Dissecting stress resilience mechanisms during epithelial homeostasis and repair

Abstract

Throughout a human’s life, our tissues are exposed to breadth of toxic insults, both endogenous
and exogenous in origin. From the external environment, we must resist damage from exposure
to various forms of ionising radiation, exposure to toxic pollutants and even endure epithelial
wounds. Internally, the biproducts of routine, homeostatic metabolism can result in collateral
damage to our own tissues. To cope with these constant insults, we have evolved an arsenal of
cytoprotective mechanisms that act to shield our tissues from these threats and repair damage
incurred. Here I have explored two contrasting yet complimentary models of tissue stress to
further our current understanding of how our bodies are able to maintain homeostatic conditions
under a barrage of endogenous and exogenous threats.
Firstly, we have investigated how renal tissues under near constant basal metabolic stress
adapt to maintain homeostatic function. Using the Drosophila renal (Malpighian) tubules and
integrating ex vivo live-imaging and spatio-temporal genetic/pharmacological perturbation we
have uncovered the distinct metabolic signatures of functionally diverse cell subtypes that are
essential to support robust renal physiology. We find that diversion of key metabolic pools is
vital to support cellular antioxidant cytoprotection and delay premature renal senescence, whilst
intense energetic demands are met by partitioning of alternative metabolites.
Secondly, we have begun to further dissect the reparative steps required to respond to transient
wound induced stress using the Drosophila pupal epithelium. Again, using advanced imaging
techniques and genetic perturbations, we observe mitochondrial and plasma membrane damage
upon epithelial wounding, which are rapidly repaired to restore subcellular, cellular and tissue
wide homeostasis.
Ultimately, we envision that this body of work furthers our understanding of cytoprotective
responses to different modes of tissue stress and additionally promotes the Drosophila renal
system as a powerful platform to decipher cell-type specific metabolic adaptations.

Date of Award	23 Jan 2024
Original language	English
Awarding Institution	University of Bristol
Supervisor	Helen M A Weavers (Supervisor)