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

The ATP-dependent Clp protease proteolytic subunit, mitochondrial (CLPP) is a critical serine protease located within the mitochondrial matrix that maintains protein homeostasis by degrading misfolded or damaged proteins. It typically functions as a multimeric complex with the AAA+ chaperone CLPX, which uses ATP hydrolysis to unfold substrates and feed them into the CLPP proteolytic core. In recent years, CLPP has emerged as a significant therapeutic target in oncology, particularly for aggressive cancers like acute myeloid leukemia and high-grade gliomas. Small molecule activators, such as the imipridone ONC201, hyperactivate CLPP by decoupling it from its regulatory chaperone, leading to the non-selective degradation of essential mitochondrial metabolic enzymes. This catastrophic proteolysis triggers the mitochondrial unfolded protein response (UPRmt) and ultimately leads to cancer cell death through apoptosis. Conversely, loss-of-function mutations in the CLPP gene are associated with Perrault syndrome, a rare autosomal recessive disorder characterized by sensorineural hearing loss and ovarian dysgenesis.

Other names

ClpPEndopeptidase ClpPutative ATP-dependent Clp protease proteolytic subunit mitochondrial

Small molecule activators (imipridones) bind to the CLPP tetradecamer, inducing a conformational change that opens the proteolytic core. This leads to the constitutive, ATP-independent degradation of mitochondrial proteins, resulting in mitochondrial dysfunction, loss of oxidative phosphorylation, and induction of apoptosis in cancer cells.