The mitochondria-regulated death pathway mediates asbestos-induced alveolar epithelial cell apoptosis
Panduri, V; Weitzman, SA; Chandel, N; Kamp, DW
HERO ID
1494992
Reference Type
Journal Article
Year
2003
Language
English
PMID
| HERO ID | 1494992 |
|---|---|
| In Press | No |
| Year | 2003 |
| Title | The mitochondria-regulated death pathway mediates asbestos-induced alveolar epithelial cell apoptosis |
| Authors | Panduri, V; Weitzman, SA; Chandel, N; Kamp, DW |
| Journal | American Journal of Respiratory Cell and Molecular Biology |
| Volume | 28 |
| Issue | 2 |
| Page Numbers | 241-248 |
| Abstract | The mechanisms underlying asbestos-induced pulmonary toxicity are not fully understood. Alveolar epithelial cell (AEC) apoptosis by iron-derived reactive oxygen species (ROS) is one important mechanism implicated. The two major pathways regulating apoptosis include (i) the mitochondrial death (intrinsic) pathway caused by DNA damage, and (ii) the plasma-membrane death receptor (extrinsic) pathway. However, it is unknown whether asbestos activates either death pathway in AEC. We determined whether asbestos triggers AEC mitochondrial dysfunction by exposing cells (A549 and rat alveolar type II) to amosite asbestos and assessing mitochondrial membrane potential changes (deltapsi(m)) using a fluorometric technique involving tetremethylrhodamine ethyl ester (TMRE) and mitotracker green. Unlike inert particulates (titanium dioxide and glass beads), amosite asbestos caused dose- and time-dependent reductions in deltapsi(m). Asbestos-induced deltapsi(m) was associated with the release of cytochrome c from the mitochondria to the cytoplasm as well as activation of caspase 9, a mitochondrial-activated caspase. In contrast, a lower level of caspase 8, the death receptor-activated caspase, was detected in asbestos-exposed AEC. An iron chelator (phytic acid or deferoxamine) or a hydroxyl radical scavenger (sodium benzoate) each blocked asbestos-induced reductions in deltapsi(m) and caspase 9 activation, suggesting a role for iron-derived ROS. Finally, Bcl-X(L), a mitochondrial antiapoptotic protein that prevents cell death by preserving the outer mitochondrial membrane integrity, blocked asbestos-induced decreases in A549 cell deltapsi(m) and reduced apoptosis as assessed by DNA fragmentation. We conclude that asbestos-induced AEC apoptosis results from mitochondrial dysfunction, in part due to iron-derived ROS, which is followed by the release of cytochrome c and caspase 9 activation. Our findings suggest an important role for the mitochondria-regulated death pathway in the pathogenesis of asbestos-associated pulmonary toxicity. |
| Doi | 10.1165/rcmb.4903 |
| Pmid | 12540492 |
| Wosid | WOS:000180855400016 |
| Is Certified Translation | No |
| Dupe Override | No |
| Comments | Source: Web of Science WOS:000180855400016 |
| Is Public | Yes |
| Language Text | English |
| Keyword | BCL2L1 protein, human; Bcl2l1 protein, rat; Cytochrome c Group; Free Radicals; Proto-Oncogene Proteins c-bcl-2; bcl-X Protein; Asbestos; 1332-21-4; E1UOL152H7; CASP9 protein, human; EC 3.4.22.-; Casp9 protein, rat; Caspase 9; Caspases; Index Medicus; Cell Line; Enzyme Activation -- drug effects; Mitochondria -- drug effects; Free Radicals -- metabolism; Caspases -- metabolism; Cytochrome c Group -- metabolism; Animals; Epithelial Cells -- pathology; Mitochondria -- metabolism; Proto-Oncogene Proteins c-bcl-2 -- metabolism; Iron -- metabolism; Epithelial Cells -- drug effects; Membrane Potentials -- drug effects; Epithelial Cells -- metabolism; Apoptosis -- drug effects; Pulmonary Alveoli -- drug effects; Apoptosis -- physiology; Pulmonary Alveoli -- metabolism; Asbestos -- toxicity; Pulmonary Alveoli -- pathology |