Document Detail

Asbestos induces mitochondrial DNA damage and dysfunction linked to the development of apoptosis.
MedLine Citation:
PMID:  12909582     Owner:  NLM     Status:  MEDLINE    
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.
Arti Shukla; Michael Jung; Maria Stern; Naomi K Fukagawa; Douglas J Taatjes; Dennis Sawyer; Bennett Van Houten; Brooke T Mossman
Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.     Date:  2003-08-08
Journal Detail:
Title:  American journal of physiology. Lung cellular and molecular physiology     Volume:  285     ISSN:  1040-0605     ISO Abbreviation:  Am. J. Physiol. Lung Cell Mol. Physiol.     Publication Date:  2003 Nov 
Date Detail:
Created Date:  2003-10-10     Completed Date:  2003-11-21     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  100901229     Medline TA:  Am J Physiol Lung Cell Mol Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  L1018-25     Citation Subset:  IM    
Department of Pathology, University of Vermont College of Medicine, Burlington, Vermont 05405, USA.
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MeSH Terms
Apoptosis / drug effects*
Asbestos / toxicity*
Cell Division / drug effects
Cells, Cultured
DNA Damage*
DNA, Mitochondrial / drug effects,  genetics*
Dose-Response Relationship, Drug
Hydrogen Peroxide / toxicity
Oxidative Stress
Pleural Cavity
Polymerase Chain Reaction / methods
Rats, Inbred F344
Respiratory Mucosa / drug effects,  pathology,  physiology*
Grant Support
Reg. No./Substance:
0/DNA, Mitochondrial; 1332-21-4/Asbestos; 7722-84-1/Hydrogen Peroxide

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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