A novel role in mitochondrial homeostasis for the anti-ageing factor RBBP5

About the project

About the Project The mitochondrion evolved from an endosymbiotic interaction between an alpha-proteobacterium and an archaeon. A defining event during this evolution was the transfer of most mitochondrial genes to the host nucleus. Although the mitochondrial genome now encodes only a dozen or so of proteins, more than 1,000 proteins form the mitochondrial proteome. Maintaining the correct balance of these proteins is essential for mitochondrial function, and disruption of this balance can have severe consequences if left unresolved. Cells therefore activate specialised mitochondrial stress responses that restore mitochondrial homeostasis by coordinating protective transcriptional and metabolic programmes. Failure to maintain mitochondrial homeostasis contributes to ageing and numerous age-associated diseases. My laboratory identified the chromatin regulator RBBP-5 as a critical factor required to maintain mitochondrial function. Our work has shown that RBBP-5 regulates the mitochondrial unfolded protein response (mitoUPR), an evolutionarily conserved stress pathway that promotes mitochondrial recovery and influences organismal ageing. RBBP-5 is a core component of the COMPASS complex responsible for histone H3 lysine 4 (H3K4) methylation, a highly conserved epigenetic modification associated with transcriptionally active chromatin. Our recent findings suggest that H3K4 methylation coordinates mitochondrial stress responses across tissues, revealing an unexpected role for chromatin in regulating organism-wide adaptation to mitochondrial dysfunction. Your project will investigate the molecular mechanisms by which RBBP-5 regulates mitochondrial homeostasis and mitochondrial stress signalling. Using C. elegans as a genetically tractable model, you will combine tissue-specific auxin-inducible degron systems, fluorescent stress reporters and genetic approaches to determine how chromatin regulates mitochondrial stress responses in different tissues. You will integrate these experiments with genome-wide approaches, including RNA-seq, ATAC-seq and quantitative proteomics, to identify the molecular pathways controlled by RBBP-5. Our preliminary data indicate that neurons play a central role in coordinating these responses with peripheral tissues, providing an opportunity to investigate how chromatin state influences inter-tissue communication during stress. Key findings will be validated using mammalian tissue culture models where appropriate. In summary, the selected student will receive interdisciplinary training in molecular genetics, epigenetics, genomics, proteomics and systems biology to address fundamental questions surrounding mitochondrial homeostasis, organismal stress signalling and healthy ageing. Eligibility Applicants must have obtained or be about to obtain a minimum Upper Second class UK honours degree, or the equivalent qualifications gained outside the UK, in a relevant discipline. Master's degree or lab experience is preferable, but not necessary. Before you Apply Applicants must make direct contact with preferred supervisors before applying. It is your responsibility to make arrangements to meet with potential supervisors, prior to submitting a formal online application. How to Apply To be considered for this project you MUST submit a formal online application form – on the application form select PhD Molecular Biology. Full details on how to apply can be found on the Website: How to apply for postgraduate research at The University of Manchester If you have any queries regarding making an application please contact our admissions team FBMH.doctoralacademy.admissions@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: Equality, diversity and inclusion (EDI | Postgraduate Research | Biology, Medicine and Health | University of Manchester

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