Chaperonopathies: Diseases in which mortalin and other hsp-chaperones play a role in etiology and pathogenesis

Abstract

Human mortalin is presented against the background of the Hsp70 family to show its distinctive properties and disease-causing potential. Seventeen genes of the Hsp70 family have recently been characterized applying the chaperonomics protocol to the human genome. One of these genes is HSPA9B, which encodes mortalin, identified in the early 1990s. Mortalin also called mtHsp70, PBP74, GRP75, and HSPA9B, resides inside the mitochondria but can also occur elsewhere. Mortalin is unique within the family because it is more closely related to bacterial than to eukaryotic orthologs, indicating distinctive evolution and functions. Its canonical role pertains to protein folding inside mitochondria in association with Hsp60 (∈Cpn60) and other molecules. However, it is involved also in other processes distinct from protein folding inside and outside mitochondria. It can be predicted that mortalin structure-function defects, inherited or acquired, will have a serious impact on key cellular events, particularly when mitochondria play a role, and in aging. Chaperonopathies due to mortalin malfunction will surely be identified, soon. Existing data indicate that mortalin can be pathogenic, particularly in some types of cancer: mortalin is normal but helps cancer cells to grow, exemplifying the chaperonopathies by mistake, in which a normal chaperone contributes to disease rather than to protection, as expected from a chaperone. Future research offers a multifaceted perspective for mortalin as etiologic factor (chaperonopathies due to chaperone malfunction or mistaken allegiance), disease biomarker, therapeutic target for anti-chaperone compounds (when mortalin is pathogenic), and therapeutic agent in replacement chaperonotherapy (when mortalin is absent or defective).