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Asbestos induces mitochondrial DNA damage and dysfunction linked to the development of apoptosis

Arti Shukla1, Michael Jung, Maria Stern

  • 1Department of Pathology, University of Vermont College of Medicine, Burlington, Vermont 05405, USA.

American Journal of Physiology. Lung Cellular and Molecular Physiology
|August 12, 2003
PubMed

Insights

Asbestos exposure causes mitochondrial DNA damage and cell death through oxidative stress. Protecting mitochondria with DNA repair enzymes can increase cell survival, indicating mitochondria are key targets.

Area of Science:

  • Cell Biology
  • Toxicology
  • Molecular Biology

Background:

  • Asbestos is a known human carcinogen.
  • The precise mechanisms of asbestos-induced cellular injury are not fully understood.
  • Mitochondria play critical roles in cellular energy production and apoptosis.

Purpose of the Study:

  • To investigate the role of mitochondria in asbestos-mediated cell injury.
  • To determine if asbestos-induced DNA damage is oxidant-dependent.
  • To explore the contribution of mitochondrial pathways to asbestos-induced apoptosis.

Main Methods:

  • Quantitative PCR to assess mitochondrial and nuclear DNA damage.
  • Confocal scanning laser microscopy to detect oxidant stress.
  • Measurement of mRNA levels for mitochondrial genes.
  • Assay of formazan production to evaluate mitochondrial function.
  • Analysis of apoptotic gene expression and cell counts.
  • Inhibition studies using caspase-9 inhibitor and catalase.
  • Mitochondrial targeting of DNA repair enzyme (8-oxoguanine DNA glycosylase) in HeLa cells.

Main Results:

  • Mitochondrial DNA damage occurred at lower asbestos concentrations than nuclear DNA damage.
  • Asbestos exposure induced significant oxidant stress in mesothelial cells.
  • Decreased mRNA levels of key mitochondrial respiratory chain components were observed.
  • Mitochondrial dysfunction, increased apoptosis, and altered apoptotic gene expression followed asbestos exposure.
  • Asbestos-induced apoptosis was reduced by caspase-9 inhibition, catalase, and mitochondrial DNA repair enzyme expression.

Conclusions:

  • Mitochondria are initial targets of asbestos-induced DNA damage.
  • Asbestos-mediated cell injury and apoptosis are driven by an oxidant-dependent mitochondrial pathway.
  • Targeting mitochondrial DNA repair offers a potential strategy to mitigate asbestos toxicity.

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