Investigating mitochondrial metabolic signalling in the nervous system (360G-Wellcome-212167_Z_18_Z)

Mitochondria generate the majority of ATP, but have key additional roles in cellular metabolism. Mitochondrial dysfunction causes neurodegeneration, but the underlying molecular mechanisms are poorly understood. Recent studies in cultured cells have shown that mitochondrial dysfunction leads to an increase in production of the oncometabolite 2-hydroxyglutarate (2HG), which plays important roles in signalling and modification of the epigenome. The host lab has recently shown that reducing 2HG levels improves neuronal function in a Drosophila mitochondrial disease model. This project will use Drosophila to study the effects of increased 2HG levels in the nervous system. We hypothesise that mitochondrial dysfunction causes increased 2HG levels in neurons, which results in neuronal dysfunction and neurodegeneration. The key goals of the project will test this hypothesis: 1. To determine whether Drosophila L2HGDH mutants, which have increased 2HG levels, have reduced locomotor activity and lifespan. 2. To determine whether Drosophila L2HGDH mutants have increased neurodegeneration. 3. To test whether increasing 2HG levels exacerbates neuronal dysfunction and neurodegeneration in a Drosophila mitochondrial disease model. Overall, this project will provide the first evidence that mis-regulation of mitochondrial metabolism contributes to neurodegeneration. It will also show that 2HG is a potential novel therapeutic target for neurodegenerative disease.