Mitoquinone Inactivates Mitochondrial Chaperone TRAP1 by Blocking the Client Binding Site.

Area of Science:

• Biochemistry
• Molecular Biology
• Oncology

Background:

• Heat shock protein 90 (Hsp90) family proteins are molecular chaperones.
• These proteins modulate substrate proteins (clients) involved in pro-tumorigenic pathways.
• Mitochondrial Hsp90, or TRAP1, plays a role in cancer progression.

Purpose of the Study:

• To identify novel inhibitors of TRAP1.
• To investigate the interaction between MitoQ and TRAP1.
• To explore the therapeutic potential of targeting TRAP1 client binding sites.

Main Methods:

• Structural analyses of MitoQ and TRAP1 interaction.
• Client competition assays.
• Identification of TRAP1-interacting proteins using MitoQ treatment.
• In vitro and in vivo anticancer activity assays.

Main Results:

• Mitoquinone (MitoQ) identified as a potent inhibitor of TRAP1.
• MitoQ binds to previously unrecognized drug binding sites in TRAP1's middle domain.
• MitoQ competes with TRAP1 clients and facilitates identification of 103 interacting mitochondrial proteins.
• MitoQ and its analogs show potent anticancer activity.

Conclusions:

• Targeting the client binding site of TRAP1 is a viable anticancer strategy.
• MitoQ represents a promising lead compound for novel anticancer drug development.
• Inhibition of TRAP1 offers a new therapeutic avenue for cancer treatment.