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Manganese activates caspase-9-dependent apoptosis in human bronchial epithelial cells

L Zhang1, H Sang, Y Liu

  • 11Department of Prevention, Tongji University School of Medicine, Shanghai, China.

Human & Experimental Toxicology
|December 25, 2012
PubMed

Insights

Manganese (Mn) exposure triggers programmed cell death in lung cells via a caspase-9 pathway. This manganese-induced lung toxicity involves mitochondrial dysfunction and altered protein levels, leading to cell apoptosis.

Area of Science:

  • Toxicology
  • Cell Biology
  • Environmental Health

Background:

  • Acute manganese (Mn) inhalation causes lung injury, including pulmonary edema.
  • While Mn's immune-mediated lung effects are known, its specific apoptotic mechanisms remain unclear.
  • Understanding Mn-induced apoptosis is crucial for assessing its respiratory toxicity.

Purpose of the Study:

  • To elucidate the apoptotic pathways involved in manganese-mediated lung toxicity.
  • To investigate the role of specific cellular mechanisms, including mitochondrial function and protein regulation, in Mn-induced cell death.

Main Methods:

  • Utilized human bronchial epithelial (16HBE) cells for in vitro experiments.
  • Assessed manganese-induced apoptosis, focusing on caspase-9 activation and the intrinsic cell death pathway.
  • Monitored mitochondrial membrane potential (ΔΨm), reactive oxygen species (ROS) generation, and cytochrome c release.
  • Analyzed the expression levels of c-Myc, p53, and phosphorylated p53 (Ser 15), and WAF1/p21.
  • Investigated the effect of proteasome inhibitor MG132 on c-Myc protein levels.

Main Results:

  • Manganese exposure induced caspase-9-mediated apoptosis in 16HBE cells.
  • Observed loss of mitochondrial membrane potential, increased ROS production, and cytochrome c release.
  • Demonstrated downregulation of c-Myc and upregulation of p53 and phosphorylated p53 (Ser 15) and WAF1/p21.
  • MG132 treatment increased c-Myc protein abundance, suggesting proteasomal degradation.

Conclusions:

  • Manganese-induced apoptosis in lung epithelial cells is mediated by the caspase-9-dependent intrinsic pathway.
  • Downregulation of c-Myc, potentially via ubiquitin-proteasome degradation, and upregulation of p53 contribute to Mn toxicity.
  • These findings clarify the molecular mechanisms underlying manganese-induced lung epithelial cell death.
Keywords:
Manganeseapoptosiscaspase-9mitochondria

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