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

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

    Research output: Contribution to journalArticlepeer-review


    Nitric oxide (NO) is a pleiotropic signalling molecule that binds to cytochrome c oxidase (complex IV) reversibly and in competition with oxygen. 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) process. 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 cytoprotection against toxic agents, including thapsigargin, a selective ER calcium-ATPase inhibitor. Cytoprotection is abolished after treatment with cyclosporin A (CsA), which disrupts mitochondrial calcium signalling, 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.
    Original languageEnglish
    Pages (from-to)1129-1134
    Number of pages5
    JournalNature Cell Biology
    Issue number11
    Publication statusPublished - Nov 2004


    • Base Sequence
    • Cell Line
    • DNA Primers
    • Endoplasmic Reticulum/*metabolism
    • Mitochondria/*metabolism
    • Nitric Oxide/*physiology
    • *Signal Transduction


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