Mitochondrial Protease Targeting Chimeras for Mitochondrial Matrix Protein Degradation

摘要

Targetedprotein degradation (TPD) is an emerging technique forprotein regulation. Currently, all TPD developed in eukaryotic cellsrelies on either ubiquitin-proteasome or lysosomal systems, thus arepowerless against target proteins in membrane organelles lacking proteasomesand lysosomes, such as mitochondria. Here, we developed a mitochondrialprotease targeting chimera (MtPTAC) to address this issue. MtPTACis a bifunctional small molecule that can bind to mitochondrial caseinolyticprotease P (ClpP) at one end and target protein at the other. Mechanistically,MtPTAC activates the hydrolase activity of ClpP while simultaneouslybringing target proteins into proximity with ClpP. Taking mitochondrialRNA polymerase (POLRMT) as a model protein, we have demonstrated thepowerful proteolytic ability and antitumor application prospects ofMtPTAC, both in vivo and in vitro. This is the first modularly designed TPD that can specificallyhydrolyze target proteins inside mitochondria.