Effect of Tim23 Knockdown IN VIVO on Protein Import into Mitochondria and Retrograde Signaling to the UPRmt in Muscle

The mitochondrial unfolded protein response (UPRmt) is a protein quality control mechanism that strives to eliminate toxic effects exerted by misfolded and misassembled proteins. We sought to understand this mechanism by perturbing the coordination between the nuclear and mitochondrial genomes by reducing the expression of a major channel of the inner mitochondrial membrane. This established a relationship between protein import, and the maintenance of mitochondrial proteostasis. Next, we sought to explore the communication between the nucleus and the mitochondrion that mediates the activation of the UPRmt. We investigated the role for proteolytically-derived peptides in this retrograde signaling. Here we highlight the relationship between the protein import pathway and its role in facilitating peptide-mediated communication in maintaining proteostasis. The UPRmt has been implicated in aging, cancer, and neurodegenerative diseases. Thus, my work has contributed to improving our understanding of this quality control mechanism, thereby providing potential future therapeutic targets.