Consequences of iron regulatory protein regulation during hypoxia

Iron is an essential element that is required for survival of all living organisms. Although all organisms require iron, excess iron can be toxic through its ability to catalyze the production of reactive oxygen species (ROS) via Fenton chemistry.{09}Thus, the control of intracellular free iron levels plays a significant role in ROS production. Iron homeostasis is maintained by the iron regulatory proteins (IRP1 and IRP2). The IRPs control intracellular free iron levels by regulating the synthesis of the transferrin receptor (TfR), a protein involved in iron uptake, and ferritin (Ft), an iron storage protein.; Given the relationship between iron and oxygen in the production of ROS and the regulation of iron homeostasis by the IRP system, it has been shown that the IRPs are differentially regulated by hypoxia, a physiologically relevant condition of low oxygen involved in many human diseases. This thesis describes the research to determine the cellular consequences of IRP regulation and elucidate the role of each IRP in the maintenance of iron homeostasis during hypoxia in mammalian cells.; The data show that hypoxia causes the differential regulation of IRPs, which is reversible upon reoxygenation (ReO₂), in both tumorigenic and primary cell culture models. Ft expression is also regulated during both hypoxia and ReO₂ with no change in TfR protein. Hypoxia causes a transient increase in Ft synthesis, which may be independent of the IRP system in primary cells. Interestingly, Ft protein accumulates during hypoxia in primary cells, while decreasing in tumorigenic cells. These data suggest that Ft expression may influence susceptibility to cell damage during hypoxia and ReO₂.{09}This work furthers our understanding of how cells regulate Ft synthesis and maintain iron homeostasis during a pathophysiological condition that has implications for the treatment of human diseases where iron is involved.