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Kotecki, Claire
(2010).
DOI: https://doi.org/10.21954/ou.ro.0000f231
Abstract
As a result of normal physiological processes, organisms generate reactive oxygen species (ROS), which include hydrogen peroxide (H2O2) and some free radicals, including superoxide radicals (O2). When the balance between pro- and antioxidants is perturbed, an organism is subjected to oxidative stress. This gives rise to oxidative damage, the accumulation of which has been implicated in ageing. This thesis describes work using Drosophila melanogaster as a model system to elucidate the relationship between oxidative stress and lifespan, focusing on glutamate-cysteine ligase (GCL), the rate-limiting enzyme in the glutathione pathway, a major component of the body’s antioxidant defence mechanism.
GCL is a dimer, consisting of a -23kDa modifier subunit (GCLM) with no individual catalytic activity and a -73kDa catalytic subunit (GCLC). Under conditions of oxidative stress, the catalytic subunit, which has some individual activity, binds to GCLM to form a more catalytically efficient holoenzyme via the formation of disulphide bridges. Using the GAL4-UAS system, this study examined the consequences of perturbation of glutathione titres in relation to whole-organism physiology, over-expressing both sub-units (individually and in combination) in a variety of tissues. Results demonstrate that pan-neural over-expression can be beneficial, leading to an increase in lifespan. However, ubiquitous over-expression has been found to have serious detrimental effects during development. No correlation was demonstrated between the extended longevity phenotype and an increase in organismal oxidative stress resistance. These findings strongly suggest that the relationship between a reduction in oxidants and the benefits to an organism is not a simple one. They also implicate neural tissue as a key lifespan-limiting tissue type.
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