Abstract
BackgroundPreviously, we reported that the “antioxidant” compound “mitoQ” (mitochondrial-targeted ubiquinol/ubiquinone) actually increased superoxide production by bovine aortic endothelial (BAE) cell mitochondria incubated with complex I but not complex II substrates.Methods and ResultsTo further define the site of action of the targeted coenzyme Q compound, we extended these studies to include different substrate and inhibitor conditions. In addition, we assessed the effects of mitoquinone on mitochondrial respiration, measured respiration and mitochondrial membrane potential in intact cells, and tested the intriguing hypothesis that mitoquinone might impart fuel selectivity in intact BAE cells. In mitochondria respiring on differing concentrations of complex I substrates, mitoquinone and rotenone had interactive effects on ROS consistent with redox cycling at multiple sites within complex I. Mitoquinone increased respiration in isolated mitochondria respiring on complex I but not complex II substrates. Mitoquinone also increased oxygen consumption by intact BAE cells. Moreover, when added to intact cells at 50 to 1000 nM, mitoquinone increased glucose oxidation and reduced fat oxidation, at doses that did not alter membrane potential or induce cell toxicity. Although high dose mitoquinone reduced mitochondrial membrane potential, the positively charged mitochondrial-targeted cation, decyltriphenylphosphonium (mitoquinone without the coenzyme Q moiety), decreased membrane potential more than mitoquinone, but did not alter fuel selectivity. Therefore, non-specific effects of the positive charge were not responsible and the quinone moiety is required for altered nutrient selectivity.ConclusionsIn summary, the interactive effects of mitoquinone and rotenone are consistent with redox cycling at more than one site within complex I. In addition, mitoquinone has substrate dependent effects on mitochondrial respiration, increases repiration by intact cells, and alters fuel selectivity favoring glucose over fatty acid oxidation at the intact cell level.
Highlights
Mitochondria are likely the predominant source of reactive oxygen species (ROS) in many cell types [1,2,3,4]
In past studies of bovine aortic endothelial (BAE) cell mitochondria, we demonstrated that a mitochondrial targeted CoQ compound termed ‘‘mitoQ’’ markedly increased or decreased reactive oxygen species (ROS) generation depending on substrate provided for fuel [20]
As we previously showed by inhibitor analysis and by comparison to complex III superoxide detected by electron paramagnetic resonance spectroscopy (EPR) [20], and as shown by others [32], H2O2 detected in this way largely derives from superoxide released by complex I
Summary
Mitochondria are likely the predominant source of reactive oxygen species (ROS) in many cell types [1,2,3,4]. This is underscored by recent evidence that mitochondrial oxidative damage may underlie problems including cell damage in degenerative diseases and aging [5,6,7], vascular disease, and complications of diabetes [8,9,10,11,12,13,14,15,16]. We reported that the ‘‘antioxidant’’ compound ‘‘mitoQ’’ (mitochondrial-targeted ubiquinol/ ubiquinone) increased superoxide production by bovine aortic endothelial (BAE) cell mitochondria incubated with complex I but not complex II substrates
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