Investigating polyamines as a treatment target for mitochondrial disease

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Mitochondrial diseases are a group of genetic disorders that cause damage to cells and tissues in the body and affect up to 1 in 4300 people in the UK. There are currently no licenced treatments and developing therapeutic strategies for mitochondrial diseases has been highlighted as a priority area. Mitochondria are tiny structures within cells, which play a critical role in cellular energy production and metabolism. When these 'powerhouses' malfunction, it can result in chronic illness. Organs with high metabolic demands are often the most severely affected and mitochondrial diseases frequently cause damage to the nervous system. Extensive evidence from animal and clinical studies also suggests that defective mitochondria play a critical role in other neurodegenerative diseases, including Alzheimer's and Parkinson's disease. In this project we will study how defective mitochondria trigger changes in the expression of key metabolic genes and how this causes neurodegeneration. We hypothesise that changes in the levels of metabolites called polyamines in the brain contribute to neurodegeneration in mitochondrial disease.We will test this hypothesis using fruit flies and mice that have been given the mitochondrial disease Leigh syndrome, which causes neurodegeneration and death in children. We will use these 'disease models' to better understand the cause of the disease and identify new treatments. The fly model is fast and inexpensive to study, while the mouse model more closely mirrors human mitochondrial disease. Using highly sensitive techniques, we will measure how mitochondria cause changes in polyamine metabolite levels in the brain in this fly model of Leigh syndrome. Using cutting-edge genetic technology, we will study the role of key metabolic genes that are switched on or off at the wrong time in nerve cells in the fly model, to discover how they contribute to nerve cell damage. We will also test whether blocking key metabolic genes, or treatment with a metabolite called spermidine, can prevent damage to the nervous system. Overall, this project will lead to a new understanding of the cause of mitochondrial disease and novel strategies to treat the disease in patients. In the long-term the project will also contribute to the understanding and treatment of other neurodegenerative diseases such as Alzheimer's and Parkinson's disease.