Mitochondrial chaperone TRAP1 as a therapeutic target in Parkinson disease

Parkinson disease (PD) is a major neurodegenerative disease that involves mitochondrial dysfunction. The lack of disease-modifying medications to stop neurodegeneration in PD highlights the need to identify new molecular targets for therapeutic intervention. TNF receptor-associated protein 1 (TRAP1) is a mitochondrial chaperone of the Hsp90 family that was identified in our proteomic screen as a substrate for PD-linked kinase PINK1. By using subcellular fractionation and dual-color 3D-SIM super-resolution imaging analyses, we have shown that TRAP1 primarily resides in the cristae membrane and intracristae space of mitochondria; and our results support a critical role of TRAP1 in these submitochondrial compartments to regulate protein folding and maintain mitochondrial homeostasis. Furthermore, our studies reveal that TRAP1 colocalizes with PINK1 in mitochondrial cristae membrane and intracristae space and functions downstream of PINK1 in cytoprotection against mitochondrial dysfunction and oxidative stress-induced apoptosis. Our findings are further supported by recent Drosophila genetic studies showing that overexpression of TRAP1 is able to ameliorate mitochondrial and motor behavioral defects in PINK1-deficient flies and to restore mitochondrial function in flies with impaired mitochondrial complex I. Together, these results indicate that TRAP1 is a viable target for development of new therapeutics to treat PD and other mitochondrial diseases.