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Carbon monoxide activates autophagy via mitochondrial reactive oxygen species formation

Authors
 Seon-Jin Lee ; Stefan W. Ryter ; Young Sam Kim ; Augustine M. K. Choi ; Hong Pyo Kim ; Kiichi Nakahira ; Jin-Fu Xu 
Citation
 American Journal of Respiratory Cell and Molecular Biology, Vol.45(4) : 867~873, 2011 
Journal Title
 American Journal of Respiratory Cell and Molecular Biology 
ISSN
 1044-1549 
Issue Date
2011
Abstract
Autophagy, an autodigestive process that degrades cellular organelles and protein, plays an important role in maintaining cellular homeostasis during environmental stress. Carbon monoxide (CO), a toxic gas and candidate therapeutic molecule, confers cytoprotection in animal models of acute lung injury. The mechanisms underlying CO-dependent lung cell protection and the role of autophagy in this process remain unclear. Here, we demonstrate that CO exposure time-dependently increased the expression and activation of the autophagic protein, microtubule-associated protein-1 light chain-3B (LC3B) in mouse lung, and in cultured human alveolar (A549) or human bronchial epithelial cells. Furthermore, CO increased autophagosome formation in epithelial cells by electron microscopy and green fluorescent protein (GFP)-LC3 puncta assays. Recent studies indicate that reactive oxygen species (ROS) play an important role in the activation of autophagy. CO up-regulated mitochondria-dependent generation of ROS in epithelial cells, as assayed by MitoSOX fluorescence. Furthermore, CO-dependent induction of LC3B expression was inhibited by N-acetyl-L-cysteine and the mitochondria-targeting antioxidant, Mito-TEMPO. These data suggest that CO promotes the autophagic process through mitochondrial ROS generation. We investigated the relationships between autophagic proteins and CO-dependent cytoprotection using a model of hyperoxic stress. CO protected against hyperoxia-induced cell death, and inhibited hyperoxia-associated ROS production. The ability of CO to protect against hyperoxia-induced cell death and caspase-3 activation was compromised in epithelial cells infected with LC3B-small interfering (si)RNA, indicating a role for autophagic proteins. These studies uncover a new mechanism for the protective action of CO, in support of potential therapeutic application of this gas.
URI
http://ir.ymlib.yonsei.ac.kr/handle/22282913/95014
DOI
10.1165/rcmb.2010-0352OC
Appears in Collections:
1. 연구논문 > 1. College of Medicine > Dept. of Internal Medicine
Yonsei Authors
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