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Mitoquinone Inactivates Mitochondrial Chaperone TRAP1 by Blocking the Client Binding Site

Nam Gu Yoon1, Hakbong Lee1, So-Yeon Kim1

  • 1Department of Biological Sciences, Ulsan National Institutes of Science and Technology (UNIST), Ulsan 44919, South Korea.

Journal of the American Chemical Society
|November 11, 2021
PubMed

Insights

Mitoquinone (MitoQ) inhibits mitochondrial Hsp90 (TRAP1) by binding to its client site, offering a new strategy for potent anticancer drug development. This approach shows promise for effective cancer therapies.

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.

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