Beyond Folding: The Dual Life of Hsp60 in Tissue Homeostasis and Pathophysiology

The heat shock protein 60 (Hsp60) is a highly conserved molecular chaperonin belonging to the chaperone system, a complex network that maintains proteostasis and regulates numerous cellular processes beyond protein folding. Initially described as a mitochondrial protein essential for the folding of newly imported polypeptides, Hsp60 is now recognized as a multifunctional molecule. Its expression, localization, and post-translational modifications dynamically influence cell fate and tissue homeostasis. Alterations in Hsp60 quantity, structure, or distribution underlie a heterogeneous group of disorders known as chaperonopathies, which may occur "by defect," "by excess," or "by mistake" (also called "by collaborationism"). Genetic Hsp60's chaperonopathies are associated with rare neurodegenerative and cardiovascular diseases, whereas acquired forms contribute to widespread conditions, including autoimmune, inflammatory, and malignant pathologies. This review provides a comprehensive overview of Hsp60 biology across human systems, emphasizing its structural plasticity, context-dependent functions, and dual role in health as both a biomarker and a therapeutic target. The emerging paradigm of chaperonotherapy, encompassing positive strategies to restore protective chaperones and negative strategies to inhibit pathogenic ones, highlights the translational potential of targeting Hsp60. Understanding the molecular mechanisms governing its activity will be essential for developing precision medicine approaches aimed at modulating the chaperone system in human disease.