Email: sophie.vaulont@inserm.fr

Team: Iron, oxygen and energy sensing in pathophysiology

Website: http://cochin.inserm.fr

Erythropoiesis and iron metabolism are inextricably linked. The goal of our group is to identify the molecular mechanisms responsible for the regulation of iron metabolism since both iron deficiency and iron excess are deleterious to the body.

Iron supply for erythrocyte precursors comes predominantly from iron recycling of senescent erythrocytes by macrophages and iron absorption from the diet by the duodenal enterocytes. These two iron delivery pathways are tightly regulated by hepcidin, the iron regulatory hormone. Hepcidin is a 25 amino acid peptide hormone synthesized primarily by hepatocytes and released into blood circulation.

Upon reaching its target tissues (enterocytes and macrophages), hepcidin binds to the cell surface iron exporter ferroportin and causes its internalization and degradation, leading to decreased serum iron. Our group has identified the function of hepcidin and has greatly contributed to the characterization of its specific regulation by iron, hypoxia and inflammation. We first showed that, during anemia, hypoxia and increased erythropoiesis, hepcidin repression was required to ensure iron mobilization necessary for increased erythropoiesis and that increased hepcidin levels in the setting of infection and inflammation was contributing to the hypoferremia of these conditions.

 We recently highlighted the role of HIF (Hypoxia Inducible Factors), locally, in the regulation of duodenal iron absorption, and systemically through the regulation of EPO synthesis, a negative regulator of hepcidin synthesis. In addition, we established the pathway of the liver serine protease matriptase 2 (MT2) signaling to down-regulate hepcidin synthesis. Finally, our recent observations have revealed an unexpected role for AMP-activated protein kinase (AMPK), a serine/threonine protein kinase that functions as an intracellular energy sensor, in the clearance of mitochondria during reticulocyte maturation and the maintenance of erythrocyte membrane elasticity. Furthermore, recent evidences suggested that during metabolic shift of cancer cells to aerobic glycolysis (Warburg effect), AMPK activation levels are reduced leading to diminished expression of the iron transporter DMT1.

Our objectives are to (1) better characterize the pathophysiological roles of HIF, AMPK and hepcidin in different key organs involved in maintaining body iron homeostasis (2) identify hepcidin regulatory pathways, in particular to characterize the signal(s) that communicate(s) the level of erythropoiesis to the liver allowing hepcidin repression and to determine whether MT2 is required to convey the erythroid signals (3) develop new hepcidin-based diagnosis and therapeutic approaches (4) demonstrate that HIF and hepcidin are at the crossing points between infection and iron metabolism and (5) decipher the mechanism governing AMPK activation and its role in the selective autophagy of mitochondria during erythropoiesis.

Expertise

 Main Publications