Role of mitochondrial hOGG1 and aconitase in oxidant-induced lung epithelial cell apoptosis

V. Panduri, G. Liu, S. Surapureddi, J. Kondapalli, S. Soberanes, N. C. de Souza-Pinto, V. A. Bohr, G. R S Budinger, P. T. Schumacker, S. A. Weitzman, D. W. Kamp*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

64 Scopus citations

Abstract

8-Oxoguanine DNA glycosylase (Ogg1) repairs 8-oxo-7,8-dihydroxyguanine (8-oxoG), one of the most abundant DNA adducts caused by oxidative stress. In the mitochondria, Ogg1 is thought to prevent activation of the intrinsic apoptotic pathway in response to oxidative stress by augmenting DNA repair. However, the predominance of the β-Ogg1 isoform, which lacks 8-oxoG DNA glycosylase activity, suggests that mitochondrial Ogg1 functions in a role independent of DNA repair. We report here that overexpression of mitochondria-targeted human α-hOgg1 (mt-hOgg1) in human lung adenocarcinoma cells with some alveolar epithelial cell characteristics (A549 cells) prevents oxidant-induced mitochondrial dysfunction and apoptosis by preserving mitochondrial aconitase. Importantly, mitochondrial α-hOgg1 mutants lacking 8-oxoG DNA repair activity were as effective as wild-type mt-hOgg1 in preventing oxidant-induced caspase-9 activation, reductions in mitochondrial aconitase, and apoptosis, suggesting that the protective effects of mt-hOgg1 occur independent of DNA repair. Notably, wild-type and mutant mt-hOgg1 coprecipitate with mitochondrial aconitase. Furthermore, overexpression of mitochondrial aconitase abolishes oxidant-induced apoptosis whereas hOgg1 silencing using shRNA reduces mitochondrial aconitase and augments apoptosis. These findings suggest a novel mechanism that mt-hOgg1 acts as a mitochondrial aconitase chaperone protein to prevent oxidant-mediated mitochondrial dysfunction and apoptosis that might be important in the molecular events underlying oxidant-induced toxicity.

Original languageEnglish (US)
Pages (from-to)750-759
Number of pages10
JournalFree Radical Biology and Medicine
Volume47
Issue number6
DOIs
StatePublished - Sep 15 2009

Keywords

  • Aconitase
  • Asbestos
  • DNA repair
  • Free radicals
  • Mitochondria
  • Ogg1

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

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