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Am J Physiol Lung Cell Mol Physiol 292: L1211-L1218, 2007. First published January 5, 2007; doi:10.1152/ajplung.00291.2006
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Cigarette smoke-induced blockade of the mitochondrial respiratory chain switches lung epithelial cell apoptosis into necrosis

Marco van der Toorn,1 Dirk-Jan Slebos,2 Harold G. de Bruin,1 Henri G. Leuvenink,3 Stephan J. L. Bakker,4 Rijk O. B. Gans,4 Gerard H. Koëter,2 Antoon J. M. van Oosterhout,1 and Henk F. Kauffman5

1Laboratory of Allergology and Pulmonary Diseases, 2Department of Pulmonary Diseases, 3Department of Surgery, 4Department of Internal Medicine, and 5Groningen University Institute for Drug Exploration, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

Submitted 3 August 2006 ; accepted in final form 29 December 2006

Increased lung cell apoptosis and necrosis occur in patients with chronic obstructive pulmonary disease (COPD). Mitochondria are crucially involved in the regulation of these cell death processes. Cigarette smoke is the main risk factor for development of COPD. We hypothesized that cigarette smoke disturbs mitochondrial function, thereby decreasing the capacity of mitochondria for ATP synthesis, leading to cellular necrosis. This hypothesis was tested in both human bronchial epithelial cells and isolated mitochondria. Cigarette smoke extract exposure resulted in a dose-dependent inhibition of complex I and II activities. This inhibition was accompanied by decreases in mitochondrial membrane potential, mitochondrial oxygen consumption, and production of ATP. Cigarette smoke extract abolished the staurosporin-induced caspase-3 and -7 activities and induced a switch from epithelial cell apoptosis into necrosis. Cigarette smoke induced mitochondrial dysfunction, with compounds of cigarette smoke acting as blocking agents of the mitochondrial respiratory chain; loss of ATP generation leading to cellular necrosis instead of apoptosis is a new pathophysiological concept of COPD development.

chronic obstructive pulmonary disease; mitochondria


Address for reprint requests and other correspondence: D.-J. Slebos, Dept. of Pulmonary Diseases, Univ. Medical Center Groningen, PO Box 30001, 9700 RB Groningen, The Netherlands (e-mail: d.j.slebos{at}int.umcg.nl)




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