title: Nitric oxide induces coupling of mitochondrial signalling with the endoplasmic reticulum stress response.
abstract: 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). 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-AM. The NO-mediated ER stress response is diminished in rho(0) cells devoid of mitochondrial DNA, consistent with our evidence that NO-dependent mitochondrial disruption is coupled to the ER stress response.
authors.affiliation: Wolfson Institute for Biomedical Research, University College London, Cruciform Building, Gower Street, London, WC1E 6BT, UK.
authors.forename: Weiming
authors.initials: W
authors.lastname: Xu
authors.forename: Lizhi
authors.initials: L
authors.lastname: Liu
authors.forename: Ian G
authors.initials: IG
authors.lastname: Charles
authors.forename: Salvador
authors.initials: S
authors.lastname: Moncada
mesh_terms: D001483:Base Sequence; D002460:Cell Line; D017931:DNA Primers; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*; D009569:Nitric Oxide / Q000502:physiology*; D015398:Signal Transduction
chemical_list: D017931:DNA Primers; D009569:Nitric Oxide