Heat shock protein family A member 9 (HSPA9) (HSPA9)

Heat shock protein family A member 9 (HSPA9), commonly known as mortalin, is a highly conserved mitochondrial chaperone belonging to the Hsp70 family [UniProt: P38646]. It is primarily localized in the mitochondrial matrix, where it facilitates the import of nuclear-encoded proteins and assists in their folding and assembly [PubMed: 12145283]. Beyond its mitochondrial roles, mortalin is found in various cellular compartments and is involved in regulating the cell cycle, centrosome duplication, and the stress response [PubMed: 16491200]. In many human cancers, mortalin is significantly overexpressed and contributes to malignancy by binding to and sequestering the tumor suppressor p53 in the cytoplasm, thereby preventing p53-mediated apoptosis [PubMed: 17440498]. Conversely, loss-of-function mutations in HSPA9 are associated with Parkinson's disease and sideroblastic anemia, highlighting its importance in maintaining cellular homeostasis [PubMed: 20639195]. The nucleotide-binding domain (NBD) of mortalin is a critical target for drug development, as binding of small molecules like MKT-077 or Mortaparib to this domain inhibits its ATPase activity and disrupts its interaction with p53, leading to tumor cell death [PubMed: 32824014].

Other names

MortalinGRP75PBP74mthsp70Mitochondrial 70 kDa heat shock proteinHSPA9B

Drugs targeting the mortalin nucleotide-binding domain (NBD) typically act by inhibiting its ATPase activity. This inhibition prevents the conformational changes necessary for mortalin to perform its chaperone functions and maintain its interaction with client proteins like p53. By disrupting the mortalin-p53 complex, these drugs allow p53 to translocate to the nucleus and activate apoptotic pathways in cancer cells [PubMed: 32824014, 10871861].