A main goal of my research is to better understand the molecular details of iron metabolism. Disturbances of iron metabolism increase morbidity and mortality and are among the most common disorders affecting humans. The three main iron-related disorders are iron deficiency, the anemia of chronic disease, and iron overload. Iron deficiency adversely affects cognitive performance, behavior, physical growth of infants, immune status, physical capacity and work performance. In the US, iron deficiency affects mainly women of reproductive age; an estimated 12% of females 12-49 years of age are iron deficient. The prevalence in college-aged women is 16%, and Mexican American women are most affected (22%). Iron deficiency is also common in the elderly, with an estimated 500,000 persons 65 years and older having iron-deficiency anemia. The elderly are particularly affected by a second form of anemia known as the anemia of inflammation or chronic disease (ACD). More than 500,000 persons 65 years and older have ACD. Anemia in the elderly has been associated with a higher incidence of cardiovascular disease, cognitive impairment, diminished physical function, elevated risks for fractures and falls, and increased mortality. ACD is also the most common form of anemia in hospitalized patients, irrespective of age. Iron overload is increasingly being recognized as a public health issue in the US. The most common form of iron overload, hereditary hemochromatosis, results mainly from a genetic mutation present in approximately 1:200 individuals of Northern European descent, making hemochromatosis the single most frequent genetic disorder in whites. Hemochromatosis markedly increases the risk for hepatic fibrosis, cirrhosis, liver cancer, cardiovascular disease and diabetes.
Despite the prevalence and adverse health effects associated with these disorders, many questions remain regarding the molecular mechanisms of iron transport. One question that my laboratory has been interested in is: How do cells export iron? The export of iron from cells is a central question in iron biology. For example, in order for dietary iron to be absorbed from the small intestine, the iron must first be imported into an intestinal cell, and then exported out of the cell into the bloodstream. We know which protein imports iron, but the export step is much less clear. Recently, a protein called “ferroportin” has been shown to serve this iron-export role in the intestine. Ferroportin is also abundantly expressed in macrophages, cells of the immune system that play a key role in iron metabolism by exporting iron recycled from old red blood cells. Indeed, iron recycling by macrophages is the largest iron transport pathway in the body (nearly 20 times more iron is recycled per day than is absorbed by the intestine). My laboratory was the first to show that ferroportin exported iron from the macrophage. Importantly, we also showed that ferroportin is negatively regulated by hepcidin, the recently discovered iron-regulatory hormone. Produced by the liver in response to inflammation, hepcidin binds to macrophage ferroportin and causes its degradation thereby reducing iron export from these cells. As a result, iron is withheld in the macrophage, causing serum iron levels to drop. Over time, low serum levels lead to anemia. These are the molecular events responsible for the anemia of inflammation. By understanding this basic mechanism, we will be better able to develop therapies designed to correct the this common form of anemia. Interactions between ferroportin and hepcidin are relevant to our understanding of iron deficiency and iron overload as well.
Contact: Mitchell Knutson, PhD - firstname.lastname@example.org