Grant: Project Grant

Mitochondria are the powerhouses of the cell. Their primary role is to generate energy in the form of ATP through oxidative phosphorylation. But their influence stretches far beyond energy production as they are involved in many critical processes such as metabolic regulation, programmed cell death, and calcium signaling, among others. Maintaining mitochondrial homeostasis is essential for cellular health as disruptions can lead to cancer, mitochondrial diseases, neurodegenerative diseases, metabolic syndromes, and aging-related decline. Our research program aims to investigate how protein homeostasis is maintained in the mitochondrion by the highly conserved ATP-dependent protease ClpXP present in the mitochondrial matrix. ClpXP plays critical roles in several diseases including cancer. Mutations in this protease also cause a rare mitochondrial disease, called Perrault syndrome. In the past funding period, my group identified compounds that dysregulate the activity of this complex, and we showed that these compounds have excellent anticancer activity. We also identified proteins that are cleaved by the dysregulated protease leading to cell death. In the current project, our goal is to investigate the physiological functions of a novel adaptor of ClpXP termed PDIP38. The adaptor enhances ClpXP-mediated degradation of specific substrates. We aim to (1) determine how PDIP38 recognizes and binds substrates for degradation by ClpXP, (2) identify a universal ClpXP-PDIP38 degron motif, and (3) elucidate the structure of ClpXP-PDIP38 complex. Our efforts will provide important insights into mechanisms that govern protein homeostasis in the mitochondria, as exquisite control of these processes is required to ensure the proper survival of the cell and the health of the organism. Furthermore, our work will have important implications to drug discovery efforts aimed at targeting this protease for various diseases.