Mitochondrial TRAP1 regulates the unfolded protein response in the endoplasmic reticulum

Neurochem Int. 2011 Jul;58(8):880-7. doi: 10.1016/j.neuint.2011.02.015. Epub 2011 Feb 19.

Abstract

Stress in mitochondria or the endoplasmic reticulum (ER) independently causes cell death. Recently, it was reported that ER stress causes mitochondrial dysfunction via p53-upregulated modulator of apoptosis (PUMA). However, little is known regarding the mitochondria molecules that mediate ER dysfunction. The present study revealed that tumor necrosis factor receptor-associated protein 1 (TRAP1), which localizes in the mitochondria, is associated with the unfolded protein response (UPR) in the ER. TRAP1 knockdown activated the ER-resident caspase-4, which is activated by ER stress, to induce cell death in humans. However, TRAP1 knockdown cells did not show a significant increase in the level of cell death at least within 24 h after early phase of ER stress in comparison with that of the control cells. This finding could be attributed to a number of reasons. TRAP1 knockdown failed to activate caspase-9, which is activated by activated caspase-4. In addition, TRAP1 knockdown increased the basal level of GRP78/BiP expression, which protects cells, and decreased the basal level of C/EBP homologous protein (CHOP) expression, which induces cell death, even under ER stress. Thus, the present study revealed that mitochondria could be a potential regulator of the UPR in the ER through mitochondrial TRAP1.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Death / physiology
  • Cell Line, Tumor
  • Cell Survival / physiology
  • Endoplasmic Reticulum / metabolism
  • Endoplasmic Reticulum / physiology*
  • HSP90 Heat-Shock Proteins / physiology*
  • Humans
  • Mitochondrial Proteins / physiology*
  • Unfolded Protein Response / physiology*

Substances

  • HSP90 Heat-Shock Proteins
  • Mitochondrial Proteins
  • TRAP1 protein, human