TY - JOUR
T1 - Activation of Hsp90/NOS and increased NO generation does not impair mitochondrial respiratory chain by competitive binding at cytochrome C Oxidase in low oxygen concentrations
AU - Presley, Tennille
AU - Vedam, Kaushik
AU - Liu, Xiaoping
AU - Zweier, Jay L.
AU - Ilangovan, Govindasamy
PY - 2009/11
Y1 - 2009/11
N2 - Nitric oxide (NO) is known to regulate mitochondrial respiration, especially during metabolic stress and disease, by nitrosation of the mitochondrial electron transport chain (ETC) complexes (irreversible) and by a competitive binding at O2 binding site of cytochrome c oxidase (CcO) in complex IV (reversible). In this study, by using bovine aortic endothelial cells, we demonstrate that the inhibitory effect of endogenously generated NO by nitric oxide synthase (NOS) activation, by either NOS stimulators or association with heat shock protein 90 (Hsp90), is significant only at high prevailing p02 through nitrosation of mitochondrial ETC complexes, but it does not inhibit the respiration, by competitive binding at CcO at very low p02. ETC complexes activity measurements confirmed that significant reduction in complex IV activity was noticed at higher p0 2, but it was unaffected at low pO2 in these cells. This was further extended to heat-shocked cells, where NOS was activated by the induction/activation of (Hsp90) through heat shock at an elevated temperature of 420C. From these results, we conclude that the entire attenuation of respiration by endogenous NO is due to irreversible inhibition by nitrosation of ETC complexes but not through reversible inhibition by competing with O 2 binding at CcO at complex IV.
AB - Nitric oxide (NO) is known to regulate mitochondrial respiration, especially during metabolic stress and disease, by nitrosation of the mitochondrial electron transport chain (ETC) complexes (irreversible) and by a competitive binding at O2 binding site of cytochrome c oxidase (CcO) in complex IV (reversible). In this study, by using bovine aortic endothelial cells, we demonstrate that the inhibitory effect of endogenously generated NO by nitric oxide synthase (NOS) activation, by either NOS stimulators or association with heat shock protein 90 (Hsp90), is significant only at high prevailing p02 through nitrosation of mitochondrial ETC complexes, but it does not inhibit the respiration, by competitive binding at CcO at very low p02. ETC complexes activity measurements confirmed that significant reduction in complex IV activity was noticed at higher p0 2, but it was unaffected at low pO2 in these cells. This was further extended to heat-shocked cells, where NOS was activated by the induction/activation of (Hsp90) through heat shock at an elevated temperature of 420C. From these results, we conclude that the entire attenuation of respiration by endogenous NO is due to irreversible inhibition by nitrosation of ETC complexes but not through reversible inhibition by competing with O 2 binding at CcO at complex IV.
KW - Electron transport chain
KW - Heat shock proteins
KW - Nitric oxide synthases
KW - Oxygen metabolism
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UR - http://www.scopus.com/inward/citedby.url?scp=77950860924&partnerID=8YFLogxK
U2 - 10.1007/s12192-009-0114-0
DO - 10.1007/s12192-009-0114-0
M3 - Article
C2 - 19412660
AN - SCOPUS:77950860924
SN - 1355-8145
VL - 14
SP - 611
EP - 627
JO - Cell Stress and Chaperones
JF - Cell Stress and Chaperones
IS - 6
ER -