Glucose-regulated protein 75 (also known as Mortalin) (GRP75)

Glucose-regulated protein 75 (GRP75), also known as Mortalin or heat shock 70 kDa protein 9 (HSPA9), is a mitochondrial matrix chaperone belonging to the Hsp70 family[1][4][16]. GRP75 plays a pivotal role in mitochondrial protein import, folding, and quality control, as well as serving as a molecular bridge facilitating Ca2+ transfer between the endoplasmic reticulum (ER) and mitochondria by linking the IP3R (ER) and VDAC1 (mitochondrial membrane)[2][7][9][13]. It is highly induced by cellular stresses such as glucose deprivation, hypoxia, and oxidative insults. GRP75 extensively regulates mitochondrial function, influences cell proliferation, senescence, metabolic reprogramming, and stress resistance, and is implicated in cancer development, progression, and therapeutic resistance[3][4][6][14]. Altered GRP75 function or expression is also associated with neurodegenerative and cardiovascular diseases via mitochondrial dysfunction[2][9][14]. Clinically, GRP75 has emerged as an anticancer therapeutic target and a potential biomarker for drug resistance, but therapeutic modulation must account for its essential physiological roles to minimize adverse effects[9].

Other names

GRP75MortalinHSPA9Heat shock 70 kDa protein 9PBP74mtHsp70CSAp66mot-1

Chaperone inhibition: Disrupts ER–mitochondria crosstalk and calcium transfer by inhibiting GRP75, protecting against oxidative stress[2][7][9]; Anti-proliferative and pro-apoptotic effect via abrogation of GRP75-mediated cytoprotection (MKT-077, JX57)[2][12]; Sensitization to chemotherapeutics by inhibiting stress and survival functions (reducing cisplatin resistance)[3][6]