mtHsp70s

mtHsp70s, or mitochondrial Hsp70 proteins, are a subfamily of the Hsp70 chaperone family localized to the mitochondrial matrix. They are encoded in the nucleus and transported into mitochondria via an N-terminal targeting sequence. In yeast, the principal mtHsp70 is Ssc1; in humans, the corresponding protein is HSPA9, commonly called mortalin.

Core function is ATP-dependent binding and release of unfolded or imported polypeptides. In mitochondria, mtHsp70s form the central component of the presequence translocase-associated motor that drives the import of matrix-destined proteins through the TIM23 complex. A J-domain-containing cochaperone stimulates ATP hydrolysis to enable tight substrate binding, while a nucleotide exchange factor promotes ADP release and re-energizes the cycle. Through repeated binding and release, mtHsp70s power the directional movement and proper folding of polypeptides in the matrix.

Beyond import, mtHsp70s assist in the folding and assembly of many mitochondrial proteins, prevent aggregation under stress, and contribute to mitochondrial proteostasis. They interact with other chaperone systems and with the mitochondrial ribosome, supporting biogenesis and quality control of matrix proteins and, in some contexts, mitochondrial DNA maintenance.

Evolutionarily, mtHsp70s trace to bacterial DnaK through endosymbiosis and are maintained as essential components in eukaryotes. They exist as isoforms with specialized roles across species. In humans, dysregulation of mortalin (HSPA9) has been linked to aging and cancer, and loss of function is typically incompatible with cell viability, reflecting their essential role in mitochondrial function.