Study to investigate how dietary iron is used by cells

A four-year study on iron metabolism within cells, an essential process that impacts both iron deficiency and iron toxicity, conditions responsible for a multitude of human diseases, is underway at the University at Buffalo funded by a $1.16 million grant from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).

Daniel Kosman, Ph.D., professor of biochemistry in the UB School of Medicine and Biomedical Sciences, is lead researcher on the study.

"The concern about how iron is managed in our cells has never been more acute," said Kosman. "The reasons for this are three-fold. First is the endemic problem of iron deficiency that the World Health Organization estimates afflicts 80 percent of the world's population, or more than 5 billion people.

"Iron deficiency is not confined to developing nations. In the U.S., 5 percent of newborns and 7 percent of new mothers have clinical symptoms of iron deficiency. Reducing the incidence of this nutritional deficit is one of the objectives of the U.S. Department of Health and Human Services' Healthy People 2010 program.

"Second is the broad recognition that the 'corrosive chemistry' associated with iron and oxygen interactions is a major factor in a multitude of human diseases."

Too much iron in tissues, called iron-loading, is thought to increase the risk of tumor development, infection, cardiomyopathy, joint disorders and several endocrine and neurodegenerative disorders.

"And third, we now have an increasingly sophisticated knowledge and understanding of iron metabolic pathways, the proteins involved in these pathways and how these pathways are regulated in all organisms, making this issue ripe for investigation," he said.

Kosman proposes that a general mechanism of cellular iron metabolism requires that iron-handling proteins involved in sequential steps in the pathway must be "architecturally arranged" contiguously in the cell's membranes, at the interfaces between membranes and soluble compartments or within soluble compartments.

The researchers will test this form-function model of ionic iron metabolism by focusing on three steps critical to maintaining the proper balance of iron in cells: 1) the reduction of ferric to ferrous iron and the subsequent transport of ferrous iron into a cell; 2) the "hand-off" of this ferrous iron from a membrane protein to iron chaperones in the cell's cytoplasm; and 3) the utilization of this ionic iron for the activation of essential iron-containing enzymes.

"These three components of cellular iron metabolism are relatively under-investigated," said Kosman, "yet they represent the essence of cell iron metabolism in all organisms."

Understanding the intermediary metabolism of iron is one of the primary objectives of a program announcement from NIH titled "Metals In Medicine," he noted. This announcement encourages studies that lead to the "identification and characterization of the macromolecular players and vesicular compartments involved in metal ion homeostasis and metal trafficking."

Arvinder Singh, Ph.D., a post-doctoral research associate in Kosman's lab; and William E. Wiltsie, a doctoral candidate in biochemistry, also will be involved in the research.

The University at Buffalo is a premier research-intensive public university, the largest and most comprehensive campus in the State University of New York. The School of Medicine and Biomedical Sciences is one of five schools that constitute UB's Academic Health Center. UB's more than 27,000 students pursue their academic interests through more than 300 undergraduate, graduate and professional degree programs.