Production of ROS by the mitochondrial electron transport chain. In cultured endothelial cells the electron donors NADH and FADH2 are generated by the oxidation of glucose-derived pyruvate. The flow of the donated electrons (eā) through the electron-transport chain in the inner mitochondrial membrane pumps H+ ions into the intermembrane space. When the voltage gradient is high due to increased flux of electron donors, more superoxide is generated. H+ ions can pass back across the inner membrane along their concentration gradient, either via ATP synthase (to produce ATP) or via uncoupling proteins (UCP), which dissipate the energy of the proton gradient as heat. ADP, adenosine diphosphate; Cyt c, cytochrome c; FAD, flavin adenine dinucleotide; NAD, nicotinamide adenine dinucleotide (Adapted From Brownlee [4]).