Heat shock 70 kDa protein 9 (HSPA9) (HSPA9)

Heat shock 70 kDa protein 9 (HSPA9), commonly known as Mortalin or GRP75, is a mitochondrial resident chaperone belonging to the Hsp70 family that is essential for mitochondrial biogenesis and cellular homeostasis [1]. It primarily functions within the mitochondrial matrix to facilitate the import and folding of nuclear-encoded proteins and plays a critical role in iron-sulfur cluster assembly [1]. In oncology, Mortalin is frequently overexpressed and functions as an oncoprotein by sequestering the tumor suppressor p53 in the cytoplasm, thereby inhibiting p53-mediated apoptosis and promoting tumor cell survival [2]. Conversely, loss-of-function mutations in HSPA9 are linked to the development of Parkinson's disease and congenital sideroblastic anemia, reflecting its importance in neuronal protection and erythropoiesis [3]. Therapeutic strategies targeting Mortalin involve small-molecule inhibitors, such as MKT-077 or Mortaparib, which aim to disrupt the Mortalin-p53 interaction or inhibit its ATPase activity to trigger apoptosis in malignant cells [4]. However, drug development faces challenges regarding systemic mitochondrial toxicity and the need for high selectivity to avoid disrupting essential physiological functions [4]. [1] UniProt Consortium, P38646; [2] Wadhwa et al. (2006) Exp Gerontol; [3] Londono et al. (2012) Adv Cancer Res; [4] Lu et al. (2020) Cancers.

Other names

MortalinGRP75PBP74Stress-70 protein, mitochondrialMitochondrial 70 kDa heat shock proteinMOTMOT2HSPA9B

Inhibition of ATPase activity and disruption of the Mortalin-p53 complex to restore p53 transcriptional activity and induce apoptosis.