Grant: Project Grant

Iron is an essential metal for life. However, it is also very reactive and just as it can rust in your car, it can also be oxidized in the cell, causing chain reactions that damage cells, tissues, and cause disease. In fact there are many diseases where iron handling in the body is disrupted, sometimes with too little iron and sometimes with too much. Therefore it is essential that we understand how elemental iron is released from its protective carrier within the bloodstream to move deep into the cells to it's final destination. That destination is the mitochondria, most famous as the "energy powerhouse of the cell". However, a second essential function of mitochondria is to act as an "iron forge" in assembling elemental iron into a more stable complex called an iron-sulfur cluster. This cluster is used as a type of co-factor in assembling numerous essential proteins both inside mitochondria and throughout the cell. Even in some single cell organisms whose mitochondria do not make energy, the only function remaining is the assembly of iron sulfur clusters. This proposal stems from some unexpected data we obtained that identifies a new kind of circuitry that tightly regulates how and when iron may leave the membrane bound endosome that carries it into the cell, and be delivered directly to mitochondria through sites of direct contact. The circuitry mechanisms we have identified so far have led us to a number of testable ideas that make up the bulk of this proposal. However, we will also immediately survey how this new circuitry may be altered in different models of iron-related diseases, from Freidrich's ataxia to anemia, Parkinsons' disease and others. We hope our work may identify new ways of treating these diseases if we can "trick" the cells to stop taking in iron, or the reverse, opening the possibility for targeted therapies for these devastating diseases.