Objective Many eukaryotes, but not the higher metazoans such as vertebrates or arthropods, possess intrinsic by-pass systems that provide alternative routes for electron flow from NADH to oxygen. Whereas the standard mitochondrial OXPHOS system couples electron transport to proton pumping across the inner mitochondrial membrane, creating the proton gradient which is used to drive ATP synthesis and other energy-requiring processes, the by-pass enzymes are non-proton-pumping, and their activity is redox-regulated rather than subject to ATP requirements. My laboratory has engineered two of these by-pass enzymes, the single-subunit NADH dehydrogenase Ndi1p from yeast, and the alternative oxidase AOX from Ciona intestinalis, for expression in Drosophila and mammalian cells. Their expression is benign, and the enzymes appear to be almost inert, except under conditions of redox stress induced by OXPHOS toxins or mutations. The research set out in this proposal will explore the utility of these by-passes for alleviating metabolic stress in the whole organism and in specific tissues, arising from mitochondrial OXPHOS dysfunction. Specifically, I will test the ability of Ndi1p and AOX in Drosophila and in mammalian models to compensate for the toxicity of OXPHOS poisons, to complement disease-equivalent mutations impairing the assembly or function of the OXPHOS system, and to diminish the pathological excess production of reactive oxygen species seen in many neurodegenerative disorders associated with OXPHOS impairment, and under conditions of ischemia-reperfusion. The attenuation of endogenous mitochondrial ROS production by deployment of these by-pass enzymes also offers a novel route to testing the mitochondrial (oxyradical) theory of ageing. Fields of science natural sciencesbiological sciencesgeneticsmutationnatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsenzymesnatural sciencesbiological scienceszoologyinvertebrate zoology Keywords OXPHOS mitochondria mitochondrial disorders Programme(s) FP7-IDEAS-ERC - Specific programme: "Ideas" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Topic(s) ERC-AG-LS4 - ERC Advanced Grant - Physiology, Pathophysiology and Endocrinology Call for proposal ERC-2008-AdG See other projects for this call Funding Scheme ERC-AG - ERC Advanced Grant Host institution TAMPEREEN YLIOPISTO EU contribution € 1 650 787,00 Address Kalevantie 4 33014 TAMPERE Finland See on map Activity type Higher or Secondary Education Establishments Administrative Contact Hannele Auffermann (Ms.) Principal investigator Howard Trevor Jacobs (Prof.) Links Contact the organisation Opens in new window Website Opens in new window Total cost No data Beneficiaries (2) Sort alphabetically Sort by EU Contribution Expand all Collapse all TAMPEREEN YLIOPISTO Finland EU contribution € 1 650 787,00 Address Kalevantie 4 33014 TAMPERE See on map Activity type Higher or Secondary Education Establishments Administrative Contact Hannele Auffermann (Ms.) Principal investigator Howard Trevor Jacobs (Prof.) Links Contact the organisation Opens in new window Website Opens in new window Total cost No data HELSINGIN YLIOPISTO Finland EU contribution € 785 213,00 Address YLIOPISTONKATU 3 00014 Helsingin Yliopisto See on map Region Manner-Suomi Helsinki-Uusimaa Helsinki-Uusimaa Activity type Higher or Secondary Education Establishments Administrative Contact Tiina Berg (Mrs.) Links Contact the organisation Opens in new window Website Opens in new window Total cost No data
