Mitochondrial ATP-Dependent Proteases—Biological Function and Potential Anti-Cancer Targets

SIMPLE SUMMARY: Alterations of cellular metabolism and bioenergetics, oxidative stress, and intracellular reactive oxygen species (ROS) levels are hallmarks of cancer development. Mitochondrial proteases, especially ATP-dependent proteases are essential to regulate mitochondrial function by maintaining protein quality. Emerging studies suggest the therapeutic potential of targeting the matrix ATP-dependent protease ClpXP for a subset of malignancies. In this review, we summarize our current knowledge on the biological function and the anticancer effects of targeting ATP-dependent proteases with a focus on ClpXP. ABSTRACT: 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.