P06 - Structural and functional studies of OPA1 to explore the mechanisms governing inner mitochondrial membrane shape
Mitochondrial fusion and fission reactions are closely linked to the maintenance of proper mitochondrial inner membrane (IM) architecture. These processes depend on the action of mechano-chemical GTPases of the dynamin superfamily. In fungi, fusion of the mitochondrial IM is catalyzed by dynamin-like Mitochondrial genome maintenance protein 1 (Mgm1), whereas the distantly related Optic Atrophy 1 (OPA1) protein carries out this function in animals and plants. Besides membrane fusion, roles of Mgm1/OPA1 in the maintenance of cristae morphology and mitochondrial IM scission have been demonstrated. How these apparently divergent functions are catalyzed by Mgm1/OPA1 on the molecular level is completely unclear.In this proposal, we wish to address the molecular mechanisms of Mgm1/OPA1-catalyzed remodeling of the mitochondrial IM by employing a structure-function approach. In preliminary work, we determined the crystal structure of a fungal Mgm1 homologue and characterized its membrane binding and assembly mode. Capitalizing on this structure, we now aim for a combination of structural, biochemical and cell-based experiments that will lead to unprecedented insights into the structure and assembly of OPA1 and will reveal the molecular mechanisms of OPA1 for maintaining IM shape and function. Furthermore, they will help to understand the molecular deficits of OPA1 mutations in optic atrophy, the most common genetic disorder leading to blindness in human.