Project 170364

Mitochondria are extremely dynamic organelles undergoing constant double membrane fusion and fission reactions. The control and mechanisms involved to regulate this activity are currently of great interest in both the health and the death of the cell. We have discovered the key action of the mitochondrial rhomboid protease in regulating membrane fusion. Rhomboids are highly conserved intramembrane proteases that process initially membrane tethered substrates. We have now identified three important substrates for the mitochondrial rhomboid: Mgm/OPA; a dynamin-related protein, Omi/HtrA2; a mitochondrial targeted protease, and Pink1; a mitochondrial targeted kinase. The rhomboid-dependent processing of these three proteins is required for their biological activities. Mutations in OPA cause the most prevalent early onset blindness mitochondrial disease called dominant optic atrophy; and both Pink1 and Omi have been linked to Parkinson's disease, underscoring the relevance of these discoveries. By undertaking a series of in vitro structure/function analyses, combined with in vivo assays in both yeast and flies, we hope to uncover the significance of the rhomboid cleavage event, and understand its relevance to mitochondrial function in human disease.

comparison of different provincial vaccination schedules