Disulfide-mediated tetramerization of TRAP1 fosters its antioxidant and pro-neoplastic activities.

The mitochondrial chaperone TRAP1 exerts protective functions under diverse stress conditions. It induces metabolic rewiring and safeguards cancer cells from oxidative insults, thereby contributing to neoplastic progression. TRAP1 works as a homodimer, but recent evidence indicated that it forms tetramers whose effects remain elusive. Here, we find that TRAP1 generates redox-sensitive tetramers via disulfide bonds involving cysteines 261 and 573. TRAP1 tetramerization is elicited by oxidative stress and abrogated upon expression of the double C261S/C573R mutant. In cancer cells, the TRAP1 C261S/C573R mutant is unable to inhibit the activity of its client succinate dehydrogenase and to confer protection against oxidative insults, thus hampering the invasiveness of aggressive sarcoma cells. Overall, our findings indicate that TRAP1 undergoes tetramerization in response to oxidative stress and identify C261 and C573 as critical for TRAP1 structural rearrangement and functions.