Exploring novel molecular targets in mitochondrial protein synthesis to develop treatments in mitochondrial disease

Most mitochondrial diseases are disabling, progressive or fatal, affecting the brain, liver, skeletal muscle, heart and other organs. Currently there are no effective cures and treatment is at best symptomatic. Although defective oxidative phosphorylation is the common final pathway, it is unknown why different mtDNA or nuclear mutations result in largely heterogeneous clinical presentations. The diagnosis in patients with multiple respiratory chain complex defects (~30% of all mitochondrial disease) due to abnormal mitochondrial translation is particularly difficult because of the massive number of nuclear genes involved in intra-mitochondrial protein synthesis. Many of these genes are not yet linked to human disease. Whole exome sequencing (WES) rapidly changed the diagnostic pathway by identifying the primary genetic defect, however, our understanding of the mitochondrial protein synthesis apparatus and expression of mitochondrial proteins in health and disease remains limited, slowing down the development of personalized therapies. This project investigates why defects of mitochondrial protein synthesis lead to extremely variable clinical presentations and explores novel functions of mitochondria in different tissues. We study mitochondrial translation in human cell lines (fibroblasts, induced neuronal progenitor cells, neurons) and zebrafish models of mitochondrial translation deficiencies. The identification of tissue specific targets will provide rationale for developing novel therapies. Potentially beneficial treatments identified in this research can be further investigated in high throughput screening projects, in pre-clinical (animal models) and clinical studies (trials), and if successful can be used in clinical practice.