ATP-dependent Clp protease proteolytic subunit, mitochondrial (ClpP) (ClpP)

ATP-dependent Clp protease proteolytic subunit, mitochondrial (ClpP) is a highly conserved serine protease located within the mitochondrial matrix that plays a central role in mitochondrial protein quality control (UniProt Q16740). It functions as the catalytic core of the ClpXP complex, where it works in tandem with the AAA+ ATPase ClpX to degrade misfolded or damaged proteins, thereby maintaining mitochondrial bioenergetics and the mitochondrial unfolded protein response (UPRmt) (PubMed: 33037181). ClpP is frequently overexpressed in various malignancies, including acute myeloid leukemia (AML) and solid tumors such as gliomas, where it is essential for sustaining the metabolic demands of cancer cells (PubMed: 31002558). Small molecule imipridones, such as ONC201 and ONC206, act as potent ClpP activators that induce its hyperactivation, leading to the unregulated degradation of essential respiratory chain subunits like TFAM and SDHA. This process triggers mitochondrial collapse, activates the integrated stress response (ISR), and ultimately results in selective cancer cell apoptosis (PubMed: 31002558, 31002559). Conversely, loss-of-function mutations in the CLPP gene are the underlying cause of Perrault syndrome type 3, a condition characterized by sensorineural hearing loss and ovarian dysgenesis (OMIM: 601119). Therapeutic targeting of ClpP represents a novel strategy in oncology, though challenges include ensuring drug penetration into the mitochondrial matrix and avoiding off-target mitochondrial toxicity in healthy tissues.

Other names

CLPPCaseinolytic mitochondrial matrix peptidase proteolytic subunitEndopeptidase ClpPRLTS3DFNB81

Pharmacological hyperactivation of ClpP proteolytic activity, leading to unregulated degradation of mitochondrial respiratory chain proteins and induction of apoptosis.