title: Na+/H+Exchanger 9 Regulates Iron Mobilization at the Blood-Brain Barrier in Response to Iron Starvation.
abstract: Iron is essential for brain function, with loss of iron homeostasis in the brain linked to neurological diseases ranging from rare syndromes to more common disorders, such as Parkinson's and Alzheimer's diseases. Iron entry into the brain is regulated by the blood-brain barrier (BBB). Molecular mechanisms regulating this transport are poorly understood. Using anin vitromodel of the BBB, we identify NHE9, an endosomal cation/proton exchanger, as a novel regulator of this system. Human brain microvascular endothelial cells (hBMVECs) that constitute the BBB receive brain iron status information via paracrine signals from ensheathing astrocytes. In hBMVECs, we show that NHE9 expression is up-regulated very early in a physiological response invoked by paracrine signals from iron-starved astrocytes. Ectopic expression of NHE9 in hBMVECs without external cues induced up-regulation of the transferrin receptor (TfR) and down-regulation of ferritin, leading to an increase in iron uptake. Mechanistically, we demonstrate that NHE9 localizes to recycling endosomes in hBMVECs where it raises the endosomal pH. The ensuing alkalization of the endosomal lumen increased translocation of TfRs to the hBMVEC membrane. TfRs on the membrane were previously shown to facilitate both recycling-dependent and -independent iron uptake. We propose that NHE9 regulates TfR-dependent, recycling-independent iron uptake in hBMVECs by fine-tuning the endosomal pH in response to paracrine signals and is therefore an important regulator in iron mobilization pathway at the BBB.
authors.affiliation: From the Department of Natural Sciences, University of Michigan-Dearborn, Dearborn, Michigan 48128.
authors.forename: Rami
authors.initials: R
authors.lastname: Beydoun
authors.affiliation: From the Department of Natural Sciences, University of Michigan-Dearborn, Dearborn, Michigan 48128.
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Hamood
authors.affiliation: From the Department of Natural Sciences, University of Michigan-Dearborn, Dearborn, Michigan 48128.
authors.forename: Daniela M
authors.initials: DM
authors.lastname: Gomez Zubieta
authors.affiliation: From the Department of Natural Sciences, University of Michigan-Dearborn, Dearborn, Michigan 48128 kondap@umich.edu.
authors.forename: Kalyan C
authors.initials: KC
authors.lastname: Kondapalli
mesh_terms: D000328:Adult; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D002478:Cells, Cultured; D011992:Endosomes / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism*; D006801:Humans; D007501:Iron / Q000378:metabolism*; D018384:Oxidative Stress; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism*
chemical_list: C478541:SLC9A9 protein, human; D017923:Sodium-Hydrogen Exchangers; D007501:Iron
keywords: NHE9; SLC9A9; blood-brain barrier; endosome; endothelial cell; iron metabolism; neurological disease; pH; sodium-proton exchange; transferrin