Two mTOR inhibitors, rapamycin and Torin 1, differentially regulate iron-induced generation of mitochondrial ROS

Biometals. 2017 Dec;30(6):975-980. doi: 10.1007/s10534-017-0059-1. Epub 2017 Oct 23.

Abstract

It is generally believed that gene-environment interaction may contribute to neurodegeneration. Of particular note is that iron overload may be one of the risk factors for neurodegeneration. However, the mechanisms underlying iron-associated neurotoxicity are not fully understood. Here we explored the effects of mechanistic target of rapamycin (mTOR) inhibition in iron-stressed human neuroblastoma cells. Two mTOR inhibitors, rapamycin and Torin 1, had similar effects in cells exposed to a relatively low concentration of iron. At a higher concentration of iron, Torin 1, instead of rapamycin, could further aggravate iron-induced cytotoxicity, and mitochondrial ROS levels were significantly higher in Torin 1-treated cells. These results suggest that mTOR inhibition may not be able to alleviate iron-induced neurotoxicity.

Keywords: ROS; Rapamycin; Torin 1; mTOR.

MeSH terms

  • Cell Line, Tumor
  • Humans
  • Iron / toxicity*
  • Mitochondria / drug effects*
  • Mitochondria / metabolism
  • Naphthyridines / pharmacology*
  • Neuroblastoma / drug therapy
  • Neuroblastoma / metabolism
  • Neuroblastoma / pathology
  • Neuroprotective Agents / pharmacology
  • Reactive Oxygen Species / metabolism
  • Sirolimus / pharmacology*
  • TOR Serine-Threonine Kinases / antagonists & inhibitors*

Substances

  • 1-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-9-(quinolin-3-yl)benzo(h)(1,6)naphthyridin-2(1H)-one
  • Naphthyridines
  • Neuroprotective Agents
  • Reactive Oxygen Species
  • Iron
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • Sirolimus