This project forms an integral part of the recently established MRC Centre of Research Excellence in Mitochondrial Genome Therapeutics (MRC CoRE-MitoGT) established in collaboration with the Lily Foundation and LHON Collective. CoRE-MitoGT is an international consortium ultimately aims to understand how mtDNA mutations cause disease and develop therapies targeting their root causes. The student will join the Whitworth lab, one of the core laboratories within CoRE-MitoGT, based at the Cambridge Institute for Medical Research, 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. In parallel, the project aims to establish whether mitochondrial quality control pathways can be manipulated to reduce mutant mtDNA levels and restore mitochondrial function in vivo, while systematically identifying nuclear-encoded regulators that could provide new therapeutic targets.
The work will centre on unique, new Drosophila models of the primary mitochondrial disease, MELAS, generated in the laboratory by mtDNA base editor-mediated mutagenesis. These models allow heteroplasmy to be measured and manipulated in a genetically tractable, short-lived animal and its consequences followed throughout development and ageing. They will be studied alongside iPSC-derived human neurons carrying pathogenic mtDNA mutations at defined heteroplasmy levels, allowing mechanisms identified in the fly to be tested for conservation in human cells.
The project will combine hypothesis-driven and unbiased approaches to:
- Define cell-type-specific disease responses: Deep phenotyping of heteroplasmic MELAS models across development and ageing, including mitochondrial and other molecular functions, and impacts on behaviour and lifespan, to establish when and where dysfunction first appears and how it relates to mutation load.
- Assess and manipulate mitochondrial quality control pathways: Determine whether QC pathways such as mitophagy and mtDNA copy number regulators are activated by mtDNA mutations; Target established and novel regulators of mitophagy and determine their effects on heteroplasmy, mitochondrial function and organismal vitality.
- Identify new regulators: Perform forward-genetic screens in heteroplasmic MELAS fly models to identify nuclear-encoded regulators of mtDNA heteroplasmy and copy number.
- Test therapeutic candidates across systems: Progress the strongest candidates into human neuronal models and, in collaboration with partner groups, mammalian systems, prioritising mechanisms with therapeutic potential, druggability and translational relevance.
Findings from these approaches will be integrated with mammalian and single-cell datasets generated by collaborating groups, positioning the mechanisms identified here within a broader multiscale understanding of mtDNA disease.
The overall goal is to establish both why some cell types are selectively vulnerable to mtDNA mutations and whether mitochondrial quality control can be harnessed to prevent or reverse this vulnerability. In doing so, the project will test the potential of enhancing mitochondrial quality control as a mutation-agnostic therapeutic strategy.
