A novel role for cytochrome c: Efficient catalysis of S-nitrosothiol formation |
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Authors: | Swati Basu Agnes Keszler Natalia A. Azarova Nneka Nwanze Andreas Perlegas Sruti Shiva Katarzyna A. Broniowska Neil Hogg Daniel B. Kim-Shapiro |
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Affiliation: | 1. Neuroscience and Aging Research Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA;2. Biomedical Sciences Graduate Program, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA;3. Graduate School of Biomedical Sciences, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA;4. Department of Neurosciences, University of California San Diego School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093, USA |
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Abstract: | Although S-nitrosothiols are regarded as important elements of many NO-dependent signal transduction pathways, the physiological mechanism of their formation remains elusive. Here, we demonstrate a novel mechanism by which cytochrome c may represent an efficient catalyst of S-nitrosation in vivo. In this mechanism, initial binding of glutathione to ferric cytochrome c is followed by reaction of NO with this complex, yielding ferrous cytochrome c and S-nitrosoglutathione (GSNO). We show that when submitochondrial particles or cell lysates are exposed to NO in the presence of cytochrome c, there is a robust formation of protein S-nitrosothiols. In the case of submitochondrial particles protein S-nitrosation is paralleled by an inhibition of mitochondrial complex I. These observations raise the possibility that cytochrome c is a mediator of S-nitrosation in biological systems, particularly during hypoxia, and that release of cytochrome c into the cytosol during apoptosis potentially releases a GSNO synthase activity that could modulate apoptotic signaling. |
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