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

Mitochondria are key to many fundamental cellular processes, including cellular energy
production and cell death. Mitochondria perform different tasks in varied cell types, but it is
generally understood that the role of mitochondria becomes even more important in tissues
with higher energy demand such as the brain and heart. In the brain, mitochondria are
required 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 the
dysfunction of mitochondrial processes is key to many neurological disorders. As such, it is
vital to understand how mitochondrial processes are regulated in the brain and whether this
varies across different cell types.
The first objective of this project is to integrate complex genetic, transcriptomic and singlecell
data to identify brain and cell-type specific regulation of key mitochondrial processes that
influence downstream function (such as transcription, RNA modification and localisation)
across a large number of human individuals. This will involve using computational methods to
consider how relationships between the nuclear and mitochondrial genomes vary across the
brain. The second objective of the project will be to identify the downstream consequences of
modulating these processes on mitochondrial function, through the genetic manipulation of
iPSC-derived neuronal and astrocyte cell models. Finally, these results will then be considered
for 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 computational
analysis of mitochondrial processes, whereas Dr Devine is an expert in using iPSCs as
functional model systems and understanding the roles of mitochondria in neurons and
neurodegenerative diseases.