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Proteomic approach to understand mitochondrial quality control under normal and stress conditions


Project Description

Defects in protein quality control lead to the accumulation of misfolded and damaged proteins, 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 thus, consequently, is also the primary source of reactive oxygen species (ROS). ROS, in excess, can lead to unwanted cellular effects including oxidative stress, damaged proteins and mitochondrial dysfunction. Therefore, there are numerous protein quality control systems in mitochondria working under both normal and/or stressed conditions which try to remove unwanted molecular damage caused by ROS. As part of this response, increasing evidence suggests that two key mitochondrial proteases, Yme1 and Oma1, play important roles in mitochondrial protein quality control. Whilst Yme1 is constitutively active, Oma1 is maintained in a quiescent state in the absence of stress, and activated in certain stress conditions, such as depolarized or ATP-depleted mitochondria in both human and yeast cells. This PhD project will investigate the function and substrate spectrum of Yme1 and Oma1 under normal and various stress conditions. Mitochondria will be isolated from the wild-type, single and double deletion mutant cells. Quantitative proteomics analysis will be used to identify substrates of these proteinases in the absence and presence of stresses. Biochemical assays will be used to verify proteomics results and understand how deletion of each gene affects the function of mitochondria and key mitochondrial proteins. The overall aims are therefore to understand the role of these two enzymes as part of wider understanding of how they integrate in to a systems-level cellular response to control against the effects of environmental stress.

Candidates are expected to hold (or be about to obtain) a minimum upper second class honours degree (or equivalent) in biochemistry, cell biology, bioinformatics or a related subject. Candidates with experience in cell culture, protein study, and proteomics or with an interest in mitochondrial protein quality control and function are encouraged 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.”

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 http://www.internationalphd.manchester.ac.uk

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 (View Website). For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (View Website).

As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.

References

1. Bohovych I, et al. Stress-triggered activation of the metalloprotease Oma1 involves its C-terminal region and is important for mitochondrial stress protection in yeast. J Biol Chem. (2014) 289(19):13259-72.

2. Cenini G and Voos W. Role of Mitochondrial Protein Quality Control in Oxidative Stress-induced Neurodegenerative Diseases. Curr Alzheimer Res. (2016) 13(2):164-73. Review

3. Quirós PM, et al. New roles for mitochondrial proteases in health, ageing and disease. Nat Rev Mol Cell Biol. (2015) 345-59. Review

4. Spiller et al. Mitochondrial Tim9 protects Tim10 from degradation by the protease Yme1. Biosci Rep. (2015) 35: pii: e00193.

5. 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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