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The mechanism, function, and medically-relevant dysfunction of mitochondrial complex I (NADH:ubiquinone oxidoreductase) (On the University’s application portal, please select "PhD in Medical Science at the MRC Mitochondrial Biology Unit").

  • Full or part time
  • Application Deadline
    Sunday, June 30, 2019
  • Funded PhD Project (European/UK Students Only)
    Funded PhD Project (European/UK Students Only)

Project Description

Complex I (NADH:ubiquinone oxidoreductase) catalyses the first step in the respiratory chain and oxidative phosphorylation: 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 respiratory enzyme; 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 aims are to define the mechanisms of catalysis and reactive oxygen species production by complex I by using structural (cryoEM), biochemical and biophysical 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 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 studying complex I from cultured human cells and mouse model systems of human disease, and studying the effects of drugs, such as the anti-diabetic drug metformin, that are known to act on complex I.


For further information see:

Agip, A. -N. A., Blaza, J. N., Bridges, H. R., Viscomi, C., Rawson, S., Muench, S. P. & Hirst, J. (2018) CryoEM structures of complex I from mouse heart mitochondria in two biochemically-defined states. Nature Struct. Mol. Biol. 25, 548-556.

Fedor, J. G., Jones, A. J. Y., Di Luca, A., Kaila, V. R. I. & Hirst, J. (2017) Correlating kinetic and structural data on ubiquinone binding and reduction by respiratory complex I. Proc. Natl. Acad. Sci. U. S. A. 114, 12737-12742.

Milenkovic, D., Blaza, J. N., Larsson, N.-G. & Hirst, J. (2017) The enigma of the respiratory chain supercomplex. Cell Metab. 25, 765-776.

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

Funding Notes

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

References

Agip, A. -N. A., Blaza, J. N., Bridges, H. R., Viscomi, C., Rawson, S., Muench, S. P. & Hirst, J. (2018) CryoEM structures of complex I from mouse heart mitochondria in two biochemically-defined states. Nature Struct. Mol. Biol. 25, 548-556.

Fedor, J. G., Jones, A. J. Y., Di Luca, A., Kaila, V. R. I. & Hirst, J. (2017) Correlating kinetic and structural data on ubiquinone binding and reduction by respiratory complex I. Proc. Natl. Acad. Sci. U. S. A. 114, 12737-12742.

Milenkovic, D., Blaza, J. N., Larsson, N.-G. & Hirst, J. (2017) The enigma of the respiratory chain supercomplex. Cell Metab. 25, 765-776.

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

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