PhD Studentship: Investigating Pathogenic Mechanisms And Therapeutic Targets mtDNA Mutations

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.

MRC CoRE funding covers UK home student tuition fee rates.