Mitochondrial RNA processing in health and disease

Mitochondria are often described as the powerhouses of the cell, providing the main cellular energy source in the form of adenosine triphosphate. Five enzyme complexes, collectively termed the oxidative phosphorylation system, use the reducing power from nutrients to synthesise adenosine triphosphate via cellular respiration. This energy conversion is dependent on factors encoded by the nuclear and mitochondrial genome, with the latter encoding 13 subunits within four of the five oxidative phosphorylation system complexes. Adenosine triphosphate synthesis is therefore under dual genetic control, and this thesis addresses mechanisms that control and regulate mitochondrial gene expression. The mitochondrial genome is transcribed as long, polycistronic premature transcripts, which need to undergo cleavage and maturation before they can be used for correct translation on mitochondrial ribosomes. However, the mechanisms of this RNA processing, as well as the mechanisms underlying mitochondrial RNA homeostasis, are not fully understood. Here I used the fruit fly, Drosophila melanogaster, to study factors involved in mitochondrial gene expression. In two studies I addressed the functions of factors involved in the mitochondrial degradosome, responsible for RNA turnover. Additionally, I addressed the role of polyadenylation in RNA degradation, and studied how the polyadenylation machinery affects mitochondrial translation. Finally, defects of mitochondrial gene expression can have severe clinical consequences and form an important part of human pathology. One study of this thesis validated the pathogenicity of mutations in a tRNA aminoacyl transferase gene, identified in two siblings suffering from mitochondrial disease