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MRC DiMeN Doctoral Training Partnership: MitoFIT: Understanding and restoring mitochondrial health in the ageing brain

Funding
Funded
Study mode
Full-time
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Subject area
Biological and Biomedical Sciences
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Overview

Investigate how neurons maintain mitochondrial fitness across a lifetime and translate these insights into strategies to support neuronal survival in ageing and Parkinson’s disease.

About this opportunity

We are looking for an enthusiastic and dedicated PhD student to join a dynamic research team aiming to make fundamental discoveries that improve our understanding of neurodegenerative diseases commonly associated with aging.

Neuronal cells rely heavily on mitochondria to meet their high energy demands. When mitochondria become damaged, they must be detected and safely removed through a process called mitophagy, allowing new functional mitochondria to replace them. The proteins PINK1 and Parkin are key regulators of this process, working together to add a phospho-ubiquitin signal that marks damaged mitochondria for removal. Mutations in these genes, identified in a subset of people with Parkinson’s disease, lead to a build-up of dysfunctional mitochondria and increased oxidative stress that harms cells. Importantly, impaired mitophagy is also seen in sporadic Parkinson’s disease and declining mitochondrial health is emerging as a feature of other neurodegenerative diseases such as Alzheimer’s. Boosting mitophagy is therefore a promising therapeutic strategy to not only alleviate symptoms but slow or halt disease progression. However, even healthy, fully differentiated (mature) neurons appear to have a limited capacity to use the PINK1 and Parkin mitophagy pathway efficiently.

In this project, we aim to uncover what restricts mitophagy in differentiated neurons and and to determine whether recently identified PINK1/Parkin-independent mitophagy pathways can be harnessed to improve mitochondrial quality control. The overarching objectives are to a) gain new mechanistic insights into how neurons maintain mitochondrial health, and b) to lay the groundwork for future strategies that could help protect neurons in ageing and neurodegenerative disease.

The PhD student will work with advanced inducible neuronal differentiation models to study the regulation of mitophagy and explore alternative pathways that may compensate for limitations of PINK1/Parkin-associated system. These inducible neurons express dCas9-KRAB, inactive Cas9 fused to a transcriptional repressor, for selective gene downregulation using CRISPRi. Complementary mechanistic studies will be carried out in established non-transformed epithelial cell models to define general principles of mitochondrial homeostasis. A range of genetically encoded fluorescent mitophagy reporters and biochemical assays will be used to quantify mitochondrial turnover and function.

The student will receive comprehensive training in molecular cell biology, genetic engineering, quantitative live and fixed cell imaging and data analysis, while developing a strong mechanistic understanding of mitochondrial biology and neurodegenerative disease.

We are looking for a student who is genuinely curious about how cells work, motivated to tackle challenging mechanistic questions, willing to learn new techniques and think critically about data, all in a supportive and collaborative environment.

Benefits of being in the DiMeN DTP:

This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle, York and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of-the-art facilities to deliver high impact research.

We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.

Being funded by the MRC means you can access additional funding for research placements, training opportunities or internships in science policy, science communication and beyond.

Further information on the programme and instructions on how to apply, including a link to the application portal, can be found on our website https://www.dimen.org.uk/

Further reading

1. Clague,M.J. and Urbé,S. (2025) Diverse routes to mitophagy governed by ubiquitylation and mitochondrial import. Trends in Cell Biology, 35, 527-538 doi: 10.1016/j.tcb.2025.01.003.
2. Pollock,L., Georgiou, I.Ch., Rusilowicz-Jones,E.V., Clague,M.J. and Urbé,S. (2025) A long-lived pool of PINK1 imparts a molecular memory of depolarisation-induced activity. Science Advances 11(9):eadr1938 DOI 10.1126/sciadv.adr1938.
3. Elcocks,H., Brazel,A.J., McCarron,K.R, Kaulich,M., Husnjak,K., Mortiboys,H., Clague,M.J. and Urbé,S. (2023) FBXL4 ubiquitin ligase deficiency promotes mitophagy by elevating NIX levels. EMBO Journal 42: e112799. DOI:10.15252/embj.2022112799
4. Rusilowicz-Jones,E.V, Barone,F., Martins Lopes, F., Stephen,E., Mortiboys,H., Urbé,S., and Clague,M.J. (2022) Benchmarking a highly selective USP30 inhibitor for enhancement of mitophagy and pexophagy. Life Science Alliance, e202101287 DOI: 10.26508/lsa.202101287.
5. Rusilowicz-Jones,E.V, Jardine,J., Kallinos,A., Pinto-Fernandez,A., Guenther, F., Giurrandino,M., Barone,F.G., McCarron,K., Burke,C.W., Murad,A., Martinez,A., Marcassa,E., Gersch,M., Kayser-Bricker,K., Buckmelter,A., Lamoliatte,F., Gajbhiyemm,A., Sidgwick,F., Davis,S., Scott,H.C., Murphy,E., England,K., Mortiboys,H., Komander,D., Kessler,B.M., Trost,M., Ioannidis,S., Ahlijanian,M., Urbé,S., Clague,M.J. (2020) USP30 sets the trigger for PINK1-PARKIN amplification of mitochondrial ubiquitylation. Life Science Alliance DOI: 10.26508/lsa.202000768.
6. Marcassa E., Martinez A., Kallinos A., Jardine J., Clague M.J. and Urbé S. (2018) Dual role of USP30 in controlling basal pexophagy and mitophagy. EMBO reports, 19, e45595. doi: 10.15252/embr.201745595.
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Who is this for?

Applicants for postgraduate research study at Liverpool are normally expected to hold a UK first degree with a First Class or Upper Second Class degree classification, or a Second Class degree plus a Master’s degree. Equivalent international qualifications are also accepted, and their equivalence will be evaluated on the basis of the information provided by the European Network of Information Centres (ENIC) formerly NARIC as well as internal guidance based on our experience of a qualification’s suitability as a preparation for our programmes.

For applicants whose first language is not English, an IELTS score of 6.5 with no band score lower than 5.5, or an equivalent University of Liverpool acceptable English language qualification. For further details and other acceptable English language qualifications please see here: http://www.liv.ac.uk/study/international/countries/english-language/

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How to apply

  1. 1. Contact supervisors

    Contact Sylvie Urbé for further information ().

  2. 2. Prepare your application documents

    All applications are made via the application form accessed on the DiMeN website at www.dimen.org.uk

    Please read the full application guidance on the website before submitting an application.

  3. 3. Apply

    Finally, register and apply online. You'll receive an email acknowledgment once you've submitted your application. We'll be in touch with further details about what happens next.

    You should only follow this step if you’ve successfully completed the DiMeN application process

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Funding your PhD

Studentships are fully funded by the Medical Research Council (MRC) for 4yrs. Funding will cover tuition fees, stipend (£20,780 for 2024/25) and project costs. We have a very small number of funded studentships for exceptional international applicants. Please read additional guidance here: View Website

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Contact us

Have a question about this research opportunity or studying a PhD with us? Please get in touch with us, using the contact details below, and we’ll be happy to assist you.

Prof Sylvie Urbé
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