Iron Requirement in Hypoxic Conditions

While highlanders in the Andes and Himalayas are well adapted to live at high altitude, adequate acclimatization time to slowly adjust to hypoxic conditions is among the most important aspects for ascending mountaineers. Accordingly, most reports emphasize on mechanisms that cope with reduced oxygenation. Notably, during a journey to high altitude coverage of the elevated iron demand is equally critical. Thus, it's crucial to focus on the crosstalk between oxygen and iron homeostasis. I will discuss the role of iron in the oxygen sensing process and erythropoietin (Epo) synthesis as well as in gene expression control mediated by the hypoxia-inducible factor-2 (HIF-2). The blood hormone Epo that is abundantly expressed by the kidney under hypoxic conditions stimulates erythropoiesis in the bone marrow, a process that requires high quantities of iron. To ensure that sufficient iron is provided, hypoxia-induced soluble factors - such as the novel Epo-controlled erythroferrone that is expressed in erythroid precursor cells - reach the liver where they reduce expression of the iron hormone hepcidin. In turn, suppression of hepcidin allows both, elevated iron release from storage organs and enhanced absorption of dietary iron by enterocytes. As recently observed in sojourners at high altitude, however, iron uptake may be hampered by reduced appetite and gastrointestinal bleeding. Overall, adequate systemic iron availability is an important prerequisite to adjust not only to high-altitude induced hypoxia but to treat disease-related hypoxic conditions.