From the Cover: Ethylmercury-Induced Oxidative and Endoplasmic Reticulum Stress-Mediated Autophagic Cell Death: Involvement of Autophagosome-Lysosome Fusion Arrest

Toxicol Sci. 2016 Nov;154(1):27-42. doi: 10.1093/toxsci/kfw155. Epub 2016 Aug 10.


Ethylmercury (EtHg) is derived from the degradation of thimerosal, the most widely used organomercury compound. In this study, EtHg-induced toxicity and autophagy in the mouse kidney was observed and then the mechanism of toxicity was explored in vitro in HK-2 cells. Low doses of EtHg induced autophagy without causing any histopathological changes in mouse kidneys. However, mice treated with high doses of EtHg exhibited severe focal tubular cell necrosis of the proximal tubules with autophagy. EtHg dose-dependently increased the production of reactive oxygen species, reduced the mitochondrial membrane potential, activated the unfolded protein response, and increased cytosolic Ca2+ levels in HK-2 cells. Cell death induced by EtHg exposure was caused by autophagy and necrosis. N-acetyl cysteine and 4-phenylbutyric acid attenuated EtHg-induced stress and ameliorated the autophagic response in HK-2 cells. Furthermore, EtHg blocked autophagosome fusion with lysosomes, which was demonstrated via treatment with wortmannin and chloroquine. Low doses of EtHg and rapamycin, which resulted in minimal cytotoxicity, increased the levels of the autophagic SNARE complex STX17 (syntaxin 17)-VAMP8-SNAP29 without altering mRNA levels, but high dose of EtHg was cytotoxic. Inhibition of autophagic flux by chloroquin increased autophagosome formation and necrotic cell death in HK-2 cells. Collectively, our results show that EtHg induces autophagy via oxidative and ER stress and blockade of autophagic flux. Autophagy might play a dual role in EtHg-induced renal toxicity, being both protective following treatment with low doses of EtHg and detrimental following treatment with high doses.

Keywords: ER stress; autophagy; blocking autophagic flux; ethylmercury; mitochondrial dysfunction.

MeSH terms

  • Animals
  • Autophagosomes / drug effects*
  • Autophagy*
  • Calcium / metabolism
  • Cell Line
  • Dose-Response Relationship, Drug
  • Endoplasmic Reticulum Stress / drug effects*
  • Ethylmercury Compounds / toxicity*
  • Humans
  • Kidney / drug effects
  • Kidney Tubules, Proximal / drug effects
  • Lysosomes / drug effects*
  • Membrane Potential, Mitochondrial
  • Mice
  • Mice, Inbred C57BL
  • Oxidative Stress / drug effects*
  • Rats
  • Reactive Oxygen Species / metabolism
  • Unfolded Protein Response


  • Ethylmercury Compounds
  • Reactive Oxygen Species
  • Calcium