Assistant Professor of Physiology and Cellular Biophysics
Department of Physiology and Cellular Biophysics
Columbia University Irving Medical Center
Title: Regulation of mitochondrial complex I assembly in Drosophila melanogaster
Abstract: Mammalian mitochondrial complex I (CI), which has 45 subunits and many associated co-factors, is the most sophisticated component of the oxidative phosphorylation system. CI is assembled through a highly choreographed process with the assistance of additional regulatory factors called CI assembly factors. In addition, as a major source of reactive oxygen species (ROS), CI is prone to disruption. Consequently, about 30% of mitochondrial disorders can be traced to a defect in CI. However, deciphering the precise molecular lesion triggering many CI disorders can be problematic as a result of the poor genotype-phenotype correlation and limited preclinical resources to thoroughly elucidate the molecular and genetic basis for the multiple disease variants. Therefore, alternative models for investigating CI assembly and pathology are urgently needed to improve our understanding of CI disorders and to accelerate the development of new therapeutics. We have exploited the limited gene redundancy and vast arsenal of genetic tools in Drosophila melanogaster (Drosophila) to improve our understanding of CI biology. We found that the cryo-EM structure of Drosophila CI is remarkably similar to that of mammalian CI. Further, we have shown that Drosophila is a powerful model system for rigorously examining how CI is assembled by specific assembly factors, for exploring how CI dysfunction impacts various cellular degradative processes and stress responses, for creating and studying various rare CI disease models and for performing genetic screens to identify new regulators of CI assembly. I will be describing some of the efforts in my lab aimed at addressing these topics.