Mitochondrial diseases strike roughly 1 in 5000 people, yet two patients with the same genetic mutation can face wildly different outcomes—one may go blind while another barely notices symptoms. This unpredictability is the core problem. Mitochondrial disorders, caused by defects in either nuclear or mitochondrial DNA, disrupt the cell's energy production. But the same biochemical flaw produces a baffling range of clinical severity. The researcher will test whether hidden genetic factors—both in the nuclear genome and in the mitochondrial genome itself—explain this variability. The project tackles three linked questions. First, it will trace how mitochondrial DNA passes through the female germline, identifying compounds that could influence transmission. Second, it will sequence the nuclear genomes of a national patient cohort to discover new disease genes, validating them in patient-derived stem cells. Third, it will hunt for nuclear modifiers that shape the course of Leber hereditary optic neuropathy, a common mitochondrial DNA disorder. This is fundamental science. If it succeeds, it will not deliver a treatment tomorrow. But understanding why mitochondrial diseases vary so dramatically could eventually guide genetic counselling, predict disease course, and point toward therapies that target the modifiers rather than the primary defect—a strategy that has worked for other complex genetic conditions.
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Mitochondrial disorders affect ~1 in 5000 of the population and cause progressive, incurable diseases which often result in premature death. The primary genetic defect affects either nuclear DNA or mitochondrial DNA (mtDNA), and ultimately leads to a biochemical defect of ATP synthesis. However, despite having the same basic biochemical basis, mitochondrial disorders have an enormously variable clinical presentation and disease course. I will test the hypothesis that nuclear and mitochondrial ge netic factors modulate the clinical expression of mitochondrial disorders, thus explaining the variable phenotype. Specifically, I will: (i) Define the sub-cellular mechanism responsible for the mtDNA genetic bottleneck during female germ cell development in a germ-line model in vitro, and validate these findings in vivo in both mice and humans, leading to the identification of compounds which influence transmission. (ii) Comprehensively characterise the nuclear gene defects in a natio nal cohort of patients with Mendelian mitochondrial disorders using whole-exome and restricted whole-genome sequencing. This will identify new mitochondrial disease genes that will undergo functional validation using tissue-specific cell lines differentiated from patient-derived induced pluripotent stem cells (iPSCs). (iii) Use state-of-the-art genomics to identify nuclear genetic factors that modulate the phenotype of the primary mitochondrial DNA disease, Leber hereditary optic neuropathy. Studying the functional consequences of the disrupted nuclear genes in tissue-specific lineages differentiated from patient-derived iPSCs will provide the first insight into the tissue-specificity of mitochondrial disorders. These three areas are inter-related in patients with mitochondrial diseases. By characterising the mechanisms, I aim to identify novel approaches to prevention and treatment.
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