Investigating polyamines as a treatment target for mitochondrial disease

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.

Mitochondrial diseases are a group of genetic disorders resulting from defects in the mitochondrial respiratory machinery, which can cause death in early childhood and are largely untreatable. Mitochondrial diseases frequently affect the nervous system, causing loss of neuronal function and neurodegeneration. Mitochondrial dysfunction triggers mitochondrial stress signalling via the transcription factor ATF4. Mitochondria are central players in metabolism, shaping the metabolome and ATF4 is a key regulator of metabolic gene expression. We hypothesise that in mitochondrial disease, ATF4 disrupts polyamine metabolism, contributing to the neurological phenotypes. In this project, we will use a Drosophila model of the mitochondrial disease Leigh syndrome that we have developed and an established Leigh syndrome mouse model to understand how ATF4 regulates polyamines and provide direct evidence that disruption of polyamine metabolism contributes to the disease. Metabolomics and analysis of polyamine enzyme gene expression will be used dissect the role of ATF4 in the brain in Leigh syndrome. We will then use state-of-the-art genetic and imaging techniques, combined with functional assays, to understand the mechanism by which polyamine metabolism contributes to this disease. Finally, we will test whether modulating levels of the polyamine spermidine alleviates the neurological phenotypes in Drosophila and mouse Leigh syndrome models. This project will lead to a greatly improved understanding of the molecular basis of mitochondrial disease and the pre-clinical validation of potential new treatment.