Proteasomes suppress anticancer drug-induced cytotoxicity by inhibiting mitochondrial protein import and promoting ROS-BNIP3-mediated mitophagy.

Multidrug resistance (MDR) is associated with increased proteasome activity, which facilitates the clearance of damaged proteins and reduced mitochondrial activity, which contributes to quiescence. However, the mechanistic link between protein damage, mitochondrial dysfunction, and proteasome activity remains elusive. Here, we demonstrate that chemical drugs bind to newly synthesized mitochondrial proteins, which are largely unfolded and are coimported into the mitochondrion before appearing in the lysosome and/or nucleus. This triggers a mitochondrion-lysosome-mediated chain reaction, including the integrity stress response (ISR) and the mitochondrial unfolded protein response (UPRmt), followed by increased lysosome biogenesis and PINK1-Parkin independent but ROS-BNIP3-mediated mitophagy. We further observed that proteasomes are the main controller of the mitochondrion-lysosome reaction by monitoring proteostasis, suppressing mitochondrial protein import and promoting mitophagy under both normal and drug-treated conditions. The combination of chemical drugs and the proteasome inhibitor bortezomib (BTZ) triggered excessive mitochondrial import of damaged proteins, overwhelming mitochondrial capacity, causing mitochondrial membrane damage, profound mitochondrial ROS production, lysosome membrane permeabilization, impaired mitophagy, and proteostasis stress-induced cell death.