Coordinated regulation of the metaboproteome by Hsp90 chaperones controls metabolic plasticity.

Heat shock protein 90 (Hsp90) chaperones participate in the stabilization and activation of hundreds of proteins, thereby acting as signaling hubs. A mitochondrial subpopulation of Hsp90 has been previously described; however, little is known about its role in metabolism. Here, we showed that loss of individual Hsp90 isoforms differentially affects oxygen consumption and metabolic flexibility. Proteomic and metabolomic evaluation demonstrated that Hsp90 regulates the mitochondrial metabolic network, including respiration, fatty acid oxidation, and redox homeostasis. Loss of the mitochondrial chaperone tumor necrosis factor receptor-associated protein 1 (TRAP1) induced compensatory binding of Hsp90s to TRAP1-dependent proteins, indicating a mechanism for the role of Hsp90 chaperones in metabolic reprogramming. When considered with previous findings, a temporal pattern of regulation emerges whereby Hsp90s control the transcription, translation, import, and assembly of mitochondrial protein complexes. Our findings expand the scope of Hsp90-regulated processes and potentially inform the effects of isoform-specific Hsp90 inhibitors on metabolic reprogramming in cancer and other diseases.