Mitochondrial diseases affect up to 1 in 4300 in the population, are largely untreatable and can result in death in early childhood. Although mitochondrial diseases are clinically heterogeneous, they frequently affect the nervous system, causing loss of neuronal function and neurodegeneration. The neurological features of mitochondrial diseases are associated with decreased ATP levels, but it is difficult to treat the primary mitochondrial defect in patients. New approaches to develop therapies for mitochondrial disease are therefore urgently needed. Drosophila have great potential to replace animal models of mitochondrial disease. However, existing Drosophila mitochondrial disease models do not focus on the signalling and metabolic changes in the brain. The encephalomyelopathy Leigh syndrome is the most common childhood mitochondrial disease, typically resulting in death by 3 years of age. We will use a new Drosophila nervous system-specific model of Leigh syndrome to provide ground-breaking new insight into mitochondrial disease metabolism, resulting in significant replacement of animal models.
Zebrafish, mice, rats and primates are all used as animal models of mitochondrial dysfunction and disease. Dozens of published studies each year model mitochondrial dysfunction in animals, using mitochondrial toxins such as rotenone, or genetic deletion of mitochondrial genes, often resulting in severe and harmful phenotypes. Given the large numbers of animal studies and variety of animal species that are used to study mitochondrial disease, our project has the potential to significantly reduce animal suffering.
Our project aims to determine how mitochondrial stress signalling regulates specific metabolites that contribute to pathogenesis in mitochondrial disease. The complex genetics required to validate potentially pathogenic metabolites is extremely laborious and costly in mice and, due to the severe phenotypes of mouse mitochondrial disease models, results in significant animal suffering. Using our fly model, we can knockdown or overexpress key metabolic enzymes to rapidly identify and genetically validate the therapeutic potential of specific metabolites. Rather than being used to screen a wide variety of potential targets requiring large numbers of animals, mouse models can then be focused on specific metabolic pathways that have been validated in our fly model. The best characterised Leigh syndrome mouse model, the Ndufs4 knockout (KO) mouse, suffers from early onset neurodegeneration, reduced locomotion and ataxia starting at five weeks of age, and death at seven weeks. We use around 200 Ndufs4 KO mice annually, under a Home Office Licence Moderate Protocol. We estimate that this project will result in replacement of ~60 Ndufs4 KO mice per year by ourselves. Moreover, based animal use by potential collaborators in Europe and the USA using Ndufs4 KO and other animal models of mitochondrial disease, who in total use around 1000 mice per year, our project would result in the replacement of ~200 mice per year in these labs. Our project will therefore accelerate the identification of new therapeutic targets and reduce animal suffering.