Ethylmalonic encephalopathy 1 initiates overactive autophagy in depleted uranium-induced cytotoxicity in the human embryonic kidney 293 cells

J Biochem Mol Toxicol. 2021 Mar;35(3):e22669. doi: 10.1002/jbt.22669. Epub 2020 Dec 4.

Abstract

The kidney is the target of the acute toxicity of depleted uranium (DU). However, the mechanism of DU-induced cytotoxicity is not clear. The study was to demonstrate the role of autophagy in DU-induced cytotoxicity and to determine the potential mechanism. We confirmed that after a 4-h exposure to DU, the autophagic vacuoles and the autophagy marker light chain 3-II in the human embryonic kidney 293 cells (HEK293) increased, and cytotoxicity decreased by abrogation of excessive autophagy using autophagy inhibitor. We also found activation of nucleus p53 and inhibiting mTOR pathways in DU-treated HEK293 cells. Meanwhile, ethylmalonic encephalopathy 1 (ETHE1) decreased as the exposure dose of DU increased, with increasing autophagy flux. We suggested that by reducing ETHE1, activation of the p53 pathway, and inhibiting mTOR pathways, DU might induce overactive autophagy, which affected the cytotoxicity. This study will provide a novel therapeutic target for the treatment of DU-induced cytotoxicity.

Keywords: ETHE1; autophagy; cytotoxicity; depleted uranium; p53.

MeSH terms

  • Autophagy / drug effects*
  • Cytotoxins / toxicity*
  • HEK293 Cells
  • Humans
  • Mitochondrial Proteins / metabolism*
  • Nucleocytoplasmic Transport Proteins / metabolism*
  • Uranium / toxicity*

Substances

  • Cytotoxins
  • ETHE1 protein, human
  • Mitochondrial Proteins
  • Nucleocytoplasmic Transport Proteins
  • Uranium