Xu et al. used human cell lines that expressed inducible nitric oxide synthase under the control of regulated promoters to investigate the effects of inhibiting mitochondrial respiration with nitric oxide (NO). NO, acting independently of soluble guanylate kinase activity, stimulated expression of glucose-regulated protein 78 (Grp78), an endoplasmic reticulum (ER)-resident chaperone protein whose expression is enhanced as part of the ER stress response. NO produced an increase in the amount of the soluble transcription factor p50 ATF6, which is generated through a calcium-dependent process involving regulated intramembrane proteolysis. NO-dependent stimulation of p50 ATF6 production and of Grp78 expression was attenuated in cells depleted of intracellular calcium, and both an intracellular calcium chelator and cyclosporin A (which interferes with mitochondrial calcium signaling) reduced NO-dependent ATF6 cleavage and prevented the NO-dependent increase in Grp78. Thus, the authors propose that NO-dependent inhibition of mitochondrial respiration affects calcium signaling between the mitochondria and the ER, thereby stimulating production of p50 ATF6 and the expression of genes involved in the ER stress response. -- EMA
Nature Cell Biol. 6, 1129 (2004).
