Caseinolytic mitochondrial matrix peptidase proteolytic subunit (CLPP) (CLPP)

The Caseinolytic mitochondrial matrix peptidase proteolytic subunit (CLPP) is a serine protease located within the mitochondrial matrix that is essential for maintaining mitochondrial protein quality control (UniProt Q16740, PMID: 30197302). It typically functions as a multimeric complex with the AAA+ ATPase chaperone ClpX to degrade misfolded or damaged proteins, thereby supporting mitochondrial respiration and metabolic homeostasis (PMID: 30197302, PMID: 31501515). CLPP has gained prominence as a therapeutic target in oncology because its hyperactivation by small molecules, such as imipridones (e.g., ONC201), leads to the non-selective degradation of respiratory chain subunits (PMID: 30612879, PMID: 33432168). This process induces severe mitochondrial dysfunction, activates the integrated stress response (ISR), and promotes apoptosis in various malignancies, including glioblastoma and acute myeloid leukemia (PMID: 33432168, PMID: 28114273). Beyond its role in cancer, loss-of-function mutations in the CLPP gene are associated with Perrault syndrome, a rare disorder characterized by sensorineural hearing loss and ovarian dysgenesis (UniProt Q16740, PMID: 23541340). Small molecule activators bind to the hydrophobic pockets of the CLPP tetradecamer, causing a conformational change that widens the proteolytic pore (PMID: 33432168, PMID: 31209035). This activation bypasses the need for the ClpX chaperone, resulting in the degradation of vital proteins like SDHA and TUFM (PMID: 31501515, PMID: 33432168). Consequently, CLPP represents a unique therapeutic switch where both its deficiency and overactivity can have profound biological consequences for cell survival (PMID: 30612879, PMID: 31209035).

Other names

ClpPCaseinolytic peptidase PMitochondrial ClpPEndopeptidase ClpATP-dependent Clp protease proteolytic subunit, mitochondrialHuman caseinolytic mitochondrial matrix peptidase proteolytic subunit

Small molecule activators bind to the CLPP tetradecamer, inducing an open-gate conformation that allows for the chaperone-independent degradation of mitochondrial proteins, leading to mitochondrial dysfunction and cell death (PMID: 31501515, PMID: 33432168, PMID: 31209035).