The role of thyroid hormones as inductors of oxidative stress and neurodegeneration

Abstract

Reactive oxygen species (ROS) are oxidizing agents amply implicated in tissue damage. ROS production is inevitably linked to ATP synthesis in most cells, and the rate of production is related to the rate of cell respiration. Multiple antioxidant mechanisms limit ROS dispersion and interaction with cell components, but, when the balance between ROS production and scavenging is lost, oxidative damage develops. Many traits of aging are related to oxidative damage by ROS, including neurodegenerative diseases. Thyroid hormones (THs) are a major factor controlling metabolic and respiratory rates in virtually all cell types in mammals. The general metabolic effect of THs is a relative acceleration of the basal metabolism that includes an increase of the rate of both catabolic and anabolic reactions. THs are related to oxidative stress not only by their stimulation of metabolism but also by their effects on antioxidant mechanisms. Thyroid dysfunction increases with age, so changes in THs levels in the elderly could be a factor affecting the development of neurodegenerative diseases. However, the relationship is not always clear. In this review, we analyze the participation of thyroid hormones on ROS production and oxidative stress, and the way the changes in thyroid status in aging are involved in neurodegenerative diseases.

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 (O₂ ^∙−). 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.