Regulatory mechanisms of iron metabolism and their biological impact

Iron is a critical micronutrient required for nearly all organisms to live. It is an important cofactor in proteins involved in DNA replication, cellular energy production, and oxygen transport. Nonphysiological levels of iron have pathological consequences ranging from iron deficiency that affects billions worldwide, to the iron overload disorder Hereditary Hemochromatosis that causes debilitating organ failure. Considering the dual nature of iron in healthy and diseased states, organisms have evolved elegant mechanisms to regulate iron homeostasis. This thesis examines the cellular mechanisms involved in controlling cellular iron uptake and storage, and highlights the importance of iron in the innate immune response and endocrine function of the mammalian pancreas. Using C. elegans as a model to study iron metabolism, we show that the nuclear receptor, NHR-14, is a potent repressor of intestinal iron uptake through the iron importer SMF-3. In addition to iron import, NHR-14 regulates a transcriptional response to bacterial infection that is dependent upon the insulin/IGF-1-like signaling (IIS) pathway transcription factor PQM-1. In mammals, cellular iron is maintained by the Iron Regulatory Proteins (IRPs). Mice lacking Iron Regulatory Protein 2 (IRP2) were shown to develop fasting hyperglycemia as a result of defective insulin biosynthesis that likely stems from mitochondrial dysfunction and Endoplasmic Reticulum (ER) stress.