Mitochondrial ClpP serine protease-biological function and emerging target for cancer therapy

Abstract

Mitochondrial ClpP is a serine protease located in the mitochondrial matrix. This protease participates in mitochondrial protein quality control by degrading misfolded or damaged proteins, thus maintaining normal metabolic function. Mitochondrial ClpP is a stable heptamer ring with peptidase activity that forms a multimeric complex with the ATP-dependent unfoldase ClpX (ClpXP) leading to proteolytic activity. Emerging evidence demonstrates that ClpXP is over-expressed in hematologic malignancies and solid tumors and is necessary for the viability of a subset of tumors. In addition, both inhibition and hyperactivation of ClpXP leads to impaired respiratory chain activity and causes cell death in cancer cells. Therefore, targeting mitochondrial ClpXP could be a novel therapeutic strategy for the treatment of malignancy. Here, we review the structure and function of mitochondrial ClpXP as well as strategies to target this enzyme complex as a novel therapeutic approach for malignancy.

Fig. 1. Schematic representation of ATP-dependent proteases.

Mammalian mitochondria contains four proteases of the AAA+ superfamily to modulate protein quality control. The Lon protease 1, and ClpXP complex in the matrix and the i-AAA, m-AAA proteases in IM. OMM outer mitochondrial membrane, IMS intermembrane space, IMM inner mitochondrial membrane.

Fig. 2. Structure and interaction of ClpP and ClpX.

a Domain organization of ClpX (top) and ClpP (bottom) with catalytic residues of Ser153, His178, and Asp227. MTS mitochondrial targeting sequence, ZBD zinc-binding domain; AAA+, ATPases associated with diverse cellular activities. b Schematic representation of the ClpX and ClpP interaction and proteolytic cycle. c Top view of hexameric ClpX (top) and heptameric ClpP (bottom).