About the Project
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 striking phenotypic heterogeneity and the unusual genetics of mtDNA, rendering these conditions very difficult to treat. Leber hereditary optic neuropathy (LHON) is one of the most common mitochondrial genetic disorders,…
severely affecting the visual system and optic nerve. A major barrier to understanding LHON pathogenesis and developing treatments has been the lack of genetically precise mammalian models carrying the disease-causing mtDNA mutation.
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 a studentship established with a charity partner - LHON Collective. CoRE-MitoGT is an international consortium that aims to understand how mtDNA mutations cause disease and to develop therapies that target their root causes. The student will join the Minczuk lab, one of the core laboratories within CoRE-MitoGT, based at the Cambridge Institute for Medical Research. The project will connect model development with mechanistic studies and therapeutic discovery.
The work will centre on a new mouse line generated in the Minczuk laboratory carrying a genetically faithful LHON mutation. The student will use this model to define how the LHON mutation affects the retina and optic nerve over time, identify the cell types and molecular pathways that are most vulnerable, and test both mutation-correcting and mutation-independent therapeutic strategies.
The project will combine genetic, molecular and physiological approaches to:
- Define disease progression in the LHON model: Establish the onset and progression of visual-system pathology across age, combining retinal and optic-nerve histology with disease-relevant functional phenotyping and measurements of complex I and mitochondrial function.
- Resolve cell-type-specific vulnerability and molecular responses: Apply single-cell approaches to retina and optic nerve to identify vulnerable cell populations and define cellular responses with disease progression.
- Test mitochondrial quality-control pathways as mutation-independent therapies: Use the model to determine whether manipulation of mitochondrial quality-control pathways can preserve retinal and optic-nerve function even when the pathogenic mtDNA genotype itself is unchanged.
- Build a preclinical platform for mitochondrial genome therapy: Evaluate whether correction of the mutation can restore mitochondrial and visual function, using improved mitochondrial editors and delivery approaches emerging from CoRE-MitoGT, including protein-engineering collaborations with the University of Manchester. Molecular and functional endpoints defined above will provide rigorous measures of therapeutic benefit.
Together, these studies will connect a genetically precise LHON model to CoRE-MitoGT programmes in multiscale disease phenotyping, single-cell biology, mitochondrial quality control and genome therapy. The project will define robust molecular, cellular and functional endpoints for LHON and establish which pathological features are reversible by genetic correction or by mutation-independent interventions.
The overall goal is to turn a genetically precise mouse model into a mechanistically informative and therapeutically useful platform for LHON. This will provide a durable resource for understanding selective visual-system vulnerability and for evaluating complementary therapeutic strategies that either correct the mtDNA mutation or increase cellular resilience to it.
Training and environment
The project forms part of a major new collaborative research centre on mtDNA disease and gene-modifying therapy, with access to purpose-built disease models and a network of clinicians and researchers across the Cambridge Biomedical Campus and beyond. The student will receive training in mouse genetics and phenotyping, mitochondrial genome editing, retinal and optic-nerve analysis, mitochondrial biochemistry and complex I assays, quantitative imaging, mtDNA copy-number analysis and next-generation sequencing. Through CoRE-MitoGT collaborations, the student will also gain experience in single-cell and spatial profiling, mitophagy and mitochondrial quality-control assays, and preclinical evaluation of genetic and mutation-independent therapies.