Caseinolytic protease P mitochondrial (ClpP)

Caseinolytic protease P (ClpP) is a serine protease located in the mitochondrial matrix, encoded in the nucleus and imported into mitochondria, where it forms a multimeric complex critical for mitochondrial protein quality control. It degrades misfolded and damaged proteins, working with its ATPase partner ClpX (the ClpXP complex) to maintain mitochondrial integrity and function. ClpP is essential for the mitochondrial unfolded protein response and regulates the stability of respiratory chain complexes and mitochondrial gene expression. Overexpression of ClpP is linked with certain cancers such as acute myeloid leukemia, and both activation and inhibition of ClpP have been shown to induce cancer cell death through disruption of mitochondrial homeostasis. Several investigational drugs target ClpP, primarily by hyperactivating its protease function, providing a novel therapeutic approach for selectively killing malignancies dependent on mitochondrial proteostasis.

Other names

Mitochondrial ClpPCaseinolytic peptidase PCaseinolytic mitochondrial matrix peptidase proteolytic subunitCLPP (gene symbol)ClpXP protease complex (when in complex with ClpX)

Activation: Small molecules (e.g., ONC201, imipridones) hyperactivate ClpP, leading to unregulated proteolysis of mitochondrial substrates, loss of respiratory chain components, and cancer cell death. Inhibition: Inhibition (genetic or chemical) leads to accumulation of defective mitochondrial proteins, disrupting respiration and inducing cell death in cancer cells where ClpP is overexpressed.