ClpP, the caseinolytic protease P, is a serine protease crucial for proteostasis in eukaryotic organelles and prokaryotic cells [3]. In mitochondria, it plays a central role in protein quality control by degrading misfolded or damaged proteins, thus maintaining normal metabolic function [1,2,6,7]. It forms a multimeric complex with the ATP-dependent unfoldase ClpX (ClpXP) to exhibit proteolytic activity [6]. Its substrates are involved in essential mitochondrial processes like the Krebs cycle, oxidative phosphorylation, and fatty acid metabolism [4].

In a conditional knockout (cKO) mouse model, ClpP/ClpX deficiency was found to impair mitochondrial functions and mTORC1 signaling during spermatogenesis. The deficiency reduced mitochondrial functions and quantity in spermatocytes, affected energy supply during meiosis, and attenuated zygotene-pachytene transformation of male germ cells, eventually leading to apoptosis and decreased testicular size [5]. In another study, reduced ClpP expression in a diet-induced non-alcoholic steatohepatitis (NASH) mouse model led to mitochondrial dysfunction, which was a key factor in NASH development. Overexpression or activation of ClpP reversed mitochondrial dysfunction and improved NASH characteristics [2]. Also, hyperactivation of ClpP selectively killed cancer cells by degrading respiratory chain protein substrates and disrupting mitochondrial structure and function, independent of p53 status [1].

In conclusion, ClpP is essential for maintaining mitochondrial protein quality control and normal metabolic function. The ClpP/ClpX cKO mouse models have revealed its critical roles in spermatogenesis, while studies on diet-induced NASH models and cancer cell lines have shown its potential as a therapeutic target in NASH and cancer [1,2,5].