Mouse models of mitochondrial dysfunction

Abstract

The compact size and organisation of the mammalian mitochondrial genome has necessitated the evolution of unique mechanisms to facilitate rapid changes in gene expression in response to the changing energy demands of the cell. The mitochondrial transcriptome encodes proteins that are subunits of the respiratory chain, responsible for most of the energy production required by the cell. Consequently the coordinated regulation of the mitochondrial transcriptome by the nucleus is of particular importance for the maintenance of cell health and energy metabolism. Next generation technologies have revealed new and unexpected complexity of transcripts encoded by the human mitochondrial genome. Despite the common origin of all mitochondrial RNAs from a few long transcripts, variation between individual mitochondrial transcripts underpins the importance of post-transcriptional regulation of mitochondrial gene expression. Over the last few years we have investigated the unusual features of mitochondrial RNAs and the RNA-binding proteins that control their production, maturation, translation and stabilisation to understand the regulation of mitochondrial gene expression and its contribution to health and disease. To investigate the importance of RNA-binding proteins in mitochondria globally we have established new methods for massively parallel sequencing and analyses of RNase-accessible regions of human mitochondrial RNA. These methods have enabled us to understand the regulation of mitochondrial gene expression in cell and animal models of disease. Impaired mitochondrial function can be the cause of, or contribute significantly to a range of human diseases including mitochondrial diseases, metabolic and neurodegenerative diseases. Therefore we have used mouse models of mitochondrial dysfunction to understand the molecular and physiological consequences of dysregulated mitochondrial gene expression. We have investigated the roles of several mitochondrial RNA-binding proteins in mice and identified tissue-specific defects that are a result of impaired mitochondrial protein synthesis.