The genetic architecture and functional role of the mitochondrial transcriptome in the Human Brain

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Mitochondria are key to many fundamental cellular processes, including cellular energyproduction and cell death. Mitochondria perform different tasks in varied cell types, but it isgenerally understood that the role of mitochondria becomes even more important in tissueswith higher energy demand such as the brain and heart. In the brain, mitochondria arerequired to dynamically change their form and function in response to fluctuating demands,and they are key players in the modulation of synaptic signalling and neurite regeneration.Their importance in the brain is underscored by the accumulating evidence that thedysfunction of mitochondrial processes is key to many neurological disorders. As such, it isvital to understand how mitochondrial processes are regulated in the brain and whether thisvaries across different cell types.The first objective of this project is to integrate complex genetic, transcriptomic and singlecelldata to identify brain and cell-type specific regulation of key mitochondrial processes thatinfluence downstream function (such as transcription, RNA modification and localisation)across a large number of human individuals. This will involve using computational methods toconsider how relationships between the nuclear and mitochondrial genomes vary across thebrain. The second objective of the project will be to identify the downstream consequences ofmodulating these processes on mitochondrial function, through the genetic manipulation ofiPSC-derived neuronal and astrocyte cell models. Finally, these results will then be consideredfor their importance in ageing processes and a range of neurological disorders.The project will be strengthened by the complementary skills sets of the two supervisors,who will provide support in each area: Dr Hodgkinson is an expert in the computationalanalysis of mitochondrial processes, whereas Dr Devine is an expert in using iPSCs asfunctional model systems and understanding the roles of mitochondria in neurons andneurodegenerative diseases.