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Nitric oxide induces coupling of mitochondrial signalling with the endoplasmic reticulum stress response

Nature Cell Biology volume 6, pages 1129–1134 (2004)Cite this article

Abstract

Nitric oxide (NO) is a pleiotropic signalling molecule that binds to cytochrome c oxidase (complex IV) reversibly and in competition with oxygen1,2,3. This action of NO has both physiological and pathophysiological consequences. Here we report that endogenously generated NO, which disrupts the respiratory chain, may cause changes in mitochondrial calcium flux. This induces cleavage of the endoplasmic reticulum (ER) stress-regulated transcription factor p90 ATF6 into an active p50 form. Cleavage depends on a calcium-dependent serine protease through a regulated intramembrane proteolysis (RIP) process4,5. p50 ATF6 then translocates to the nucleus to upregulate expression of the ER-resident molecular chaperone, glucose-regulated protein 78 (Grp78)4. The increase in Grp78 provides significant cytoprotection6 against toxic agents, including thapsigargin, a selective ER calcium–ATPase inhibitor7. Cytoprotection is abolished after treatment with cyclosporin A (CsA), which disrupts mitochondrial calcium signalling8, or with the calcium chelator BAPTA-AM9. The NO-mediated ER stress response is diminished in rho0 cells devoid of mitochondrial DNA10, consistent with our evidence that NO-dependent mitochondrial disruption is coupled to the ER stress response.

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Figure 1: NO increases expression of Grp78 and cleavage of p90 ATF6.
Figure 2: Calcium dependence of NO-mediated ATF6 cleavage and upregulation of Grp78.
Figure 3: NO-mediated cytoprotection is calcium dependent.
Figure 4: NO-mediated Grp78 expression in mitochondrial DNA-deficient cell lines.

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Acknowledgements

This work was supported by the Medical Research Council, UK. We thank E. A. Higgs for help in the preparation of this manuscript. We also thank R. Prywes for providing the 3×Flag–ATF6 plasmid.

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  1. Wolfson Institute for Biomedical Research, University College London, Cruciform Building, Gower Street, London, WC1E 6BT, UK

    Weiming Xu, Lizhi Liu, Ian G. Charles & Salvador Moncada

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Correspondence to Salvador Moncada.

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Xu, W., Liu, L., Charles, I. et al. Nitric oxide induces coupling of mitochondrial signalling with the endoplasmic reticulum stress response. Nat Cell Biol 6, 1129–1134 (2004). https://doi.org/10.1038/ncb1188

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