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1 Department of Pathology, University of Vermont College of Medicine, Burlington, VT, USA
2 University of Texas at Galveston, Galveston, TX, USA
3 National Institutes of Environmental Health Sciences, Research Triangle Park, NC, USA
* To whom correspondence should be addressed. E-mail: Brooke.Mossman{at}uvm.edu.
To test the hypothesis that asbestos-mediated cell injury is mediated through an oxidant dependent mitochondrial pathway, isolated mesothelial cells were examined for mitochondrial DNA damage as determined by quantitative PCR (QPCR). Mitochondrial DNA damage occurred at 4-fold lower concentrations of crocidolite asbestos as compared to concentrations required for nuclear DNA damage. DNA damage by asbestos was preceded by oxidant stress as shown by confocal scanning laser microscopy (CSLM) using MitoTracker Green FM and the oxidant probe, Redox Sensor Red CC-1. These events were associated with dose-related decreases in steady-state mRNA levels of cytochrome c oxidase, subunit 3 (COIII) and NADH dehydrogenase 5 (ND5). Subsequently, dose-dependent decreases in formazan production, an indication of mitochondrial dysfunction, increased mRNA expression of pro- and anti-apoptotic genes, and increased numbers of apoptotic cells were observed in asbestos-exposed mesothelial cells. The possible contribution of mitochondria-derived pathways to asbestos-induced apoptosis was confirmed by its significant reduction after pretreatment of cells with a caspase-9 inhibitor. Apoptosis was decreased in the presence of catalase. Lastly, use of HeLa cells transfected with a mitochondrial transport sequence targeting the human DNA repair enzyme, 8-oxoguanine DNA glycosylase (hOGG) to mitochondria, demonstrated that asbestos-induced apoptosis was ameliorated with increased cell survival. Studies collectively indicate that mitochondria are initial targets of asbestos-induced DNA damage and apoptosis via an oxidant-related mechanism.
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