Atg5-dependent autophagy plays a protective role against methylmercury-induced cytotoxicity

Toxicol Lett. 2016 Nov 16;262:135-141. doi: 10.1016/j.toxlet.2016.09.007. Epub 2016 Sep 22.

Abstract

Methylmercury (MeHg) is a widespread environmental pollutant and causes a serious hazard to health worldwide. However, molecular mechanisms underlying MeHg toxicity remain elusive. We show that MeHg reduced mouse embryonic fibroblast (MEF) viability in a dose-dependent manner. Furthermore, MeHg treatment increased levels of autophagy markers LC3-II and p62, possibly by acting on the MAPKs signaling pathway in several cell types. MeHg exposure elevated the number of LC3 puncta in stable GFP-LC3 MEFs and the number of autophagic vacuoles. The accumulation of LC3-II and p62 increased further when complementing MeHg with autophagy inhibitor, chloroquine. Moreover, we found that autophagy-related gene 5-deficient (Atg5-/-) MEFs exhibited higher sensitivity and higher levels of p62 compared to their wild-type counterparts following MeHg exposure. This suggested that p62 was upregulated at the transcription level by MeHg and degraded by Atg5-dependent autophagy. Our data demonstrate that MeHg exposure promotes autophagy, and Atg5-dependent autophagy serves to protect cells from MeHg cytotoxicity.

Keywords: Atg5; Autophagy; LC3; Methylmercury; p62.

MeSH terms

  • Animals
  • Autophagy / genetics*
  • Autophagy-Related Protein 5 / genetics
  • Autophagy-Related Protein 5 / metabolism*
  • Cell Survival / drug effects
  • Chloroquine / pharmacology
  • Dose-Response Relationship, Drug
  • Gene Knockout Techniques
  • Methylmercury Compounds / toxicity*
  • Mice
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism
  • Mitogen-Activated Protein Kinases / metabolism
  • Phagosomes / drug effects
  • Phagosomes / metabolism
  • Sequestosome-1 Protein / metabolism
  • Signal Transduction / drug effects

Substances

  • Atg5 protein, mouse
  • Autophagy-Related Protein 5
  • MAP1LC3 protein, mouse
  • Methylmercury Compounds
  • Microtubule-Associated Proteins
  • Sequestosome-1 Protein
  • Chloroquine
  • Mitogen-Activated Protein Kinases