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| Nitric oxide induces coupling of mitochondrial signalling with the endoplasmic reticulum stress response |
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| Author(s): Xu WM, Liu LZ, Charles IG, Moncada S |
| Source: NATURE CELL BIOLOGY Volume: 6 Issue: 11 Pages: 1129-U32 Published: NOV 2004 |
| Times Cited: 58 References: 30 |
| Abstract: Nitric oxide ( NO) is a pleiotropic signalling molecule that binds to cytochrome c oxidase (complex IV) reversibly and in competition with oxygen(1-3). 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) process(4,5). 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 cytoprotection(6) against toxic agents, including thapsigargin, a selective ER calcium-ATPase inhibitor(7). Cytoprotection is abolished after treatment with cyclosporin A (CsA), which disrupts mitochondrial calcium signalling(8), or with the calcium chelator BAPTA-AM(9). The NO-mediated ER stress response is diminished in rho(0) cells devoid of mitochondrial DNA(10), consistent with our evidence that NO-dependent mitochondrial disruption is coupled to the ER stress response. |
| Document Type: Article |
| Language: English |
| Reprint Address: Moncada, S (reprint author), UCL, Wolfson Inst Biomed Res, Cruciform Bldg,Gower St, London WC1E 6BT, England |
Addresses:
1. UCL, Wolfson Inst Biomed Res, London WC1E 6BT, England |
| Publisher: NATURE PUBLISHING GROUP, MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND |
| Subject Category: Cell Biology |
| IDS Number: 867BI |
| ISSN: 1465-7392 |
| DOI: 10.1038/ncb1188 |
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