Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 14-Day Trial for You or Your Team.

Learn More →

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

Asbestos induces mitochondrial DNA damage and dysfunction linked to the development of apoptosis 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. Mitochondrial DNA damage occurred at fourfold lower concentrations of crocidolite asbestos compared with concentrations required for nuclear DNA damage. DNA damage by asbestos was preceded by oxidant stress as shown by confocal scanning laser microscopy 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. Subsequently, dose-dependent decreases in formazan production, an indication of mitochondrial dysfunction, increased mRNA expression of pro- and antiapoptotic genes, and increased numbers of apoptotic cells were observed in asbestos-exposed mesothelial cells. The possible contribution of mitochondrial-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. Last, use of HeLa cells transfected with a mitochondrial transport sequence targeting the human DNA repair enzyme 8-oxoguanine DNA glycosylase 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. mitochondria; mesothelial cells; oxidants Address for reprint requests and other correspondence: B. T. Mossman, Dept. of Pathology, Univ. of Vermont College of Medicine, 89 Beaumont Ave., Burlington, VT 05405 (E-mail: Brooke.Mossman@uvm.edu ). http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png AJP - Lung Cellular and Molecular Physiology The American Physiological Society

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

Loading next page...
 
/lp/the-american-physiological-society/asbestos-induces-mitochondrial-dna-damage-and-dysfunction-linked-to-rq6LSZtA71

References (43)

Publisher
The American Physiological Society
Copyright
Copyright © 2011 the American Physiological Society
ISSN
1040-0605
eISSN
1522-1504
DOI
10.1152/ajplung.00038.2003
pmid
12909582
Publisher site
See Article on Publisher Site

Abstract

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. Mitochondrial DNA damage occurred at fourfold lower concentrations of crocidolite asbestos compared with concentrations required for nuclear DNA damage. DNA damage by asbestos was preceded by oxidant stress as shown by confocal scanning laser microscopy 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. Subsequently, dose-dependent decreases in formazan production, an indication of mitochondrial dysfunction, increased mRNA expression of pro- and antiapoptotic genes, and increased numbers of apoptotic cells were observed in asbestos-exposed mesothelial cells. The possible contribution of mitochondrial-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. Last, use of HeLa cells transfected with a mitochondrial transport sequence targeting the human DNA repair enzyme 8-oxoguanine DNA glycosylase 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. mitochondria; mesothelial cells; oxidants Address for reprint requests and other correspondence: B. T. Mossman, Dept. of Pathology, Univ. of Vermont College of Medicine, 89 Beaumont Ave., Burlington, VT 05405 (E-mail: Brooke.Mossman@uvm.edu ).

Journal

AJP - Lung Cellular and Molecular PhysiologyThe American Physiological Society

Published: Nov 1, 2003

There are no references for this article.