Identification and characterization of novel mitochondrial complex I assembly factors

• Applicant: Dr. Fabian Bärtling
• Subject Area: Pediatric and Adolescent Medicine
• Term: from 2016 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 317344712

The proposed project is dedicated to the identification and characterization of novel mitochondrial complex I assembly factors in order to gain further insight into the intricate biogenesis of this respiratory chain enzyme as a basis for new approaches to therapy.Oxidative phosphorylation disorders affect approximately one in 5000 newborns. In these patients, mitochondrial complex I, also called NADH:ubiquinone oxidoreductase, is the most commonly affected enzyme and accounts for about every third case. Oxidative phosphorylation disorders lead to variable multisystem disorders that most commonly affect the brain and the muscles. Overall prognosis is poor and treatment options are scarce.Mitochondrial complex I is the largest membrane-bound protein of the cell. The biogenesis of complex I is a highly intricate process, since it involves the concerted action of two genomes, the nuclear and the mitochondrial genome, and their individual protein synthesis machinery. This process, furthermore, relies on the aid of so-called assembly factors, which comprise proteins that aid in the biogenesis but are not part of the mitochondrial complex I itself. So far, relatively few of the assembly factors have been identified and their mode of action is poorly understood. Understanding the details of the mitochondrial complex I assembly process is an essential prerequisite for the development of new approaches for the treatment of mitochondrial disorders.In preliminary experiments, many new important details of the mitochondrial complex I assembly process could be demonstrated, including data on the composition of CI subcomplexes and the assembly sequence. Particularly, novel complex I assembly factor candidates were identified. The proposed laboratory project serves to verify, whether these proteins are actually required for complex I biogenesis and to identify their exact mode of action. Amongst others, the experiments include knock-down experiments, in which cells will be deprived of these proteins and the detailed effects of their loss on the complex I assembly process and on the other respiratory chain complexes will be studied.

• DFG Programme: Research Fellowships
• International Connection: Netherlands
• Host: Leo Nijtmans, Ph.D.