O-GlcNAcylation suppresses TRAP1 activity and promotes mitochondrial respiration

Cell Stress Chaperones. 2022 Sep;27(5):573-585. doi: 10.1007/s12192-022-01293-x. Epub 2022 Aug 17.


The molecular chaperone TNF-receptor-associated protein-1 (TRAP1) controls mitochondrial respiration through regulation of Krebs cycle and electron transport chain activity. Post-translational modification (PTM) of TRAP1 regulates its activity, thereby controlling global metabolic flux. O-GlcNAcylation is one PTM that is known to impact mitochondrial metabolism, however the major effectors of this regulatory PTM remain inadequately resolved. Here we demonstrate that TRAP1-O-GlcNAcylation decreases TRAP1 ATPase activity, leading to increased mitochondrial metabolism. O-GlcNAcylation of TRAP1 occurs following mitochondrial import and provides critical regulatory feedback, as the impact of O-GlcNAcylation on mitochondrial metabolism shows TRAP1-dependence. Mechanistically, loss of TRAP1-O-GlcNAcylation decreased TRAP1 binding to ATP, and interaction with its client protein succinate dehydrogenase (SDHB). Taken together, TRAP1-O-GlcNAcylation serves to regulate mitochondrial metabolism by the reversible attenuation of TRAP1 chaperone activity.

Keywords: GlcNAcylation; Metabolism; Molecular chaperone; Post-translational modification; TRAP1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphatases / metabolism
  • Adenosine Triphosphate / metabolism
  • HSP90 Heat-Shock Proteins / metabolism
  • Humans
  • Molecular Chaperones* / metabolism
  • Protein Processing, Post-Translational
  • Respiration
  • Succinate Dehydrogenase* / metabolism
  • TNF Receptor-Associated Factor 1 / chemistry
  • TNF Receptor-Associated Factor 1 / metabolism


  • HSP90 Heat-Shock Proteins
  • Molecular Chaperones
  • TNF Receptor-Associated Factor 1
  • TRAP1 protein, human
  • Adenosine Triphosphate
  • Succinate Dehydrogenase
  • Adenosine Triphosphatases