Mitochondrial caseinolytic protease P (ClpP)

Mitochondrial caseinolytic protease P (ClpP) is a highly conserved serine protease located in the mitochondrial matrix, encoded by the nuclear CLPP gene and imported into mitochondria via an N-terminal targeting sequence[1][3][5]. ClpP forms a barrel-like oligomeric complex—typically a tetradecamer—that functions together with the AAA+ ATPase chaperone ClpX as the ClpXP complex; ClpX recognizes, unfolds, and delivers substrate proteins to the protease[1][3][10]. The primary function of ClpP is to degrade misfolded, denatured, or damaged mitochondrial proteins, maintaining mitochondrial protein homeostasis and the integrity of the respiratory chain[1][3][2]. ClpP also plays a pivotal role in the mitochondrial unfolded protein response (UPRmt) and is essential for proper mitochondrial energy metabolism[3][1][2]. ClpP is upregulated in various cancers and is being explored as a novel therapeutic target, with both inhibition and hyperactivation shown to disrupt tumor cell viability by impairing mitochondrial function and inducing cell death[4][2]. Drugs such as ONC201 trigger hyperactivation of ClpP, driving cancer cell apoptosis through mitochondrial stress[4].

Other names

ATP-dependent Clp protease proteolytic subunitCLPPClp proteaseCaseinolytic peptidase PClpXP complex (with ClpX chaperone)

ONC201/ONC212: Activation (hyperactivation) of ClpP induces mitochondrial dysfunction, impairs oxidative phosphorylation, and promotes apoptosis in cancer cells[4][2][3]. A2-32-01: Inhibition of ClpXP leads to reduced mitochondrial metabolism and impaired cancer cell viability[2]. Inhibitors/blockers: Blockade of proteolytic activity or disruption of ClpP–ClpX assembly