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The mechanism, function, and medically-relevant dysfunction of mitochondrial complex I (NADH:ubiquinone oxidoreductase)

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  • Full or part time
    Dr J Hirst
  • Application Deadline
    Applications accepted all year round

Project Description

Complex I (NADH:ubiquinone oxidoreductase) catalyses the first step in the mitochondrial electron transport chain: NADH oxidation and quinone reduction, coupled to proton translocation across the inner membrane. It is also a major locus of cellular reactive oxygen species production. Complex I is the largest and least understood enzyme of the respiratory chain; it contains more than forty different subunits and nine redox-active cofactors: a flavin to catalyse NADH oxidation, and iron-sulphur clusters to transport the electrons to ubiquinone. How proton translocation across the membrane is enforced by the redox reaction is not understood. Our first aim is to define the mechanisms of catalysis and reactive oxygen species production by complex I by using biochemical, biophysical and structural techniques to study highly-active enzyme and coupled-membrane preparations. We employ a wide range of kinetic, spectroscopic, and electrochemical methods, in combination with cryo-EM for structrual studies and genetic techniques for generating site-directed mutations.

Complex I is important in medicine. It is a common cause of genetic mitochondrial diseases, increasingly associated with neuromuscular diseases (including Parkinson’s), and implicated in ageing. Our second aim is to apply mechanistic information and strategies to determine the molecular causes of complex I dysfunctions, and how complex I is affected by challenging cellular conditions (for example, oxidative stress, ischaemia-reperfusion) and therapeutic drugs, and then to integrate this function/dysfunction information into cellular and pathological contexts. For example, we are developing methods for studying complex I from cultured human cells and rodent model systems, and are studying the effects of drugs, such as the anti-diabetic drug metformin, that are known to act on complex I.

For further information see:
Hirst, J. (2013) Mitochondrial complex I. Annu. Rev. Biochem. 82, 551-575.
Zhu, J., Vinothkumar, K. R. & Hirst, J. (2016) Structure of mammalian respiratory complex I. Nature 536, 354-358.
Jones, A. J. Y. et al. (2016) A self-assembled respiratory chain that catalyzes NADH oxidation by ubiquinone-10 cycling between complex I and the alternative oxidase. Angew. Chem. Int. Ed. Engl. 55, 728-731.



Funding Notes

(Full funding available for UK and EU applicants; others can apply if they wish)

References

Hirst, J. (2013) Mitochondrial complex I. Annu. Rev. Biochem. 82, 551-575.

Zhu, J., Vinothkumar, K. R. & Hirst, J. (2016) Structure of mammalian respiratory complex I. Nature 536, 354-358.

Jones, A. J. Y. et al. (2016) A self-assembled respiratory chain that catalyzes NADH oxidation by ubiquinone-10 cycling between complex I and the alternative oxidase. Angew. Chem. Int. Ed. Engl. 55, 728-731.

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