Development of Oma1 inhibitors for the analysis of mitochondrial fusion pathways, apoptosis and mitochondrial related diseases.

• Applicant: Dr. Janos Steffen
• Subject Area: Biochemistry
• Term: from 2011 to 2012
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 199725649

Defects in mitochondrial function contribute to a wide range of diseases including cancer, cardiovascular disease, and degenerative disorders. Particularly, mitochondrial dysfunction has been linked to defects in apoptosis and mitochondrial fusion pathways. Regulation of these pathways converges at the mitochondrial proteolytic system, where regulated proteolysis is required for processing key proteins in mitochondrial fusion pathways and apoptosis. However, how the mitochondrial proteolytic system regulates mitochondrial homeostasis and dynamics is not clearly understood. The goal of this application is to develop small molecule effectors that modulate the proteolytic activity of Oma1, an inner membrane mitochondrial zinc-metalloprotease, for studying mitochondrial fusion pathways and apoptosis. Oma1 is responsible for the inducible cleavage of Opa1, a member of the dynamin-related GTPases and involved in the controlling of mitochondrial fusion, when mitochondrial membrane potential is lost, or the mitochondrial ATP level is low. The cleavage of Opa1 leads to impaired mitochondrial fusion and consequently to apoptosis. Therefore the development of tools to alter the function of Oma1 will provide a platform to subsequently dissect the role of the mitochondrial proteolytic system contributing to mitochondrial-based diseases, particularly through apoptotic and fusion pathways. To identify Oma1 inhibitors, two screens will be developed: An in vitro screen with recombinant human Oma1 and a fluorogenic peptide and an in vivo genetic screen with bakers yeast. As these probes are developed, they will be characterized and studied in cultured cells to determine the consequences of altered Oma1 activity. The medical importance of events regulated by Oma1, including apoptosis, indicates that the chemical genetic approach may also lead to the identification and development of novel therapeutic agents for diseases affected by dysfunctional mitochondria.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professorin Dr. Carla M. Koehler, Ph.D.