Reactive oxygen-mediated protein oxidation in aging and disease

Endogenous proteins are highly susceptible to modification by ROS produced as byproducts of normal metabolic processes, or upon exposure to oxidative stress and atmospheric pollutants. The ROS-mediated modification of proteins may lead to loss of biological function and to conversion of the proteins to forms that are rapidly degraded by endogenous proteases, especially by the multicatalytic protease. One of many different kinds of protein modification elicited by ROS is the oxidation of some amino acid side chains to carbonyl derivatives. The carbonyl content of protein is therefore a convenient marker of ROS-mediated protein damage. By means of highly sensitive methods for the detection and quantitation of protein carbonyl groups, it has been established in several different animal models that there is an exponential increase in the level of oxidized protein during aging and that elevated levels of oxidized proteins are associated with a number of diseases, including Alzheimer's disease, amyotrophic lateral sclerosis, rheumatoid arthritis, diabetes, muscular dystrophy, and cataractogenesis, to name a few. Although protein oxidation probably contributes to the biological dysfunction associated with these diseases, a causal relationship between protein oxidation and the etiology or progression of a disease has not been established. Nevertheless, in the case of some neurological disorders, there is a positive correlation between the loss of a particular biological function and an elevation of the level of oxidized protein in the brain (153) and in specific regions of the brain that control that function (154). Finally, because oxidized proteins are readily degraded by endogenous proteases, the steady state intracellular level of oxidized proteins is a complex function of a multiplicity of factors that govern the generation of ROS, the antioxidant systems that scavenge ROS, the susceptibility of proteins to oxidative modification, and the activities of the proteases that degrade oxidized proteins. Accordingly, the accumulation of oxidized protein that occurs during aging and in various diseases is likely attributable to the accumulated genetic damage (ROS-mediated mutations?) that affects one or more of the numerous factors that determine the balance between protein oxidation on the one hand and the degradation of oxidized proteins on the other.