Functionalizing the Unannotated Mitochondrial Proteome

Mitochondria are dynamic and complex organelles that play a central role in all aspects of biology, including energy production, intermediary metabolism, and apoptosis. These broad cellular functions also place mitochondria as a central player in human health. Mitochondrial dysfunction is associated with a wide range of diseases, including cancer, type 2 diabetes, and most neurodegenerative disorders. As a result of these wide‐ranging critical activities, many efforts have focused on identifying and characterizing the mitochondrial proteome, with over 1,000 proteins identified to date in mammals. Remarkably, however, roughly one‐quarter of these proteins remain essentially uncharacterized. These include many proteins that are highly conserved throughout eukarya, a strong indication that they perform a fundamentally important function. Our studies of a handful of these uncharacterized mitochondrial conserved proteins support this proposal, revealing new roles for these proteins in critical aspects of mitochondrial function, including mitochondrial protein quality control, lipid synthesis and mitochondrial ETC complex and supercomplex assembly. In two cases, these fundamental observations led directly to the elucidation of new human disease genes. One of these discoveries provided the first molecular identification of the protein complex that is necessary and sufficient for mitochondrial pyruvate entry. We have made progress in understanding the biochemical mechanisms governing the activity and structure of this complex. We have also found that loss of its activity is an important feature of cancer metabolism. The overall goal in this research is to provide a new understanding of the biochemical and cellular function of each conserved uncharacterized mitochondrial protein, determine how they contribute to normal mitochondrial activity and human disease.