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Understanding the function and functional mechanism of mitochondrial AAA proteinases


   Faculty of Biology, Medicine and Health

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  Dr Hui Lu, Prof Simon Hubbard  Applications accepted all year round  Self-Funded PhD Students Only

About the Project

The mitochondrion is a vitally important organelle of eukaryotic cells. Mitochondrial AAA proteinases play important roles in mitochondrial function and protein homeostasis (proteostasis) by removal of unwanted proteins and regulating the function of mitochondrial proteins. Defects in mitochondrial protein homeostasis (quality control) can lead to mitochondrial dysfunction, which play an important role in many diseases (e.g. cancer, diabetes, various neurodegenerative diseases) and ageing. Mitochondrial protein quality control is particularly important, since this organelle is the primary energy source for all biological activities and consequently the primary source of reactive oxygen species. Moreover, most mitochondrial proteins are not accessible to the cytosolic ubiquitin-proteasome system. Therefore, i-AAA (mitochondrial intermembrane space facing) and m-AAA (matrix facing) proteinases play a key role in mitochondrial proteostasis and function. Our recent mitochondrial proteomics analysis showed that mitochondrial i-AAA proteinase Yme1 play an important role in proteostasis of various mitochondrial functions, not only proteins associated with the electron transport chain were affected, but also proteins in metabolism processes. This PhD project will investigate the mechanism of mitochondrial AAA proteinases (i-AAA and m-AAA) in mitochondrial proteostasis and regulation of mitochondrial function, using both bioinformatics and experimental methods. Using yeast as a model, mitochondria will be isolated from the wild type and proteinase deletion (mutant) cells. Mass spectrometry-based mitochondrial proteomic analysis will be used to identify how the absence of a proteinase affect the levels of mitochondrial proteins and potential biological processes. Biochemical assays will be used to verify proteomics results and understand how deletion of each gene affects the function of key mitochondrial proteins and associated biological processes. Taken together, the overall aim is to understand the role of mitochondrial AAA proteinase and as part of wider understanding how they integrate into a systems-level to maintain mitochondrial proteostasis and mitochondrial function.

Entry Requirements

Candidates are expected to hold (or be about to obtain) a minimum Upper Second class Honours degree (or equivalent) in biochemistry, cell biology or a related subject. Candidates with experience in protein folding, characterisation, and/or computer modelling, with an interest in protein folding and protein biotechnology are encouraged to apply. 

How to Apply

For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (https://www.bmh.manchester.ac.uk/study/research/apply/). Informal enquiries may be made directly to the primary supervisor. On the online application form select PhD Biochemistry.

For international students, we also offer a unique 4 year PhD programme that gives you the opportunity to undertake an accredited Teaching Certificate whilst carrying out an independent research project across a range of biological, medical and health sciences. For more information please visit www.internationalphd.manchester.ac.uk

Equality, Diversity and Inclusion 

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 https://www.bmh.manchester.ac.uk/study/research/apply/equality-diversity-inclusion/ 


Funding Notes

Applications are invited from self-funded students. This project has a Band 2 fee. Details of our different fee bands can be found on our website (https://www.bmh.manchester.ac.uk/study/research/fees/).

References

Baker, M. J., Tatsuta, T., and Langer, T. (2011) Quality control of mitochondrial proteostasis. Cold Spring Harb. Perspect. Biol. 3, a007559
Moehle, E. A., K. Shen and A. Dillin (2019). Mitochondrial proteostasis in the context of cellular and organismal health and aging. J Biol Chem 294(14): 5396-5407.
Quirós PM, et al. New roles for mitochondrial proteases in health, ageing and disease. Nat Rev Mol Cell Biol. (2015) 345-59
Spiller et al. Mitochondrial Tim9 protects Tim10 from degradation by the protease Yme1. Biosci Rep. (2015) 35: pii: e00193.
Stefely JA, et al. Mitochondrial protein functions elucidated by multi-omic mass spectrometry profiling. Nat Biotechnol. (2016) 34(11):1191-1197.
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