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This Article Full Text Full Text (PDF) All Versions of this Article: 290/5/L978    most recent 00296.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via ISI Web of Science (3) Citing Articles via Google Scholar Google Scholar Articles by Arita, Y. Articles by Li, Y. Search for Related Content PubMed PubMed Citation Articles by Arita, Y. Articles by Li, Y.

Mitochondrial localization of catalase provides optimal protection from H₂O₂-induced cell death in lung epithelial cells

Departments of ¹Pediatrics, ²Medicine, and ³Thoracic-Cardiovascular Surgery, ⁴CardioPulmonary Research Institute, Winthrop University Hospital, State University of New York Stony Brook School of Medicine, Mineola; ⁵Center for Immunology and Microbial Disease, Albany Medical College, Albany; and ⁶Department of Pediatrics, University Hospital, Stony Brook, New York

Submitted 13 July 2005 ; accepted in final form 21 December 2005

Reactive oxygen species (ROS) can cause cell injury and death via mitochondrial-dependent pathways, and supplementation with antioxidants has been shown to ameliorate these processes. The c-Jun NH₂-terminal kinase (JNK) pathway has been shown to play a critical role in ROS-induced cell death. To determine if targeting catalase (CAT) to the mitochondria provides better protection than cytosolic expression against H₂O₂-induced injury, the following two approaches were taken: 1) adenoviral-mediated transduction was performed using cytosolic (CCAT) or mitochondrial (MCAT) CAT cDNAs and 2) stable cell lines were generated overexpressing CAT in mitochondria (n = 3). Cells were exposed to 250 µM H₂O₂, and cell survival, mitochondrial function, cytochrome c release, and JNK activity were analyzed. Although all viral transduced cells had a transient twofold increase in CAT activity, MCAT cells had significantly higher survival rates, the best mitochondrial function, and lowest JNK activity compared with CCAT and LacZ controls. The improved protection with MCAT was observed in primary type II lung epithelial cells and in transformed lung epithelial cells. In the three stable cell lines, cell survival directly correlated with extent of mitochondrial localization (r = 0.60572, P < 0.05) and not overall CAT activity (r = –0.45501, P < 0.05). Data indicate that targeting of antioxidants directly to the mitochondria is more effective in protecting lung epithelial cells against ROS-induced injury. This has important implications in antioxidant supplementation trials to prevent ROS-induced lung injury in critically ill patients.

antioxidants; apoptosis; reactive oxygen species; c-Jun NH₂-terminal kinase; c-Jun NH₂-terminal kinase pathway