Doctoral Student

INVESTIGATING PATHOGENIC MECHANISMS AND THERAPEUTIC TARGETS FOR MTDNA MUTATIONS Background Mutations in mitochondrial DNA (mtDNA) are the most common cause of inherited mitochondrial disease and are increasingly implicated in common age-related conditions including neurodegeneration. The pathogenic mechanisms of mtDNA mutations are poorly understood partly due to the striking phenotypic heterogeneity and complications of dynamic mutation heteroplasmy, rendering these conditions very difficult to treat.  This project forms an integral part of the recently established MRC Centre of Research Excellence in Mitochondrial Genome Therapeutics (MRC CoRE-MitoGT) and is supported by one of several studentships established in collaboration with the Lily Foundation and LHON Collective. CoRE-MitoGT is an international consortium that ultimately aims to understand how mtDNA mutations cause disease and develop therapies targeting their root causes. The student will join the Ahola lab, one of the core laboratories within CoRE-MitoGT, based at the University of Birmingham, Department of Metabolism and Systems Science, to investigate how different cell types respond to pathogenic mtDNA mutations and identify the mechanisms that determine whether cells degenerate or tolerate a comparable mutation load. The project will combine detailed physiological and metabolic phenotyping to determine how mitochondrial dysfunction is translated into tissue-specific disease and to identify mechanisms that distinguish successful adaptation from progressive cellular dysfunction. The work will centre on new mouse models of mitochondrial disease generated within CoRE-MitoGT, in which defined pathogenic mtDNA mutations can be studied across different tissues and stages of disease progression. Whole-organism and tissue-level phenotyping will be combined with metabolic and molecular characterisation to identify early changes that precede overt pathology and determine how metabolic responses differ between vulnerable and resilient tissues. Particular emphasis will be placed on clinically relevant phenotypes, including cardiac and neuromuscular dysfunction, and on defining metabolic adaptations associated with different levels of mtDNA mutation burden. Key observations from the mouse models can be investigated mechanistically in complementary human iPSC-derived cell models carrying pathogenic mtDNA mutations. Approaches will include metabolic flux analysis, mitochondrial bioenergetics, metabolomics and lipidomics, together with molecular and functional characterisation of mitochondrial stress responses. Findings will be integrated with single-cell, molecular and clinical datasets generated across CoRE-MitoGT, connecting cellular metabolic responses to organism-level disease phenotypes and helping to establish biomarkers and mechanistic endpoints for future therapeutic studies. The overall goal is to establish why different tissues respond differently to pathogenic mtDNA mutations and which metabolic adaptations determine whether mitochondrial dysfunction is tolerated or progresses to disease. In doing so, the project will provide a mechanistic bridge between mtDNA mutation burden, cellular metabolism and tissue-specific pathology, helping to identify pathways that could ultimately be targeted therapeutically. Training and environment The project forms part of a major new collaborative research centre on mtDNA disease and gene-modifying therapy, with access to unique disease models and a network of clinicians and researchers across the University of Birmingham, Cambridge Biomedical Campus and beyond. The student will join a large and interactive mitochondrial research community with access to state-of-the-art imaging, metabolomics, proteomics and sequencing facilities and an active postgraduate research environment. The student will receive multidisciplinary training spanning in vivo, cellular and molecular approaches to mitochondrial disease. Depending on the precise evolution of the project, this will include physiological and functional phenotyping of mouse models, tissue and mitochondrial biochemistry, human iPSC-derived cell culture, mitochondrial bioenergetics, metabolic flux analysis and stable-isotope tracing, metabolomics and lipidomics, molecular biology, mtDNA genotyping and heteroplasmy analysis, quantitative imaging, and integration and analysis of complex phenotypic and molecular datasets. This combination will provide strong training in experimental design, quantitative analysis and the integration of findings across organism, tissue and cellular scales, providing the multidisciplinary skills required for an independent researcher. In addition, CoRE-MitoGT will provide an extensive programme of personal and professional training, including ECR-focused events, opportunities to work with collaborating laboratories across the Centre and wider mitochondrial research community, and career-development activities, while promoting best practice in equality, diversity and inclusion and a positive research culture. MRC CoRE funding covers UK home student tuition fee rates To be considered for this studentship, please send the following documents to Dr Sofia Ahola, s.ahola@bham.ac.uk -             A detailed CV, including your nationality and country of birth; -             Names and addresses of two referees; -             A covering letter highlighting your research experience/capabilities; -             Copies of your degree certificates with transcripts; -             Evidence of your proficiency in the English language, if applicable.