Identifying common and tissue-specific genetic drivers of fundamental biological processes taking place in human mitochondria

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Mitochondria are 'organelles' (which can be thought of as analogous to the organs of the human body) that perform specific roles in the cell to help it to function normally. Primarily mitochondria are responsible for generating chemical 'energy' that is used for fundamental processes like muscle movement, respiration and heart function, but they are also involved in processes like signal transmission in the brain and generating body heat. Due to their central role in these important processes, poor functioning mitochondria have been implicated in a wide range of diseases such as Parkinson's disease, diabetes and cancer, with high-energy tissues such as the brain often being the most affected. As a consequence, understanding the biological processes taking place in the mitochondria across tissues is key to human health.Alongside genetic material (DNA) that is present in the nucleus, which provides the blueprint for life, mitochondria also have their own DNA. This genetic code provides information to create proteins that are required for mitochondria to generate cellular energy. Before these proteins can be utilized, mitochondrial DNA is converted to RNA (expression of the gene), which is then processed in different ways before being translated into proteins. The steps converting mitochondrial DNA into proteins are complex, multi-staged and at all points rely on genes that are coded in the nuclear genome. As a result, there are strong relationships between the nuclear and mitochondrial genomes: mutations in the nuclear genome are known to cause mitochondrial disorders. Although we understand a great deal about the nuclear genes involved in mitochondrial processes, there is still a lack of understanding of all stages of the molecular processes influencing mitochondrial function, and we are lacking a catalogue of common genetic mutations carried by healthy individuals that can influence the levels of expression of mitochondrial genes and the processing of mitochondrial RNA. In this study we will use novel techniques to quantify the expression levels of mitochondrial genes across a large number of individuals and in many different tissue types, therefore creating a frame of reference for all future studies interested in comparing mitochondrial RNA levels in healthy and diseased individuals. Using this data we will then identify genetic variation in the nuclear genome that is associated with variation in mitochondrial gene expression and test whether this genetic variation is only important in certain tissues, or whether it acts across the entire human body. Following this, we will compare the genetic variation we identify as being associated with mitochondrial gene expression to databases of the features and annotations of the human genome, as well as catalogues of mutations linked to disease. In this way, we will attempt to understand the mechanisms by which mitochondrial gene expression is regulated and whether these processes may help researchers to understand the underlying causes of disease.Studying these processes in healthy individuals will allow us to identify genes that are important in the normal functioning of mitochondria, but will also create a list of target genes (and mutations) that may become dysfunctional in some individuals and are therefore important for the study of diseases. Since mitochondria tend to be more important in high-energy tissues such as the heart and brain, understanding if these processes vary in different tissues will be key to inferring the potential impacts on human health. Finally, genes and genetic mutations identified here may identify biological processes that are important in ageing, since poor functioning mitochondria are one hallmark of the ageing process, and could also highlight nuclear genes associated with mitochondrial function that are important to study in the context of three-parent embryos.