Role of CLK-1 in regulating the mitochondrial unfolded protein response and longevity

Abstract

Ageing is a complex process which involves conserved signalling pathways, alterations in which can regulate the lifespan of multiple organisms from mice to Caenohabditis elegans (C. elegans). The mitochondria are strongly implicated as key organelles in regulating ageing. As they provide the major source of energy within cells, it is vital that their functioning is maintained and that they can communicate any defects to the nucleus, where the majority of mitochondrial components are encoded. In the event of mitochondrial stress, the mitochondrial unfolded protein response (UPRmt) becomes activated, which controls the levels of mitochondrial protein folding and import as well as the degradation of damaged proteins. Loss of activity of the mitochondrial monooxygenase CLK-1, which is required to produce ubiquinone, leads to robust activation of the UPRmt. C. elegans clk-1 null mutants have pleiotropic phenotypes including an extended lifespan, however the role of the UPRmt in these phenotypes is not fully understood. Here it is demonstrated that the transcription factors ATFS-1 and DVE-1 play an important role in the activation of the UPRmt in clk-1 null worms and are also required for their increased longevity. This suggests that activation of the UPRmt contributes to the longevity phenotype. It is further shown that the expression of CLK-1 in a single worm tissue is sufficient to rescue all the clk-1 null phenotypes. This argues that the mitochondrial stress signalling mechanism in clk-1 null mutants is distinct from a previously characterised cell non-autonomous mitochondrial stress pathway that regulates the UPRmt and lifespan. Finally, to further investigate the role of CLK-1, CRSISPR gene editing technology was successfully set up to modify the clk-1 genomic locus. Taken together, the data presented in this thesis uncovers signalling events underpinning the stress response and longevity phenotypes of clk-1 mutants.

Date of Award	1 Aug 2018
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Alan Whitmarsh (Supervisor) & Gino Poulin (Supervisor)