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Molecular analyses of clinically-relevant mutations in human complex I


   Mitochondrial Biology Unit

  ,  Thursday, January 05, 2023  Competition Funded PhD Project (Students Worldwide)

About the Project

Complex I (NADH:ubiquinone oxidoreductase) is an intricate ~1 MDa multimeric membrane-bound complex that is essential for mitochondrial metabolism: its dysfunctions lead to neuromuscular and metabolic diseases and it is implicated in ischaemia-reperfusion injury.

In our research group we combine structural, biochemical and biophysical methods to study complex I, and aim to apply our molecular knowledge to understand in vivo function and dysfunction [1]. As a central group in the MRC Mitochondrial Biology Unit, with a mission to understand mitochondrial biology in health and disease, we aim to contribute to understanding disease mechanisms, and support clinical diagnoses and development of complex I-based therapies [2].

This aim of this project is to combine the genetic versatility of cultured mammalian cells with an adapted toolbox of methods for assessing complex I structure and function. The project will be a collaboration with the Prudent group at the MBU, who are experts in cell biology, and will start by developing methods for evaluating and optimising complex I function and molecular integrity in cultured cells. The student working on this project will therefore learn cell culture techniques, proteomics and mass spectrometry, and microscale assay development. As the project develops there will then be opportunities to create clinically-relevant variants and determine how the complex I is affected, and/or to develop methods to isolate the enzyme for more detailed studies. The project therefore represents an exciting opportunity to develop research skills and expertise in both cell biology and biochemical approaches.

Keywords

General: mammalian cell culture, mitochondria, assays, genetics, respiratory chain

More specific: complex I, redox enzyme, mitochondrial disease, rare genetic diseases

Research Groups:

https://www.mrc-mbu.cam.ac.uk/research-groups/hirst-group

https://www.mrc-mbu.cam.ac.uk/research-groups/prudent-group


Funding Notes

Details about funding and eligibility are available on our website: View Website
The start date: October 2023.
The University's application portal opens on 15 September 2022.
Applications will not be accepted via the enquiry email address. This address is to ask the supervisors for further information about the project. For details on how to apply please see our postgraduate studies webpage: View Website.

References

1. Yin, Z…. Murphy, M. P. & Hirst, J. (2021) Structural basis for a complex I mutation that blocks pathological ROS production. Nature Commun. 12, 707.
2. Chung, I., Serreli, R., Cross, J. B., Di Francesco, M. E., Marszalek, J. R. & Hirst, J. (2021) Cork-in-bottle mechanism of inhibitor binding to mammalian complex I. Sci. Adv. 7, eabg4000.

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