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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