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J. Biol. Chem., Vol. 283, Issue 12, 7682-7689, March 21, 2008

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Nitric Oxide Evokes an Adaptive Response to Oxidative Stress by Arresting Respiration^*

Maroof Husain, Travis J. Bourret, Bruce D. McCollister, Jessica Jones-Carson, James Laughlin, and Andrés Vázquez-Torres¹

From the Departments of Microbiology and Medicine, University of Colorado Health Sciences Center at Fitzsimons, Aurora, Colorado 80045

Aerobic metabolism generates biologically challenging reactive oxygen species (ROS) by the endogenous autooxidation of components of the electron transport chain (ETC). Basal levels of oxidative stress can dramatically rise upon activation of the NADPH oxidase-dependent respiratory burst. To minimize ROS toxicity, prokaryotic and eukaryotic organisms express a battery of low-molecular-weight thiol scavengers, a legion of detoxifying catalases, peroxidases, and superoxide dismutases, as well as a variety of repair systems. We present herein blockage of bacterial respiration as a novel strategy that helps the intracellular pathogen Salmonella survive extreme oxidative stress conditions. A Salmonella strain bearing mutations in complex I NADH dehydrogenases is refractory to the early NADPH oxidase-dependent antimicrobial activity of IFN-activated macrophages. The ability of NADH-rich, complex I-deficient Salmonella to survive oxidative stress is associated with resistance to peroxynitrite (ONOO^-) and hydrogen peroxide (H₂O₂). Inhibition of respiration with nitric oxide (NO) also triggered a protective adaptive response against oxidative stress. Expression of the NDH-II dehydrogenase decreases NADH levels, thereby abrogating resistance of NO-adapted Salmonella to H₂O₂. NADH antagonizes the hydroxyl radical (OH^·) generated in classical Fenton chemistry or spontaneous decomposition of peroxynitrous acid (ONOOH), while fueling AhpCF alkylhydroperoxidase. Together, these findings identify the accumulation of NADH following the NO-mediated inhibition of Salmonella's ETC as a novel antioxidant strategy. NO-dependent respiratory arrest may help mitochondria and a plethora of organisms cope with oxidative stress engendered in situations as diverse as aerobic respiration, ischemia reperfusion, and inflammation.

Received for publication, October 26, 2007 , and in revised form, December 17, 2007.

^* This work was supported by National Institutes of Health Grant AI54959, the Schweppe Foundation, and the Burroughs Wellcome Fund. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Table S1.

¹ To whom correspondence should be addressed: Dept. of Microbiology; Mail Box 8333; UCHSC School of Medicine at Fitzsimons; P. O. Box 6511; Rm. P18-9120; Aurora, CO 80045. Tel.: 303-724-4218; Fax: 303-724-4226; E-mail: andres.vazquez-torres{at}uchsc.edu.

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