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(BBSRC DTP) Understanding mitochondrial protein quality control under normal and stress conditions


Project Description

Mitochondria are vitally important organelles within living cells and are often described as their powerhouses, as the primary energy source for all biological activities. Mitochondrial dysfunctions are hallmarks of ageing and are associated with many diseases, which are accompanied by increased protein damage and misfolding. Mitochondrial protein quality control is therefore particularly important, since this organelle is the primary energy source for all biological activities and consequently, is also the primary source of reactive oxygen species (ROS). Therefore, there are numerous quality control systems in mitochondria working under both normal and/or stressed conditions trying to remove unwanted and damaged proteins to secure mitochondria function. However, the mechanisms of the mitochondrial quality control systems are unclear. As part of this response, increasing evidence suggests that mitochondrial proteases play important roles in mitochondrial protein quality control. This project will focus on two key proteases, Yme1 and Oma1, which have been reported to be reactive to environmental stresses, and which both have their proteolytic domains localized in the mitochondrial intermembrane space (IMS). Whilst Yme1 is constitutively active, Oma1 is maintained in a quiescent state in the absence of stress, and is activated principally under certain stress conditions, such as depolarized or ATP-depleted mitochondria in both human and yeast cells. This PhD project will investigate the activity 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 proteomic analysis will be used to identify substrates of these proteinases in the absence and presence of stresses. Biochemical assays will be used to understand how loss of the proteases affects the function of mitochondria and key mitochondrial proteins. The overall aim is therefore to understand the role of mitochondrial proteases as part of a wider understanding of how they integrate into a systems-level cellular response to control against the effects of environmental stress.

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/simon.hubbard.html

Entry Requirements:
Applications are invited from UK/EU nationals only. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.

Funding Notes

This project is to be funded under the BBSRC Doctoral Training Partnership. If you are interested in this project, please make direct contact with the Principal Supervisor to arrange to discuss the project further as soon as possible. You MUST also submit an online application form - full details on how to apply can be found on the BBSRC DTP 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

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.
Quirós PM, et al. New roles for mitochondrial proteases in health, ageing and disease. Nat Rev Mol Cell Biol. (2015) 345-59.
Rainbolt TK, Lebeau J, Puchades C, Wiseman RL. Reciprocal Degradation of YME1L and OMA1 Adapts Mitochondrial Proteolytic Activity during Stress. Cell Rep. (2016) 14(9):2041-2049.
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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