mortalin

Mortalin, also known as mitochondrial heat shock protein 70 (mtHsp70), Grp75, or HSPA9, is a member of the Hsp70 family of molecular chaperones located predominantly in mitochondria. In humans, the HSPA9 gene encodes mortalin. The protein contains an N-terminal mitochondrial targeting sequence that is cleaved after import, yielding a mature mitochondrial matrix chaperone essential for mitochondrial proteostasis.

Mortalin functions as a central component of the mitochondrial protein import apparatus. It binds unfolded precursor polypeptides translocated into the mitochondrial matrix and, with co-chaperones such as mitochondrial J-proteins, uses ATP hydrolysis to drive translocation, folding, and assembly of mitochondrial proteins. Through its activity, mortalin supports mitochondrial biogenesis, the maintenance of respiratory chain complexes, and overall mitochondrial function, contributing to cellular energy production and stress tolerance.

In addition to its housekeeping role, mortalin participates in cellular signaling linked to aging and cancer. It interacts with the tumor suppressor protein p53, sequestering it in the cytoplasm and diminishing p53-dependent transcription. This interaction can promote cell survival and may contribute to tumor progression in some contexts. Disrupting the mortalin–p53 complex can reactivate p53 signaling and induce senescence or apoptosis, which has spurred interest in mortalin as a potential anticancer target.

Expression and regulation of mortalin are responsive to developmental cues and cellular stress, and alterations in its levels have been observed in aging and disease models. Therapeutic strategies aim to modulate mortalin function, including the development of inhibitors to restore p53 activity in cancer, though clinical progress is tempered by challenges such as specificity and toxicity.

Mortalin is a mitochondrial Hsp70 chaperone essential for protein import and mitochondrial proteostasis, with additional relevance to aging, stress responses, and cancer biology.