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NADPH oxidase 2 mediates intermittent hypoxia-induced mitochondrial complex I inhibition: relevance to blood pressure changes in rats. Antioxid Redox Signal 2011 Feb 15;14(4):533-42

Date

07/14/2010

Pubmed ID

20618070

Pubmed Central ID

PMC3038125

DOI

10.1089/ars.2010.3213

Scopus ID

2-s2.0-79251546780 (requires institutional sign-in at Scopus site)   69 Citations

Abstract

Previous studies identified NADPH oxidases (Nox) and mitochondrial electron transport chain at complex I as major cellular sources of reactive oxygen species (ROS) mediating systemic and cellular responses to intermittent hypoxia (IH). In the present study, we investigated potential interactions between Nox and the mitochondrial complex I and assessed the contribution of mitochondrial ROS in IH-evoked elevation in blood pressure. IH treatment led to stimulus-dependent activation of Nox and inhibition of complex I activity in rat pheochromocytoma (PC)12 cells. After re-oxygenation, Nox activity returned to baseline values within 3 h, whereas the complex I activity remained downregulated even after 24 h. IH-induced complex I inhibition was prevented by Nox inhibitors, Nox2 but not Nox 4 siRNA, in cell cultures and was absent in gp91(phox-/Y) (Nox2 knock-out; KO) mice. Using pharmacological inhibitors, we show that ROS generated by Nox activation mobilizes Ca(2+) flux from the cytosol to mitochondria, leading to S-glutathionylation of 75- and 50-kDa proteins of the complex I and inhibition of complex I activity, which results in elevated mitochondrial ROS. Systemic administration of mito-tempol prevented the sustained but not the acute elevations of blood pressure in IH-treated rats, suggesting that mitochondrial-derived ROS contribute to sustained elevation of blood pressure.

Author List

Khan SA, Nanduri J, Yuan G, Kinsman B, Kumar GK, Joseph J, Kalyanaraman B, Prabhakar NR

Author

Balaraman Kalyanaraman PhD Professor in the Biophysics department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Blood Pressure
Electron Transport Complex I
Glutathione
Hypoxia
Male
Mice
Mice, Knockout
Mitochondria
NADH, NADPH Oxidoreductases
PC12 Cells
Rats
Rats, Sprague-Dawley
Reactive Oxygen Species