TRAP-1, the mitochondrial Hsp90

Abstract

Protein folding quality control does not occur randomly in cells, but requires the action of specialized molecular chaperones compartmentalized in subcellular microenvironments and organelles. Fresh experimental evidence has now linked a mitochondrial-specific Heat Shock Protein-90 (Hsp90) homolog, Tumor Necrosis Factor Receptor-Associated Protein-1 (TRAP-1) to pleiotropic signaling circuitries of organelle integrity and cellular homeostasis. TRAP-1-directed compartmentalized protein folding is broadly exploited in cancer and neurodegenerative diseases, presenting new opportunities for therapeutic intervention in humans. This article is part of a Special Issue entitled: Heat Shock Protein 90 (Hsp90).

Figure 1. TRAP-1 cytoprotection

The differential expression of TRAP-1 in cancer, as opposed to normal tissues has been implicated in inhibition of mitochondrial apoptosis, suppression of ROS production, and acquisition of resistance to standard chemotherapeutics. Effective cytoprotection under these conditions may require TRAP-1 phosphorylation by the mitochondrial-localized kinase, PINK1, which associates with TRAP-1, in vivo. The Ca²⁺ binding protein, Sorcin is also a TRAP-1-associated molecule, which opposes TRAP-1 degradation within the organelle.

Figure 2. Regulation of mitochondrial permeability pore opening by an organelle-specific chaperone network

Molecular chaperones Hsp90, Hsp60 and TRAP-1 physically associate with CypD, and mediate ATPase dependent closing of the permeability transition pore (PTP). Two potential models of PTP regulation are presented: an organized PTP comprising CypD, VDAC and ANT (left), and a dynamic PTP (right), characterized by the pore-forming properties of clusters of misfolded and aggregated proteins generated at the outer mitochondrial membrane under conditions of stress. VDAC, voltage-dependent anion channel; ANT, adenine nucleotide translocator; CypD, cyclophilin D; C, cytochrome c.

Figure 3. TRAP-1 control of cell survival and stress response

Inhibition of TRAP-1 and mitochondrial Hsp90 ATPase activity by subcellularly targeted small molecule, Gamitrinibs, results in activation of apoptosis, induction of UPR with transcriptional upregulation of a stress response gene signature, and compensatory autophagy.