Exploring novel molecular targets in mitochondrial protein synthesis to develop treatments in mitochondrial disease. (360G-Wellcome-109915_A_15_Z)

Mitochondrial diseases are usually disabling, progressive or fatal, affecting the brain, liver, skeletal muscle, heart and other organs. Our understanding of the mitochondrial protein synthesis apparatus in health and disease is still limited. Currently there are no effective cures for patients with mitochondrial disease and treatment is at best symptomatic. The proposed research will identify novel molecular targets in mitochondrial diseases and will explore why mutations in different genes aff ect certain tissues only. I will study mitochondrial protein synthesis in different neuronal cell types (motor neurons, oligodendroglia cells and astrocytes) in vitro, converted from skin fibroblasts of patients with different pathogenic mutations. To explore the effect of mitochondrial translation defects in vivo, I will use zebrafish. These models will improve our understanding of the molecular mechanisms of different defects of mitochondrial protein synthesis in the affected tissues and organ s, and will enable the development of novel approaches for therapy. The long-term goal is to up-regulate or boost compensatory factors in patients with mitochondrial disease for therapy. 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.