The spectrum of human Hsp60 genetic variants and associated chaperonopathies

Abstract

Hsp60 is one of the chief members of the chaperone system (CS) present in all organisms excepting the Archaea, with key roles in maintaining life and in resistance to the damaging effects of stressors of all types. Initially, it was believed that Hsp60 occurred only inside cells, in the mitochondria of animals and the chloroplast of plants. Now we know that Hsp60 occurs also outside the mitochondria (e.g., in the cytosol and plasma-cell membrane) and extracellularly, e.g., on the outside of the cell membrane, intercellular space, and circulating liquids (e.g., lymph, blood, and cerebrospinal fluid). Like other members of the CS, Hsp60 has canonical and noncanonical functions, the former pertinent to maintenance of protein homeostasis inside the organelles of eukaryotic cells, whereas the latter include a variety of roles, mostly relevant to inflammation, autoimmunity, viral infections, and cancer. While Hsp60 is typically cytoprotective, if abnormal, it can be pathogenic and cause diseases, the Hsp60 chaperonopathies. These, like many other diseases, can be genetic or acquired. This chapter deals with various genetic Hsp60 chaperonopathies, presenting salient clinical, pathological, genetic, and molecular biological features of the most studied examples. The major goal is to explain the subject matter for instructing physicians and other healthcare professionals about these disorders. The take-home messages are that these conditions are more prevalent, perhaps much more, than currently believed and that research should dramatically increase to elucidate the molecular mechanisms in Hsp60 chaperonopathies, so diagnosis and treatment, at present unsatisfactory, will improve substantially.