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(BBSRC DTP) Homeostasis and regulation of mitochondrial pyruvate carrier


Faculty of Biology, Medicine and Health

About the Project

Mitochondrion is a critically important organelle and plays a key role in energy metabolism. Consequently, mitochondrial dysfunctions are hallmarks of ageing and associated with many diseases. Mitochondrial respiration and TCA cycle generate a large amount of ATP and various important metabolites allowing mitochondria to integrate many essential activities in eukaryotic cells. Mitochondrial pyruvate carrier (MPC) is a highly conserved mitochondrial inner membrane complex and a major checkpoint for cytosolic glycolysis and mitochondrial respiration by mediating pyruvate uptake from the cytosol to mitochondrial matrix. MPC was identified recently, in yeast which consists of Mpc1p and Mpc2p during fermentative growth, or Mcp1p and Mpc3p during respiratory growth. Mutation in human ortholog MPC1 was shown to be associated with lactic acidosis and hyperpyruvatemia. Whilst their function has been characterised, it is unknown how the homeostasis of these proteins is regulated. Our recent studies showed that mitochondrial i-AAA proteases Yme1 play an important role in quality control of MPC proteins. Thus, this PhD project is aiming to understand how their homeostasis is regulated by the mitochondrial Yme1 in the organelle. Baker’s yeast will be used as model system. Mitochondria will be isolated from the wild-type (WT) and YME1 deletion strains. Molecular biology technique will be used to generate DNA constructs for in vitro synthesis of MPC precursor proteins. Mitochondrial import and various biochemical assays will be used to investigate the effect of the mitochondrial i-AAA on the import and homeostasis of the MPC proteins. Taken together, the overall aim is to understand the homeostasis and regulation of MPC as a part of deep understanding of regulation of mitochondrial function. This project will provide an excellent opportunity for a self-motivated student to learn and develop many essential experimental skills and knowledge in biochemistry and cell biology.

https://www.research.manchester.ac.uk/portal/hui.lu.html
https://www.research.manchester.ac.uk/portal/chris.grant.html
https://www.research.manchester.ac.uk/portal/martin.r.pool.html

Entry Requirements:
Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.

UK applicants interested in this project should make direct contact with the Principal Supervisor to arrange to discuss the project further as soon as possible. International applicants (including EU nationals) must ensure they meet the academic eligibility criteria (including English Language) as outlined before contacting potential supervisors to express an interest in their project. Eligibility can be checked via the University Country Specific information page (https://www.manchester.ac.uk/study/international/country-specific-information/).

If your country is not listed you must contact the Doctoral Academy Admissions Team providing a detailed CV (to include academic qualifications – stating degree classification(s) and dates awarded) and relevant transcripts.

Following the review of your qualifications and with support from potential supervisor(s), you will be informed whether you can submit a formal online application.

To be considered for this project you MUST submit a formal online application form - full details on how to apply can be found on the BBSRC DTP website http://www.manchester.ac.uk/bbsrcdtpstudentships

Funding Notes

Funding will cover UK tuition fees/stipend only. The University of Manchester aims to support the most outstanding applicants from outside the UK. We are able to offer a limited number of scholarships that will enable full studentships to be awarded to international applicants. These full studentships will only be awarded to exceptional quality candidates, due to the competitive nature of this scheme.

Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website View Website

References

• Bender T, Martinou JC. The mitochondrial pyruvate carrier in health and disease: To carry or not to carry? Biochim Biophys Acta. (2016) 1863 (10): 2436-42. Review.
• Rampelt, H., Sucec, I., Bersch, B. et al. The mitochondrial carrier pathway transports non-canonical substrates with an odd number of transmembrane segments. BMC Biol. (2020) 18, 2.
• Tavoulari S, et al., Kunji ER. The yeast mitochondrial pyruvate carrier is a hetero-dimer in its functional state. EMBO J. (2019) 38(10):e100785.
• Voos W, Ward LA, Truscott KN. The role of AAA+ proteases in mitochondrial protein biogenesis, homeostasis and activity control. Subcell Biochem. (2013) 66:223-63. Review.

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