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A novel model for brain iron uptake: introducing the concept of regulation.

ABSTRACT: Neurologic disorders such as Alzheimer's, Parkinson's disease, and Restless Legs Syndrome involve a loss of brain iron homeostasis. Moreover, iron deficiency is the most prevalent nutritional concern worldwide with many associated cognitive and neural ramifications. Therefore, understanding the mechanisms by which iron enters the brain and how those processes are regulated addresses significant global health issues. The existing paradigm assumes that the endothelial cells (ECs) forming the blood-brain barrier (BBB) serve as a simple conduit for transport of transferrin-bound iron. This concept is a significant oversimplification, at minimum failing to account for the iron needs of the ECs. Using an in vivo model of brain iron deficiency, the Belgrade rat, we show the distribution of transferrin receptors in brain microvasculature is altered in luminal, intracellular, and abluminal membranes dependent on brain iron status. We used a cell culture model of the BBB to show the presence of factors that influence iron release in non-human primate cerebrospinal fluid and conditioned media from astrocytes; specifically apo-transferrin and hepcidin were found to increase and decrease iron release, respectively. These data have been integrated into an interactive model where BBB ECs are central in the regulation of cerebral iron metabolism.

SUBMITTER: Simpson IA

PROVIDER: S-EPMC4294394 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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A novel model for brain iron uptake: introducing the concept of regulation.

Simpson Ian A IA Ponnuru Padmavathi P Klinger Marianne E ME Myers Roland L RL Devraj Kavi K Coe Christopher L CL Lubach Gabriele R GR Carruthers Anthony A Connor James R JR

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 20141015 1

Neurologic disorders such as Alzheimer's, Parkinson's disease, and Restless Legs Syndrome involve a loss of brain iron homeostasis. Moreover, iron deficiency is the most prevalent nutritional concern worldwide with many associated cognitive and neural ramifications. Therefore, understanding the mechanisms by which iron enters the brain and how those processes are regulated addresses significant global health issues. The existing paradigm assumes that the endothelial cells (ECs) forming the blood ...[more]

PMID: 25315861

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Project description:Iron is one of most abundant environmental metal ions but is highly limited in organisms. It is an important metal ion as it facilitates various biological processes, including catalysis of metabolic enzymes and DNA biogenesis. In bacteria, the ferric uptake regulator (Fur) protein controls iron uptake by regulating genes coding for iron transporters in response to iron concentration. This iron response is ascribed to Fur's intrinsic affinity for iron because its binding to iron dictates its regulatory function. However, we now report that the pathogen Salmonella achieves a proper response of Fur to changes in environmental iron concentrations via EIIANtr (a nitrogen metabolic phosphotransferase system component). We establish that EIIANtr increases expression of iron transporter-coding genes under low-iron conditions (i.e., nanomolar ranges) in a Fur-dependent manner, which promotes Salmonella growth under such conditions. EIIANtr directly hampers Fur binding to DNA, thereby inducing expression of those genes. This regulation allows Salmonella to express Fur-regulated genes under low-iron conditions. Our findings reveal a potentially widespread control mechanism of bacterial iron uptake systems operating in response to iron availability.IMPORTANCE Iron is a fundamental metal ion for living organisms as it facilitates various biological processes. The ferric uptake regulator (Fur) protein controls iron homeostasis in various bacterial species. It is believed that Fur's iron-dependent regulatory action is sufficient for it to function as an iron sensor. However, we now establish that the bacterial pathogen Salmonella enables Fur to properly reflect changes in surrounding iron availability by fine-tuning its responsiveness to iron. This process requires a protein that hampers Fur DNA binding at low iron concentrations. In this way, Salmonella broadens the range of iron concentrations that Fur responds to. Our findings reveal a potentially widespread control mechanism of bacterial iron homeostasis.

Project description:The MerR family of transcriptional regulators are dimeric proteins with an N-terminal helix-turn-helix DNA binding domain (DBD), followed by an antiparallel coiled-coil subunit interaction region, and usually by a C-terminal effector binding domain (EBD). This family is distinguished by the high amino acid similarity in the DBD and low similarity in the EBD, consistent with the role of this domain in each protein in sensing effector molecules. Most members of the family are activators, and act at promoters with long spacer regions and respond to the binding of inducers by distorting the promoter DNA to allow open complex formation and transcriptional activation. In MerR proteins the EBD contains a metal binding pocket formed by three cysteines. This Cys center characteristic of MerR regulators is primarily suited for metal binding and mediates activation of metal detoxification systems in bacteria. Over the last decade, it has become clear that the MerR family of regulators is more diverse than originally recognized. The availability of completed bacterial genome sequences has enabled the search for additional types of MerR-like regulators. We here present a novel MerR-like transcription factor lacking an EBD involved in iron uptake regulation (MliR) present in the marine bacterium Bizionia argentinensis (JUB59). An in silico analysis revealed that homologues of the MliR protein are widely distributed among different bacterial species. Deletion of the mliR gene led to decreased cell growth, increased cell adhesion and filamentation. RNA sequencing analysis showed that expression of several iron uptake-related mRNAs were downregulated in mliR-deletion mutant. Through NMR-based metabolomics, ICP-MS, fluorescence microscopy and biochemical analysis we evaluated metabolic and phenotypic changes associated with mliR deletion. This work provides the first evidence of a MerR-family regulator involved in iron uptake and contributes to expanding our current knowledge on iron metabolism.in bacteria.

Dataset Information

A novel model for brain iron uptake: introducing the concept of regulation.

Publications

A novel model for brain iron uptake: introducing the concept of regulation.

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