Cells must eliminate excess or damaged
proteins to maintain protein homeostasis. To ensure protein homeostasis in the cytoplasm, cells rely on the
ubiquitin-
proteasome system and autophagy. In the mitochondria, protein homeostasis is regulated by mitochondria
proteases, including four core
ATP-dependent proteases, m-AAA, i-AAA, LonP, and ClpXP, located in the mitochondrial membrane and matrix. This review will discuss the function of mitochondrial
proteases, with a focus on ClpXP as a novel therapeutic target for the treatment of
malignancy. ClpXP maintains the integrity of the mitochondrial respiratory chain and regulates metabolism by degrading damaged and misfolded
mitochondrial proteins. Inhibiting ClpXP genetically or chemically impairs oxidative phosphorylation and is toxic to malignant cells with high ClpXP expression. Likewise, hyperactivating the
protease leads to increased degradation of ClpXP substrates and kills
cancer cells. Thus, targeting ClpXP through inhibition or hyperactivation may be novel approaches for patients with
malignancy.