Mitochondrial caseinolytic peptidase proteolytic subunit (CLPP) (CLPP)

Mitochondrial caseinolytic peptidase proteolytic subunit (CLPP) is a serine protease located within the mitochondrial matrix that plays a central role in maintaining mitochondrial protein homeostasis (UniProt: Q16740). It typically functions as a tetradecameric complex that, in association with the AAA+ ATPase CLPX, identifies and degrades misfolded or damaged proteins to prevent proteotoxic stress (PubMed: 26365345). Recently, CLPP has been identified as a promising therapeutic target in oncology, particularly for the treatment of acute myeloid leukemia (AML) and certain solid tumors like glioblastoma (PubMed: 30639100). Small molecule activators, such as the imipridone ONC201, bind to CLPP and induce a conformational change that widens the proteolytic pore, leading to the uncontrolled degradation of essential mitochondrial proteins, including subunits of the respiratory chain (PubMed: 31499147). This hyperactivation results in severe mitochondrial dysfunction, metabolic collapse, and the induction of apoptosis in malignant cells. Conversely, loss-of-function mutations in the CLPP gene are the underlying cause of Perrault syndrome type 3, a rare autosomal recessive disorder characterized by sensorineural hearing loss and ovarian dysgenesis (PubMed: 23583981). Thus, CLPP serves as a critical metabolic switch whose modulation can either drive cell death in cancer or lead to developmental defects when deficient.

Other names

Caseinolytic mitochondrial matrix peptidase proteolytic subunitEndopeptidase ClpCLPPutative ATP-dependent Clp protease proteolytic subunit mitochondrial

Small molecule activators (e.g., ONC201, ONC206, and Acyldepsipeptides) bind to the hydrophobic pockets of the CLPP tetradecamer, stabilizing an open-gate conformation that allows for the non-selective, ATP-independent degradation of mitochondrial proteins, leading to mitochondrial proteotoxic stress and cell death (PubMed: 30639100, PubMed: 31499147).