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Manganese activates autophagy to alleviate endoplasmic reticulum stress-induced apoptosis via PERK pathway

Chang Liu1, Dong-Ying Yan1, Can Wang1

  • 1Department of Environmental Health, School of Public Health, China Medical University, Shenyang, China.

Journal of Cellular and Molecular Medicine
|October 23, 2019
PubMed

Insights

Manganese (Mn) neurotoxicity involves endoplasmic reticulum (ER) stress and autophagy. This study reveals Mn activates protective autophagy via the PERK/eIF2α/ATF4 pathway to reduce ER stress-induced cell death.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Toxicology

Background:

  • Manganese (Mn) overexposure causes neurotoxicity.
  • Endoplasmic reticulum (ER) stress and autophagy are implicated in early Mn neurotoxicity.
  • The precise mechanisms linking ER stress signaling to autophagy initiation in Mn toxicity are unclear.

Purpose of the Study:

  • To investigate the role of ER stress and autophagy in Mn-induced neurotoxicity.
  • To elucidate the molecular mechanisms by which ER stress regulates autophagy.
  • To determine if autophagy acts protectively against Mn-induced apoptosis.

Main Methods:

  • Utilized SH-SY5Y cells exposed to manganese.
  • Administered 4-phenylbutyrate (4-PBA) to inhibit ER stress and 3-methyladenine (3-MA) to block autophagy.
  • Performed gene knockdown of protein kinase RNA-like ER kinase (PERK).
  • Assessed cell apoptosis, ER stress markers, and autophagy-related proteins (LC3).

Main Results:

  • ER stress was accompanied by autophagy in Mn-treated SH-SY5Y cells.
  • Inhibiting ER stress (4-PBA) reduced apoptosis and ER stress markers.
  • Blocking autophagy (3-MA) exacerbated Mn-induced cell apoptosis, indicating a protective role.
  • PERK knockdown inhibited Mn-induced autophagy and the ATF4-LC3 promoter interaction.
  • Mn exposure activates protective autophagy via the PERK/eIF2α/ATF4 pathway.

Conclusions:

  • Autophagy is activated as a protective mechanism against manganese-induced neurotoxicity.
  • The PERK/eIF2α/ATF4 signaling pathway mediates ER stress-induced autophagy.
  • This pathway plays a crucial role in alleviating manganese-induced cell apoptosis in neuronal cells.
Keywords:
PERK signalling pathwayautophagyendoplasmic reticulum stressmanganeseneurotoxicity

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