Mitoquinone Inactivates Mitochondrial Chaperone TRAP1 by Blocking the Client Binding Site

Heat shock protein 90 (Hsp90) family
proteins are molecular chaperones
that modulate the functions of various substrate proteins (clients)
implicated in pro-tumorigenic pathways. In this study, the mitochondria-targeted
antioxidant mitoquinone (MitoQ) was identified as a potent inhibitor
of mitochondrial Hsp90, known as a tumor necrosis factor receptor-associated
protein 1 (TRAP1). Structural analyses revealed an asymmetric bipartite
interaction between MitoQ and the previously unrecognized drug binding
sites located in the middle domain of TRAP1, believed to be a client
binding region. MitoQ effectively competed with TRAP1 clients, and
MitoQ treatment facilitated the identification of 103 TRAP1-interacting
mitochondrial proteins in cancer cells. MitoQ and its redox-crippled
SB-U014/SB-U015 exhibited more potent anticancer activity in vitro and in vivo than previously reported
mitochondria-targeted TRAP1 inhibitors. The findings indicate that
targeting the client binding site of Hsp90 family proteins offers
a novel strategy for the development of potent anticancer drugs.