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J. Biol. Chem., Vol. 283, Issue 47, 32590-32597, November 21, 2008

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Nitrite Reductase Activity of Cytochrome c^*

Swati Basu, Natalia A. Azarova, Michael D. Font, S. Bruce King, Neil Hogg^¶, Mark T. Gladwin^||**, Sruti Shiva^**1, and Daniel B. Kim-Shapiro²

From the Departments of Physics and Chemistry, Wake Forest University, Winston-Salem, North Carolina 27109, the ^¶Department of Biophysics and Free Radical Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, the ^||Pulmonary, Allergy, and Critical Care Medicine Division, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15213, and the ^**Hemostasis and Vascular Biology Research Institute and the Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania 15213

Small increases in physiological nitrite concentrations have now been shown to mediate a number of biological responses, including hypoxic vasodilation, cytoprotection after ischemia/reperfusion, and regulation of gene and protein expression. Thus, while nitrite was until recently believed to be biologically inert, it is now recognized as a potentially important hypoxic signaling molecule and therapeutic agent. Nitrite mediates signaling through its reduction to nitric oxide, via reactions with several heme-containing proteins. In this report, we show for the first time that the mitochondrial electron carrier cytochrome c can also effectively reduce nitrite to NO. This nitrite reductase activity is highly regulated as it is dependent on pentacoordination of the heme iron in the protein and occurs under anoxic and acidic conditions. Further, we demonstrate that in the presence of nitrite, pentacoordinate cytochrome c generates bioavailable NO that is able to inhibit mitochondrial respiration. These data suggest an additional role for cytochrome c as a nitrite reductase that may play an important role in regulating mitochondrial function and contributing to hypoxic, redox, and apoptotic signaling within the cell.

Received for publication, September 8, 2008

^* This work was supported, in whole or in part, by National Institutes of Health Grants HL058091 and HL078706. 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.

¹ To whom correspondence may be addressed: Dept. of Pharmacology and Chemical Biology and Hemostasis and Vascular Biology Research Institute, University of Pittsburgh, Pittsburgh, PA 15213. Tel.: 412-383-5799; E-mail: shivas{at}upmc.edu. ² To whom correspondence may be addressed: Dept. of Physics, Wake Forest University, Winston-Salem, NC 27109. Tel.: 336-758-4993; Fax: 336-758-6142; E-mail: shapiro{at}wfu.edu.

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