The trace metals copper (Cu) and iron (Fe) are nutrients that are essential to life, serving as catalytic cofactors in a wide variety of enzymatic reactions involved in blood clotting, energy generation, DMA replication, peptide hormone maturation, oxygen transport and a variety of other essential processes. Defects in Cu or Fe balance cause severe human diseases that include Menkes and Wilson diseases, hemochromatosis, anemia and others, and are implicated in Alzheimer's, Parkinson's and prion diseases and in cancer and aging. The essentiality of both Cu and Fe, and the functional interactions of these two metals require that organisms possess fine-tuned homestatic mechanisms to ensure that sufficient levels of Cu and Fe are acquired, distributed and utilized to drive biochemical reactions. Furthermore, cells must respond to changes that limit Cu or Fe availability to mobilize stores of these metals, or to reprogram cellular metabolism to cope with metal limitation. This proposal describes avenues of investigation, using yeast as a model system, to understand fundamental mechanisms whereby eukaryotic cells regulate Cu and Fe availability. In the first specific aim experiments are outlined to understand the physiological role, regulation and mechanism by which the yeast Ctr2 protein mobilizes intracellular Cu stores under conditions of Cu deprivation. The second specific aim outlines experiments to understand the function, mechanism of action and role of the Cth2 protein in targeting specific mRNA molecules for degradation under conditions of Cu or Fe deficiency, as a means of prioritizing Fe utilization. Given the importance of proper homeostatic control of Cu and Fe in human health, and the presence of potential functional orthologues of both Ctr2 and Cth2 in humans, the studies described in this proposal will provide fundamentally important information on the mechanisms whereby cells maintain Cu and Fe homeostasis in health and disease. ? ?
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