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Title: A nuclear role for the respiratory enzyme CLK-1 in regulating reactive oxygen species, the mitochondrial unfolded protein response and longevity
Author: Barnes, Robert
ISNI:       0000 0004 6059 9780
Awarding Body: University of Manchester
Current Institution: University of Manchester
Date of Award: 2016
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As the major source of energy in the cell, mitochondria need to be able to effectively communicate their status to the nucleus. Defects in this process can have profound effects on the health of an organism and may affect its lifespan. The mitochondrial enzyme CLK-1 is required to produce ubiquinone for respiration and CLK-1 loss of function mutants have been shown to increase lifespan in both Caenorhabditis elegans and mammals. In this thesis, it is demonstrated that in addition to its mitochondrial role, CLK-1 also localises to the nucleus in C. elegans. This nuclear localisation is mediated by reactive oxygen species (ROS) and can be blocked using anti-oxidant treatment. In the nucleus CLK-1 regulates gene expression to suppress ROS production, suppresses the mitochondrial unfolded protein response and regulates lifespan. The importance of CLK-1 enzymatic activity for its nuclear role was also tested and it appears that enzymatic function is required to regulate ROS homeostasis but not for lifespan regulation. Interestingly, in fertile adult hermaphrodites nuclear CLK-1::GFP was only detected during the reproductive period. This suggests that there is a second mechanism regulating its localisation. This research indicates that CLK-1 may be part of a homeostatic regulatory mechanism that acts to suppress activation of stress responses in response to minor fluctuations in ROS levels.
Supervisor: Whitmarsh, Alan Sponsor: BBSRC
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: CLK-1