Dependent Dynamic Protein Aggregation Regulates Bacterial Dormancy Depth Critical for Antibiotic Tolerance. Mol. Cell 143–156.