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Asbestos-induced alveolar epithelial cell apoptosis: Role of mitochondrial dysfunction caused by iron-derived free radicals

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Abstract

Asbestos causes asbestosis and malignancies by mechanisms that are not fully understood. Alveolar epithelial cell (AEC) injury by iron-derived reactive oxygen species (ROS) is one important mechanism implicated. We previously showed that iron-catalyzed ROS in part mediate asbestos-induced AEC DNA damage and apoptosis. Mitochondria have a critical role in regulating apoptosis after exposure to agents causing DNA damage but their role in regulating asbestos-induced apoptosis is unknown. To determine whether asbestos causes AEC mitochondrial dysfunction, we exposed A549 cells to amosite asbestos and assessed mitochondrial membrane potential changes (ΔΨm) using a fluorometric technique involving tetremethylrhodamine ethyl ester (TMRE) and mitotracker green. We show that amosite asbestos, but not an inert particulate, titanium dioxide, reduces ΔΨm after a 4 h exposure period. Further, the ΔΨm after 4 h was inversely proportional to the levels of apoptosis noted at 24 h as assessed by nuclear morphology as well as by DNA nucleosome formation. A role for iron-derived ROS was suggested by the finding that phytic acid, an iron chelator, blocked asbestos-induced reductions in A549 cell ΔΨm and attenuated apoptosis. Finally, overexpression of Bcl-xl, an anti-apoptotic protein that localizes to the mitochondria, prevented asbestos-induced decreases in A549 cell ΔΨm after 4 h and diminished apoptosis. We conclude that asbestos alters AEC mitochondrial function in part by generating iron-derived ROS, which in turn can result in apoptosis. This suggests that the mitochondrial death pathway is important in regulating pulmonary toxicity from asbestos.

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Authors and Affiliations

  1. Veterans Administration Chicago Health Care System: Lakeside Division and the Department of Medicine, Divisions of Pulmonary and Critical Care Medicine, Northwestern University Medical School, Chicago, IL, 60611, USA

    David W. Kamp, Vijayalakshmi Panduri & Navdeep Chandel

  2. Hematology-Oncology, Northwestern University Medical School, Chicago, IL, 60611, USA

    Sigmund A. Weitzman

Authors
  1. David W. Kamp
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  2. Vijayalakshmi Panduri
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  3. Sigmund A. Weitzman
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  4. Navdeep Chandel
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Kamp, D.W., Panduri, V., Weitzman, S.A. et al. Asbestos-induced alveolar epithelial cell apoptosis: Role of mitochondrial dysfunction caused by iron-derived free radicals. Mol Cell Biochem 234, 153–160 (2002). https://doi.org/10.1023/A:1015949118495

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