HSPA9

HSPA9, also known as mortalin or mitochondrial HSP70 (mtHSP70), is a member of the Hsp70 family of molecular chaperones encoded by the HSPA9 gene in humans. Like other Hsp70 proteins, it has an N-terminal ATPase domain and a C-terminal substrate-binding domain, and it operates as part of an ATP-dependent chaperone cycle to assist protein folding and stabilization.

Localization and function are centric to mitochondria. Mortalin is primarily found in the mitochondrial matrix where it supports import and folding of nuclear-encoded mitochondrial proteins, cooperating with the translocase machinery to ensure proper mitochondrial biogenesis and maintenance. It also contributes to mitochondrial quality control, aiding refolding of misfolded proteins under stress and helping preserve mitochondrial DNA integrity and function. Under certain conditions, mortalin can be detected in the cytosol or nucleus, reflecting a broader role in cellular stress responses.

Mortalin interacts with other cellular pathways, including a notable association with the tumor suppressor p53. By binding p53, mortalin can sequester it in the cytoplasm, reducing p53-dependent transcription and apoptosis. This anti-apoptotic activity has drawn attention to mortalin in cancer, where HSPA9 is often upregulated and may support tumor cell survival and resistance to stress. Conversely, loss or inhibition of mortalin can promote p53 reactivation and apoptotic signaling.

Clinical relevance and research directions emphasize HSPA9 as a potential biomarker and therapeutic target. Approaches under investigation include modulating mortalin expression or function to restore mitochondrial quality control, promote cancer cell death, or mitigate mitochondrial dysfunction in aging and neurodegenerative contexts.