Team: Iron, oxygen and energy sensing in pathophysiology
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.
- Generation of transgenic mouse models
- Cellular biology (primary culture of hepatocytes, macrophages, adipocytes and muscle cells and immortalized cell lines)
- Molecular biology and physiology
- Generation and in vivo injection of recombinant adenovirus
- Models of infection and inflammation
- Deletion of HIF-2a in the enterocytes decreases the severity of tissue iron loading in hepcidin knockout mice. Mastrogiannaki M, Matak P, Delga S, Deschemin JC, Vaulont S, Peyssonnaux C. Blood. 2012 Jan 12;119(2):587-90.
- Iron-deficiency anemia from matriptase-2 inactivation is dependent on the presence of functional Bmp6. Lenoir A, Deschemin JC, Kautz L, Ramsay AJ, Roth MP, Lopez-Otin C, Vaulont S, Nicolas G. Blood. 2011 Jan 13;117(2):647-50.
- The AMPKg1 subunit plays an essential role in erythrocyte membrane elasticity, and its genetic inactivation induces splenomegaly and anemia. Foretz M, Hébrard S, Guihard S, Leclerc J, Do Cruzeiro M, Hamard G, Niedergang F, Gaudry M, Viollet B. FASEB J. 2011 Jan;25(1):337-47.
- Maintenance of red blood cell integrity by AMP-activated protein kinase alpha1 catalytic subunit. Foretz M, Guihard S, Leclerc J, Fauveau V, Couty JP, Andris F, Gaudry M, Andreelli F, Vaulont S, Viollet B. FEBS Lett. 2010 Aug 20;584(16):3667-71.
- HIF-2alpha, but not HIF-1alpha, promotes iron absorption in mice. Mastrogiannaki M, Matak P, Keith B, Simon MC, Vaulont S, Peyssonnaux C. J Clin Invest. 2009 May;119(5):1159-66.
- Regulation of iron homeostasis by the hypoxia-inducible transcription factors (HIFs). Peyssonnaux C, Zinkernagel AS, Schuepbach RA, Rankin E, Vaulont S, Haase VH, Nizet V, Johnson RS. J Clin Invest. 2007 Jul;117(7):1926-32.
- Targeted disruption of the hepcidin 1 gene results in severe hemochromatosis. Lesbordes-Brion JC, Viatte L, Bennoun M, Lou DQ, Ramey G, Houbron C, Hamard G, Kahn A, Vaulont S. Blood. 2006 Aug 15;108(4):1402-5.
- Severe iron deficiency anemia in transgenic mice expressing liver hepcidin. Nicolas G, Bennoun M, Porteu A, Mativet S, Beaumont C, Grandchamp B, Sirito M, Sawadogo M, Kahn A, Vaulont S. Proc Natl Acad Sci U S A. 2002 Apr 2;99(7):4596-601.
- Constitutive hepcidin expression prevents iron overload in a mouse model of hemochromatosis. Nicolas G, Viatte L, Lou DQ, Bennoun M, Beaumont C, Kahn A, Andrews NC, Vaulont S. Nat Genet. 2003 May;34(1):97-101.
- The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation. Nicolas G, Chauvet C, Viatte L, Danan JL, Bigard X, Devaux I, Beaumont C, Kahn A, Vaulont S. J Clin Invest. 2002 Oct;110(7):1037-44.