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Molecular by-pass therapy for mitochondrial dysfunction

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.

Field of science

  • /natural sciences/biological sciences/biochemistry/biomolecules/proteins/enzymes
  • /natural sciences/biological sciences/genetics and heredity/mutation

Call for proposal

ERC-2008-AdG
See other projects for this call

Funding Scheme

ERC-AG - ERC Advanced Grant

Host institution

TAMPEREEN YLIOPISTO
Address
Kalevantie 4
33014 Tampere
Finland
Activity type
Higher or Secondary Education Establishments
EU contribution
€ 1 650 787
Principal investigator
Howard Trevor Jacobs (Prof.)
Administrative Contact
Hannele Auffermann (Ms.)

Beneficiaries (2)

TAMPEREEN YLIOPISTO
Finland
EU contribution
€ 1 650 787
Address
Kalevantie 4
33014 Tampere
Activity type
Higher or Secondary Education Establishments
Principal investigator
Howard Trevor Jacobs (Prof.)
Administrative Contact
Hannele Auffermann (Ms.)
HELSINGIN YLIOPISTO
Finland
EU contribution
€ 785 213
Address
Yliopistonkatu 3
00014 Helsingin Yliopisto
Activity type
Higher or Secondary Education Establishments
Administrative Contact
Tiina Berg (Mrs.)