Title: Redox Metabolism
Funder: Medical Research Council

Abstract: Redox regulation is emerging as an important modulator of cellular pathways, integrating signals from metabolic status and reactive oxygen species (ROS) production. Redox signalling is mediated by reversible changes in the ratios of redox couples (such as glutathione, thioredoxin, NADPH, NADH), or in the levels of ROS (such as hydrogen peroxide). Target proteins are changed by reversible modification of particular redox-sensitive thiol groups on cysteine residues. These thiol modifications (such as disulphide formation, oxidation, glutathionylation, S-nitrosylation) alter the biological function of the protein (e.g. activity of an enzyme, localisation of a transcription factor, binding interaction with a partner). Critically, redox signalling is distinct from irreversible oxidative damage and operates as a reversible “redox switch” on a protein, which can be recycled back the basal, reduced thiol state through the action of endogenous antioxidant systems. Therefore, akin to phosphorylation, redox signalling allows the rapid and reversible regulation of target pathways in response to metabolic and environmental cues. The goals of the group are: firstly, to investigate the importance of redox signalling and metabolism in physiology and pathology; and secondly, to develop novel molecular techniques to assay redox biology in vivo, expanding on our successful design of a mass spec probe approach to quantify hydrogen peroxide levels in vivo. We use the fruit fly Drosophila melanogaster as a model organism, which has many advantages including the availability of powerful genetic tools and the strong evolutionary conservation to mammals. Flies are an excellent, tractable system to study complex processes in vivo, since we can easily control their nutrition and environment, as well as treat with drugs, either through the diet or by microinjection. We aim to identify, characterise and manipulate redox-sensitive targets using a combination of biochemical, genetic and proteomic approaches, in order to unravel the physiological and metabolic effects of redox signalling. For instance, using a candidate approach, we are generating knock-in fly lines for predicted redox-responsive targets in which the key redox-active cysteine residue has been substituted to produce a redox-inactive mutant, and then assessing the impact in vivo. In parallel, we are performing an unbiased redox proteomic screen in flies to identify novel redox-reactive targets that are altered with age or in response to stress. Many interventions can improve health and extend lifespan in model organisms including Drosophila, such as manipulating nutrient-sensing pathways either pharmacologically or genetically. However, the underlying molecular mechanisms are unclear. Therefore we are researching whether altered redox metabolism can explain these longevity benefits, and conversely whether the dysregulation of redox signalling networks contributes to the pathophysiology of diseases such as diabetes and to the ageing process.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE