Role of HIF-1 in iron regulation: potential therapeutic strategy for neurodegenerative disorders.
A disruption in optimal iron levels within different brain regions has been demonstrated in several neurodegenerative disorders. Although iron is an essential element that is required for many processes in the human body, an excess can lead to the generation of free radicals that can damage cells. Iron levels are therefore stringently regulated within cells by a host of regulatory proteins that keep iron levels in check. The iron regulatory proteins (IRPs) have the ability to sense and control the level of intracellular iron by binding to iron responsive elements (IREs) of several genes encoding key proteins such as the transferrin receptor (TfR) and ferritin. Concurrently, the hypoxia-inducible factor (HIF) has also been shown in previous studies to regulate intracellular iron by binding to HIF-responsive elements (HREs) that are located within the genes of iron-related proteins such as TfR and heme oxygenase-1 (HO-1). This review will focus on the interactions between the IRP/IRE and HIF/HRE systems and how cells utilize these intricate networks to regulate intracellular iron levels. Additionally, since iron chelation has been suggested to be a therapeutic treatment for disorders such as Parkinson's and Alzheimer's disease, understanding the exact mechanisms by which iron acts to cause disease and how the brain would be impacted by iron chelation could potentially give us novel insights into new therapies directed towards preventing or slowing neuronal cell loss associated with these disorders.
Lee
Donna W
DW
Buck Institute for Age Research, 8001 Redwood Blvd., Novato, CA 94945, USA.
Andersen
Julie K
JK
D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005786:Gene Expression Regulation; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007501:Iron / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000494:pharmacology; D035925:Iron-Regulatory Proteins / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000188:drug therapy* / Q000209:etiology*; D011393:Procollagen-Proline Dioxygenase / Q000037:antagonists & inhibitors*; D020218:Response Elements / Q000187:drug effects
D004791:Enzyme Inhibitors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007502:Iron Chelating Agents; D035925:Iron-Regulatory Proteins; D007501:Iron; D011393:Procollagen-Proline Dioxygenase