Pumping Iron, Handling Heme: Forging New Links in Health and Disease

The major portion of iron in the body is found in hemoglobin, reflecting the intimate connection between iron metabolism and heme synthesis. Beyond the traditional area of erythropoiesis, proper pumping of iron and handling of heme is essential for a variety of biological processes such as mitochondrial respiration, cell proliferation, and DNA synthesis and repair. This session will present new insights into iron homeostasis and heme utilization pathways as well as demonstrate the importance of iron restriction for infection control.

Dr. Emanuela Tolosano will explain heme's pivotal role in cell energy metabolism, including its role as a cofactor for respiratory chain complexes and interactions with translocases responsible for the ADP/ATP exchange between mitochondria and cytosol. She will describe heme biosynthesis and the mechanisms of heme trafficking at the cellular level. In addition, Dr. Tolosano will highlight data demonstrating the existence of a heme biosynthesis/heme export axis that contributes to the regulation of the tricarboxylic acid (TCA) cycle as well as oxidative metabolism and discuss the implications for cell proliferation and survival. Finally, she will emphasize that heme synthesis is a major cellular iron-consuming process, competing for iron with the mitochondrial assembly of iron-sulfur clusters, which are crucial cofactors for electron transport chain complexes and some TCA cycle enzymes.

Dr. Jodie Babitt will discuss how the liver orchestrates systemic iron homeostasis by producing the iron hormone hepcidin, which regulates expression and function of the iron exporter ferroportin to control iron entry into circulation from the gut, iron recycling macrophages, and hepatocyte stores. Hepcidin production in the liver is regulated by a number of systemic cues that indicate the need for more or less iron, including serum and tissue iron levels, iron demand of erythropoietic cells, and inflammation. A pivotal pathway by which the liver regulates hepcidin transcription in response to these diverse signals is the bone morphogenetic protein (BMP)-Smad signaling pathway. This talk will focus on recent insights into how BMP-Smad signaling coordinates hepcidin production to control systemic iron homeostasis.

Dr. Tracey Rouault will address novel insights into molecular mechanisms of iron handling and illustrate the important link between iron homeostasis and infection control. Her research determined that mature red blood cells contain large amounts of the iron exporter, ferroportin, and she believes that this iron exporter transfers iron released from oxidation of heme to protect the red blood cells from iron-related oxidative damage. There is a mutation in ferroportin, Q248H, which leads to increased ferroportin mediated iron export relative to controls. It appears to confer a selective advantage in malaria endemic areas because low levels of free iron in red blood cells protects from malaria by preventing the parasites from acquiring enough iron to grow and divide.