Background:
Mitochondria are organelles of eukaryotic cells critical for energy production (ATP), metabolic regulation and biosynthesis. They are complex, dynamic structures composed of a double outer and inner-membrane, encapsulating an inter-membrane space (IMS) and the interior matrix. The importance of mitochondria for cell function and homeostasis requires well-regulated maintenance involving biogenesis and degradation. Most of the mitochondrial proteome is nuclear-encoded, so biogenesis requires protein import from the cytosol. This occurs through translocases of the outer-membrane (TOM) and inner-membrane (TIM). The major route for precursor protein import into and across the inner-membrane occurs via the TIM23-pathway driven by the membrane-potential (Δψ) and the turnover of ATP. Problems arising in this process restrict the cell’s ability to maintain mitochondrial function.
The quality-control process also requires the degradation of mitochondria that have become damaged beyond repair. This process is controlled by the precursor protein PINK1, which in functional mitochondrial is incorporated into the inner-membrane, via the TIM23-pathway, and cleaved by the rhomboid protease PARL. Cleavage results in retro-translocation, back to the outer-membrane and proteasomal degradation, and no further action is taken. In compromised mitochondria this process fails and PINK1 is activated at the outer-membrane, which initiates mitophagy. Failure of this quality control process, e.g. caused by the mutations in pink1, can bring about neurodegenerative disease, including early-onset Parkinson’s disease.
Our analysis of PINK1 import within intact cells reveals an unexpected alternative destination–by way of the TIM23-pathway–into the matrix. Structural modelling predicts that PINK1’s trans-membrane domain (TMD) forms either an α-helix or α/β-hybrid. We propose this structural plasticity underlies PINK1’s destiny, respectively for matrix import or cleavage/retro-translocation. The results reveal new insights of PINK1’s role in mitochondrial quality control and function. The analysis also predicts that some of the PINK1 variants linked to early-onset Parkinson’s disease will disturb the balance of its distribution to either the matrix or outer-membrane. Thus, we believe we have uncovered a hitherto unknown aspect of the accelerated progression of Parkinson’s Disease.
These predictions need to be tested and elaborated. Therefore, we seek to a PhD student to explore these new discoveries by exploiting an arsenal of cutting-edge technologies developed in the supervisory team’s laboratories. The objectives will be:
(1) To conduct biochemical, biophysical and computational analyses of the conformational switch within the TMD of PINK1 and the consequential interactions with PARL and the TIM23 protein import machinery.
(2) The role of PINK1 in the matrix has not been widely studied, so we will examine its effect on mitochondrial function. This will be achieved through the biochemical and cellular analysis of cells subject to matrix exposure or depletion of PINK1.
(3) To examine the variants of PINK1 linked to early-onset Parkinson’s disease to see how they affect the destiny of PINK, disturb mitochondrial quality control and function, and bring about disease.
The project is interdisciplinary, combining computational methods with experimental empiricism of biochemical, biophysical and cell biology techniques. This multi-scale and innovative approach will provide the student with outstanding opportunities for training and discovery.
How to apply
You can submit an application via the University of Bristol application portal: Start your application | Study at Bristol | University of Bristol selecting the relevant 4-year PhD programme, e.g. “Biochemistry (PhD) (4yr)”.
Search for your programme and select it from the dropdown list to see the available start dates. Select ‘apply’ next to your chosen start date to begin your application.
Link to prospectus pages for School of Biochemistry giving entry requirements and admissions statement: Biochemistry | Study at Bristol | University of Bristol
In the funding section of the application form, please select “University of Bristol Scholarship - Black Heritage”.
In the research section please enter the exact project title of the scholarship you are applying for along with the supervisor's name. You can upload a blank document instead of the research statement, which is not needed.
You can find more information on how to prepare your application and what we are looking for at the “PhD Application Workshop” which will be held on Teams on Monday 24th November 2025 at 2pm (GMT): PhD Application Workshop.
The application deadline is 11.59pm (GMT) Tuesday 6th January 2026.
Bristol PGR scholarships for applicants of Black heritage
As part of our commitment to the Black community, the University of Bristol has launched a number of PGR research scholarships exclusively for students of Black heritage for 2026/27 entry. These are open to UK-domiciled, home fee applicants of Black African, Black Caribbean or other Black or mixed Black heritage. The scholarships aim to address the under-representation of black people in postgraduate research and support our work to improve representation across all levels of study and academia.
We have a wide range of support networks, student societies and community groups for students of Black heritage. These include our Be More Empowered for Success PGR Programme which aims to influence positive change across the themes of access, belonging and empowerment.
Further information about the Black Heritage Scholarship scheme can be found on our website: https://www.bristol.ac.uk/health-life-sciences/postgraduate-research/bristol-postgraduate-research-scholarships/black-heritage/
For project-related enquiries, please contact the project supervisor directly.