Document Type

Article

Publication Date

5-18-2004

Publication Title

Proceedings of the National Academy of Sciences of the United States of America

Department

Geisel School of Medicine

Abstract

We have investigated in whole cells whether, at low oxygen concentrations ([O(2)]), endogenous nitric oxide (NO) modulates the redox state of the mitochondrial electron transport chain (ETC), and whether such an action has any signaling consequences. Using a polarographic-and-spectroscopic-coupled system, we monitored redox changes in the ETC cytochromes b(H), cc(1), and aa(3) during cellular respiration. The rate of O(2) consumption (VO(2)) remained constant until [O(2)] fell below 15 microM, whereas the onset of reduction of cytochromes aa(3), part of the terminal ETC enzyme cytochrome c oxidase, occurred at approximately 50 microM O(2). Incubation of the cells with an inhibitor of NO synthase lowered significantly (P < 0.05) the [O(2)] at which reduction of the cytochromes occurred. We also measured intracellular superoxide (O(2)(-)) production at different [O(2)] and found there was no increase in O(2)(-) generation in control cells, or those treated with the NO synthase inhibitor, when incubated at 21% O(2). However, after 30-min exposure of control cells to 3% O(2), an increase in O(2)(-) generation was observed, accompanied by translocation to the nucleus of the transcription factor NF-kappa B. Both of these responses were diminished by NO synthase inhibition. Our results suggest that endogenous NO, by enhancing the reduction of ETC cytochromes, contributes to a mechanism by which cells maintain their VO(2) at low [O(2)]. This, in turn, favors the release of O(2)(-), which initiates the transcriptional activation of NF-kappa B as an early signaling stress response.

DOI

10.1073/pnas.0401723101

Original Citation

Palacios-Callender M, Quintero M, Hollis VS, Springett RJ, Moncada S. Endogenous NO regulates superoxide production at low oxygen concentrations by modifying the redox state of cytochrome c oxidase. Proc Natl Acad Sci U S A. 2004 May 18;101(20):7630-5. doi: 10.1073/pnas.0401723101. Epub 2004 May 10. PMID: 15136725; PMCID: PMC419657.

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