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Figure 1: Main pathway of ROS generation in the cell and sites where it is modified by the thyroid hormones. Continuous lines represent the “normal” energy yielding pathway; dotted lines represent the pathways leading to ROS production. The respiratory chain in the internal mitochondrial membrane receives a pair of electrons coming from the oxidation of metabolic fuels and brought to the site by intermediaries (mainly reduced NAD, NADH). The electrons are transferred through an energetic downhill flux to the final acceptor O2 to yield H2O. The energy extracted from electrons is used to pump protons (H+) to the intermembrane space. The proton gradient that builds up powers the proton flux through the ATP-synthase complex (F1F0) which drives ADP phosphorylation to produce ATP. ATP provides energy for cell reactions where it is broken down to ADP plus phosphate. Unpaired electrons can divert from this pathway in an intermediate step of the respiratory chain and combine with other species, mainly O2, to form the superoxide anion ( ). Further reactions produce highly reactive radicals that combine with and alter structural and functional elements of the mitochondria, thus producing local oxidative damage. The radicals can permeate outside the mitochondrion and cause cell oxidative damage. Both mitochondrial and cytosolic antioxidant systems scavenge and neutralize radicals and destroy or repair damaged elements. The shaded area in the left includes the processes promoting ROS formation. These favor electron diversion by “pushing” electrons through the respiratory chain (i.e., state 4). The processes in the right reduce the diversion of electrons by “pulling” them from the end side of the pathway (i.e., state 3), thus reducing ROS formation. Thyroid hormones (THs) stimulate both ROS-producing and ROS-reducing processes (from left to right): they favor a reductive state by promoting the oxidation of fuels to produce NADH and extramitochondrial ATP (with depletion of ADP). They also stimulate the synthesis of elements of the respiratory chain, which enhances the reductive state. On the other hand, THs act as radical scavengers and promote the expression of antioxidant enzymes, thus decreasing the oxidative damage. The general metabolic activation caused by THs increases the ATP breakdown and raises ADP availability. Finally, the dissipation of the proton-motive force by means of the uncoupling proteins (UCP) decreases the electron diversion and the formation of ROS. UCP genes are targets of the THs.