Mitochondrial DNA-depleted A549 cells are resistant to bleomycin.

Published

Journal Article

Alveolar epithelial cells are considered to be the primary target of bleomycin-induced lung injury, leading to interstitial fibrosis. The molecular mechanisms by which bleomycin causes this damage are poorly understood but are suspected to involve generation of reactive oxygen species and DNA damage. We studied the effect of bleomycin on mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) in human alveolar epithelial A549 cells. Bleomycin caused an increase in reactive oxygen species production, DNA damage, and apoptosis in A549 cells; however, bleomycin induced more mtDNA than nDNA damage. DNA damage was associated with activation of caspase-3, cleavage of poly(ADP-ribose) polymerase, and cleavage and activation of protein kinase D1 (PKD1), a newly identified mitochondrial oxidative stress sensor. These effects appear to be mtDNA-dependent, because no caspase-3 or PKD1 activation was observed in mtDNA-depleted (ρ(0)) A549 cells. Survival rate after bleomycin treatment was higher for A549 ρ(0) than A549 cells. These results suggest that A549 ρ(0) cells are more resistant to bleomycin toxicity than are parent A549 cells, likely in part due to the depletion of mtDNA and impairment of mitochondria-dependent apoptotic pathways.

Full Text

Duke Authors

Cited Authors

  • Brar, SS; Meyer, JN; Bortner, CD; Van Houten, B; Martin, WJ

Published Date

  • September 2012

Published In

Volume / Issue

  • 303 / 5

Start / End Page

  • L413 - L424

PubMed ID

  • 22773697

Pubmed Central ID

  • 22773697

Electronic International Standard Serial Number (EISSN)

  • 1522-1504

International Standard Serial Number (ISSN)

  • 1040-0605

Digital Object Identifier (DOI)

  • 10.1152/ajplung.00343.2011

Language

  • eng