Modulation of the activity of human mitochondrial protease complex ClpXP as potential therapeutic strategy for cancer

Mitochondrial chaperones and proteases, crucial for mitochondrial proteostasis, are overexpressed in most tumor types, and are involved in cell metabolic reprogramming that allows evasion of apoptosis and increased survival (1). Among the effectors of mitochondrial proteostasis, human ClpXP (hClpXP) is a soluble mitochondrial matrix protease complex, formed by the protease ClpP and the chaperone ClpX. The complex degrades misfolded or aggregated proteins in mammalian mitochondria and is part of the UPRmt system (1). hClpXP is upregulated in many primary and metastatic human tumors and in some cases is correlated with shortened overall survival. Its overexpression is also associated with mitochondrial stress. Both hClpXP inhibition and activation result in tumor cell death. In fact, on the one hand, inhibition leads to the accumulation of misfolded and damaged respiratory chain proteins and impairs oxidative phosphorylation (OXPHOS) that results in the selective death of cancer cells. On the other hand, hClpXP overactivation results in mitochondrial morphological damage and decrease in OXPHOS, which, in turn, can cause tumor cell death. To date, it is unknown whether inhibiting or activating hClpXP is the preferred therapeutic strategy (2). To study the effect of hClpP activity modulation, a recombinant human ClpP protease has been produced and used in a fluorogenic enzymatic in vitro assay (3). The results of this study will be presented, as well as the characterization of the mitochondrial functions in different tumor cell lines overexpressing hClpP. 1. Nouri, K. et al. Cell Death Dis 2020, 11, 841 2. Perrone, M.G. et al. Curr. Med. Chem. 2021, 28, 3287 3. Ishizawa, J. et al. Cancer Cell, 2019, 35, 721