Cataract is a significant health and economic problem worldwide. Oxidative damage has been implicated as a major causative factor in cataract formation. While iron (Fe) catalyzed free radical reactions are responsible for virtually all oxidative tissue damage, little information is available concerning Fe metabolism, storage and utilization in the lens. Storage of Fe in a non-reactive form in ferritin, prevents oxidative damage. Ferritin is made by the lens and a mutation resulting in dysregulation of the synthesis of ferritin subunits results in early bilateral cataracts in humans. The overlying Hypothesis of this proposal is that the uptake of Fe by lens epithelial cells and its movement between a cytoplasmic pool and sites of storage and utilization are carefully controlled under normal physiological conditions. Factors which increase the concentration of Fe in a low molecular weight cytoplasmic pool cause increased susceptibility to oxidative stress and UV irradiation, while a decrease in the size of this pool is protective. The first specific aim of this proposal is to determine how intracellular Fe dynamics, including Fe uptake and efflux, synthesis and concentration of ferritin, storage of Fe in ferritin and the amount of Fe in a low molecular weight cytoplasmic pool are altered by environmental factors and changes in ferritin subunit composition. The second specific aim is to determine whether disturbances in normal Fe distribution within lens epithelial cells result in altered cellular metabolism and affect their ability to withstand oxidative stress or UV irradiation. The results of these studies will provide information essential to our understanding of the metabolism and safe storage of Fe, the central component of damaging oxidative reactions. Such information could lead to the development of effective therapeutic interventions for the delay or prevention of cataract progression.
