Mechanisms of Mitochondrial Complex 1 Inhibition by Intermittent Hypoxia

Abstract

We previously reported that intermittent hypoxia (IH) inhibits the mitochondrial complex I but not the complex III. IH has been shown to activate NADPH oxidases. The present study tests the hypothesis that activation of NADPH oxidases and the resulting increase in reactive oxygen species (ROS) mediate complex I inhibition by IH. To test this possibility, experiments were performed on rat PC12 cells exposed to IH or normoxia. IH increased NADPH oxidase activity in a stimulus‐dependent manner and the effects could be reversed following re‐oxygenation for 3h. Apocynin (1mM), an inhibitor of NADPH oxidase as well as ROS scavengers prevented IH‐evoked inhibition of complex I. ROS are known to mobilize intracellular Ca2+. 2APB (75μM; inhibitor of IP3 receptors) but not nifedipine (3μM; L‐type calcium channel blocker) restored IH‐evoked complex I inhibition. Furthermore, ruthenium red (20μM; inhibitor of mitochondrial Ca2+ uniporter) or CGP37157 (10μM; inhibitor of mitochondrial Na+/Ca2+ exchanger) prevented complex I inhibition by IH. Taken together these observations suggest that ROS generated by NADPH oxidases mobilize Ca2+ flux from cytosol to mitochondria during IH resulting in inhibition of complex I. (Supported by NIH HL‐25830).