Iron is necessary for life, but can also cause cell death. Accordingly, cells evolved a robust, tightly regulated suite of genes for maintaining iron homeostasis. Previous mechanistic studies on iron homeostasis have granted insight into the role of iron in human health and disease. We highlight new regulators of iron metabolism, including iron-trafficking proteins [solute carrier family 39, SLC39, also known as ZRT/IRT-like protein, ZIP; and poly-(rC)-binding protein, PCBP] and a cargo receptor (NCOA4) that is crucial for release of ferritin-bound iron. We also discuss emerging roles of iron in apoptosis and a novel iron-dependent cell death pathway termed ‘ferroptosis’, the dysregulation of iron metabolism in human pathologies, and the use of iron chelators in cancer therapy.
Iron is an essential nutrient for life. During infection, a fierce battle of iron acquisition occurs between the host and bacterial pathogens. Bacteria acquire iron by secreting siderophores, small ferric iron binding molecules. In response, host immune cells secrete lipocalin 2 (also known as siderocalin), a siderophore-binding protein, to prevent bacterial reuptake of iron-loaded siderophores. To counter this threat, some bacteria can produce lipocalin 2-resistant siderophores. This review discusses the recently described molecular mechanisms of siderophore iron trafficking between host and bacteria, highlighting the therapeutic potential of exploiting pathogen siderophore machinery for the treatment of antibiotic-resistant bacterial infections. As the latter reflect a persistent problem in hospital settings, siderophore-targeting or siderophore-based compounds represent a promising avenue to combat such infections.
Highlights d Cisplatin covalently binds to human IRP2 at Cys512 and Cys516 d Cisplatin represses IRP2 binding on ferritin and TfR1 mRNAs (iron metabolism genes) d IRP2 dysregulation by cisplatin promotes intracellular iron deficiency d Cisplatin/iron chelator co-treatment potentiates iron deficiency and cancer cell death
Intracellular iron is tightly regulated by coordinated expression of iron transport and storage genes, such as transferrin receptor-1 (TfR1) and ferritin. They are primarily regulated by iron through iron-induced dissociation of iron-regulatory proteins (IRPs) from iron-responsive elements (IREs) in the 3'-UTR (untranslated region) of TfR1 or 5'-UTR of ferritin mRNA, resulting in destabilization of TfR1 mRNA and release of ferritin translation block. Thus high iron decreases iron transport via TfR1 mRNA degradation and increases iron storage via ferritin translational up-regulation. However, the molecular mechanism of TfR1 mRNA destabilization in response to iron remains elusive. Here, we demonstrate that miR-7-5p and miR-141-3p target 3'-TfR1 IREs and down-regulate TfR1 mRNA and protein expression. Conversely, miR-7-5p and miR-141-3p antagomiRs partially but significantly blocked iron- or IRP knockdown-induced down-regulation of TfR1 mRNA, suggesting the interplay between these microRNAs and IRPs along with involvement of another uncharacterized mechanism in TfR1 mRNA degradation. Luciferase reporter assays using 3'-UTR TfR1 IRE mutants suggested that the IREs C and E are targets of miR-7-5p and miR-141-3p, respectively. Furthermore, miR-7 expression was inversely correlated with TfR1 mRNA in human pancreatic adenocarcinoma patient samples. These results suggest a role of microRNAs in the TfR1 regulation in the IRP-IRE system.
Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental condition being diagnosed in increasing numbers. While the link between sleep and ADHD is of increasing interest, the relationship between sleep duration and ADHD remains largely uninvestigated in adult populations. We evaluated the association between self-reported sleep duration and ADHD in a cohort of American adults using data from the 2012 National Health Interview Survey (Centers for Disease Control and Prevention, 2012). Of the 30,858 participants eligible for our analyses, there were 1,122 cases of ADHD. Elevated and diminished sleep durations were both associated with increased odds of reporting ADHD (≤ 6 hr: OR = 1.50, 95% CI 1.19, 1.90; ≥ 9 hr: OR = 1.49, 95% CI 1.26, 1.75) in fully adjusted models. Future prospective studies are necessary to further examine this association in adult patients.
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