The mitochondrial chaperone TRAP1 regulates F-ATP synthase channel formation

Cell Death Differ. 2022 Dec;29(12):2335-2346. doi: 10.1038/s41418-022-01020-0. Epub 2022 May 25.


Binding of the mitochondrial chaperone TRAP1 to client proteins shapes bioenergetic and proteostatic adaptations of cells, but the panel of TRAP1 clients is only partially defined. Here we show that TRAP1 interacts with F-ATP synthase, the protein complex that provides most cellular ATP. TRAP1 competes with the peptidyl-prolyl cis-trans isomerase cyclophilin D (CyPD) for binding to the oligomycin sensitivity-conferring protein (OSCP) subunit of F-ATP synthase, increasing its catalytic activity and counteracting the inhibitory effect of CyPD. Electrophysiological measurements indicate that TRAP1 directly inhibits a channel activity of purified F-ATP synthase endowed with the features of the permeability transition pore (PTP) and that it reverses PTP induction by CyPD, antagonizing PTP-dependent mitochondrial depolarization and cell death. Conversely, CyPD outcompetes the TRAP1 inhibitory effect on the channel. Our data identify TRAP1 as an F-ATP synthase regulator that can influence cell bioenergetics and survival and can be targeted in pathological conditions where these processes are dysregulated, such as cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • HSP90 Heat-Shock Proteins / metabolism
  • Humans
  • Mitochondria / metabolism
  • Mitochondrial Membrane Transport Proteins* / metabolism
  • Mitochondrial Permeability Transition Pore* / metabolism
  • Mitochondrial Proton-Translocating ATPases / metabolism
  • Molecular Chaperones / metabolism
  • Peptidyl-Prolyl Isomerase F / metabolism


  • Mitochondrial Permeability Transition Pore
  • Mitochondrial Membrane Transport Proteins
  • Mitochondrial Proton-Translocating ATPases
  • Peptidyl-Prolyl Isomerase F
  • Molecular Chaperones
  • Adenosine Triphosphate
  • TRAP1 protein, human
  • HSP90 Heat-Shock Proteins