Abstract
Mitochondria use oxygen as the final acceptor of the respiratory chain, but its incomplete reduction can also produce reactive oxygen species (ROS), especially superoxide. Acute hypoxia produces a superoxide burst in different cell types, but the triggering mechanism is still unknown. Herein, we show that complex I is involved in this superoxide burst under acute hypoxia in endothelial cells. We have also studied the possible mechanisms by which complex I could be involved in this burst, discarding reverse electron transport in complex I and the implication of PTEN-induced putative kinase 1 (PINK1). We show that complex I transition from the active to ‘deactive’ form is enhanced by acute hypoxia in endothelial cells and brain tissue, and we suggest that it can trigger ROS production through its Na+/H+ antiporter activity. These results highlight the role of complex I as a key actor in redox signalling in acute hypoxia.
Highlights
Eukaryotic organisms use oxygen (O2) as the final electron acceptor in the mitochondrial electron transport chain, producing water (H2O) and driving the production of the high-energy molecule ATP through oxidative phosphorylation (OXPHOS)
We have recently assessed by several methods that different types of cells produce a superoxide burst in the first minutes of the transition from normoxia to hypoxia [32]
In order to analyse the relationship between the superoxide burst in acute hypoxia and complex I function, we silenced in bovine aortic endothelial cells (BAECs) the expression of genes encoding for either an accessory or a core complex I subunit, NDUFS4 and NDUFS2 respectively
Summary
Eukaryotic organisms use oxygen (O2) as the final electron acceptor in the mitochondrial electron transport chain, producing water (H2O) and driving the production of the high-energy molecule ATP through oxidative phosphorylation (OXPHOS). Mitochondrial complex I is a major site of superoxide anion production in the mitochondria [1,24] through both forward and reverse reactions (electron transfer from NADH to ubiquinone, or from reduced ubiquinone to NAD+, respectively). The reverse reaction or reverse electron transfer (RET) needs a large pool of reduced ubiquinone which is normally generated from succinate oxidation through mitochondrial complex II, can be inhibited by rotenone and is dependent on high ΔΨmt [25,26]. A decrease in oxygenation (hypoxia) induces a series of acute and long-term cellular, tissue-specific and systemic adaptive responses [29]. Both types of responses have been linked to the production of ROS. We describe that complex I is involved in the ROS burst produced in acute hypoxia, in endothelial cells and in brain tissue, and the mechanism by which complex I may be involved in triggering this response
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