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Published ahead of print on November 1, 2006, doi:10.1165/rcmb.2006-0214OC

Am. J. Respir. Cell Mol. Biol., Volume 36, Number 4, April 2007, 409-417

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Submitted on June 14, 2006
Revised on October 31, 2006

Mitochondrial Localization and Function of Heme Oxygenase-1 in Cigarette Smoke-Induced Cell Death

Dirk-Jan Slebos1, Stefan W Ryter2, Marco van der Toorn1, Fang Liu2, Fengli Guo3, Catherine J Baty3, Jenny M Karlsson3, Simon C Watkins3, Hong Pyo Kim2, Xue Wang2, Janet S Lee2, Dirkje S Postma1, Henk F Kauffman4, and Augustine MK Choi2*

1 Department of Pulmonary Diseases, University Medical Center Groningen, Groningen, The Netherlands, 2 Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh, School of Medicine, Pittsburgh, PA, USA, 3 Center for Biologic Imaging, Department of Cell Biology and Physiology, University of Pittsburgh, School of Medicine, Pittsburgh, PA, USA, 4 Department of Allergology, University Medical Center Groningen, Groningen, The Netherlands

* To whom correspondence should be addressed. E-mail: choiam{at}upmc.edu.

Cigarette smoke-induced apoptosis and necrosis contribute to the pathogenesis of chronic obstructive pulmonary disease. The induction of heme oxygenase-1 provides cytoprotection against oxidative stress, and may protect in smoking-related disease. Since mitochondria regulate cellular death, we examined the functional expression and mitochondrial localization of heme oxygenase-1 in pulmonary epithelial cells exposed to cigarette smoke extract (CSE), and its role in modulating cell death. Heme oxygenase-1 expression increased dramatically in cytosolic and mitochondrial fractions of human alveolar (A549), or bronchial epithelial cells (Beas-2b) exposed to either hemin, lipopolysaccharide, or CSE. Mitochondrial localization of heme oxygenase-1 was also observed in a primary culture of human small airway epithelial cells. Furthermore, heme oxygenase activity increased dramatically in mitochondrial fractions, and in whole cell extracts of Beas-2b following exposure to hemin and CSE. The mitochondrial localization of heme oxygenase-1 in Beas-2b was confirmed using immunogold-electron microscopy and immunofluorescence labeling on confocal laser microscopy. CSE caused loss of cellular ATP and rapid depolarization of mitochondrial membrane potential. Apoptosis occurred in Beas-2b at low concentrations of cigarette smoke extract whereas necrosis occurred at high concentrations. Overexpression of heme oxygenase-1 inhibited cigarette smoke extract-induced Beas-2b cell death and preserved cellular ATP levels. Finally, heme oxygenase-1 mRNA expression was elevated in the lungs of mice chronically exposed to cigarette smoke. We demonstrate the functional compartmentalization of heme oxygenase-1 in the mitochondria of lung epithelial cells, and its potential role in defense against mitochondria-mediated cell death during cigarette smoke extract exposure.




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