A new class of high-contrast Fe(<scp>ii</scp>) selective fluorescent probes based on spirocyclized scaffolds for visualization of intracellular labile iron delivered by transferrin

Niwa, Masato; Hirayama, Tasuku; Okuda, K; Nagasawa, Hideko

doi:10.1039/c4ob00935e

Cited by 90 publications

(79 citation statements)

References 70 publications

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“…RhoNox‐1 interacts with Fe 2+ resulting in the release of fluorescent rhodamine and was recently reported to selectively detect endogenous changes in LIP of lung carcinoma cells (Niwa et al . ; Adachi et al . ), while IP‐1 relies on an oxygen‐dependent, three‐component sensing mechanism to detect Fe 2+ (Au‐Yeung et al .…”

Section: Resultsmentioning

confidence: 99%

“…Background fluorescence was subtracted and data were expressed as mean +/À SD from 6 replicates. Fe 2+ -specific probes Rho-Nox1 and IP-1 were prepared by Allegra Aron, Ho Yu Au-Yeung and Christopher J. Chang (Department of Chemistry, University of California, Berkeley) and freshly dissolved in dimethylsulfoxide at a stock concentration of 2 mmol (Au-Yeung et al 2013;Niwa et al 2014). Cells were incubated with DMEM media alone or increasing Mn doses for 24 h, washed with PBS and loaded with 5 lmol RhoNox-1 dissolved in OptiMEM media for 60 min.…”

Section: Quantification Of the Labile Iron Pool (Lip)mentioning

confidence: 99%

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Manganese causes neurotoxic iron accumulation via translational repression of amyloid precursor protein and H‐Ferritin

Venkataramani

Doeppner

Willkommen

et al. 2018

Journal of Neurochemistry

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For more than 150 years, it is known that occupational overexposure of manganese (Mn) causes movement disorders resembling Parkinson's disease (PD) and PD-like syndromes. However, the mechanisms of Mn toxicity are still poorly understood. Here, we demonstrate that Mn dose- and time-dependently blocks the protein translation of amyloid precursor protein (APP) and heavy-chain Ferritin (H-Ferritin), both iron homeostatic proteins with neuroprotective features. APP and H-Ferritin are post-transcriptionally regulated by iron responsive proteins, which bind to homologous iron responsive elements (IREs) located in the 5'-untranslated regions (5'-UTRs) within their mRNA transcripts. Using reporter assays, we demonstrate that Mn exposure repressed the 5'-UTR-activity of APP and H-Ferritin, presumably via increased iron responsive proteins-iron responsive elements binding, ultimately blocking their protein translation. Using two specific Fe -specific probes (RhoNox-1 and IP-1) and ion chromatography inductively coupled plasma mass spectrometry (IC-ICP-MS), we show that loss of the protective axis of APP and H-Ferritin resulted in unchecked accumulation of redox-active ferrous iron (Fe ) fueling neurotoxic oxidative stress. Enforced APP expression partially attenuated Mn-induced generation of cellular and lipid reactive oxygen species and neurotoxicity. Lastly, we could validate the Mn-mediated suppression of APP and H-Ferritin in two rodent in vivo models (C57BL6/N mice and RjHan:SD rats) mimicking acute and chronic Mn exposure. Together, these results suggest that Mn-induced neurotoxicity is partly attributable to the translational inhibition of APP and H-Ferritin resulting in impaired iron metabolism and exacerbated neurotoxic oxidative stress. Open Data: Materials are available on https://cos.io/our-services/open-science-badges/ https://osf.io/93n6m/.

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Section: Resultsmentioning

confidence: 99%

Section: Quantification Of the Labile Iron Pool (Lip)mentioning

confidence: 99%

Manganese causes neurotoxic iron accumulation via translational repression of amyloid precursor protein and H‐Ferritin

Venkataramani

Doeppner

Willkommen

et al. 2018

Journal of Neurochemistry

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“…2B). Because increased DMT1 expression potentially leads to elevated iron uptake, we next determined Fe 2+ uptake using RhoNox-1, a fluorescent probe that specifically recognizes Fe 2+ (34,41). We showed that duodena treated with FeSO 4 showed a stronger signal in IECs by RhoNox-1 staining (Supplemental Fig.…”

Section: Dmt1 Mrna Expression and Iron Uptake Are Increased In Diabetmentioning

confidence: 99%

“…RhoNox-1, a fluorescent probe that specifically binds Fe 2+ (34), was purchased from Goryo Chemical (Sapporo, Japan). Rabbit anti-HIF2a (NB100) and mouse anti-human DMT1 (H00004891) antibodies were purchased from Novus Biologicals (Littleton, CO, USA).…”

Section: Reagents and Antibodiesmentioning

confidence: 99%

Hyperglycemia promotes microvillus membrane expression of DMT1 in intestinal epithelial cells in a PKCα‐dependent manner

et al. 2018

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Excessive iron increases the incidence of diabetes and worsens diabetic complications. Reciprocally, diabetes induces iron loading, partially attributable to elevated intestinal iron export according to a recent report. Herein, we show that iron uptake and the mRNA expression of iron importer divalent metal transporter 1 (DMT1) were significantly increased in the duodenum of streptozotocin‐induced diabetic mice. Immunofluorescence staining of human intestinal biopsies revealed increased brush border membrane (BBM) and decreased cytoplasmic DMT1 expression in patients with diabetes, suggesting translocation of DMT1. This pattern of DMT1 regulation was corroborated by immunoblotting results in diabetic mice showing that BBM DMT1 expression was increased by 210%, in contrast to a 60% increase in total DMT1. PKC mediates many diabetic complications, and PKCα activity was increased in diabetic mouse intestine. Intriguingly, diabetic mice with PKCα deficiency did not show increases in iron uptake and BBM DMT1 expression. High‐glucose treatment increased plasma membrane DMT1 expression via the activation of PKCα in cultured IECs. Inhibition of PKCv potentiated the ubiquitination and degradation of DMT1 protein. We further showed that high glucose suppressed membrane DMT1 internalization. These findings demonstrate that PKCα promotes microvillus membrane DMT1 expression and intestinal iron uptake, contributing to diabetic iron loading.—Zhao, L., Bartnikas, T., Chu, X., Klein, J., Yun, C., Srinivasan, S., He, P. Hyperglycemia promotes microvillus membrane expression of DMT1 in intestinal epithelial cells in a PKCα‐dependent manner. FASEB J. 33, 3549–3561 (2019). http://www.fasebj.org

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“…In this regard, detection of iron with both metal and oxidation state specificity is of central importance, because while iron is stored primarily in the ferric oxidation state, a ferrous iron pool loosely bound to cellular ligands, defined as the labile iron pool (LIP), exists at the center of highly regulated networks that control iron acquisition, trafficking, and excretion. Indeed, as a weak binder on the Irving-Williams stability series (13), Fe 2+ provides a challenge for detection by traditional recognition-based approaches (14), and as such we (15)(16)(17) and others (18)(19)(20) have pursued activity-based sensing approaches to detect labile Fe 2+ stores in cells (21)(22)(23)(24)(25). These tools have already provided insights into iron biology, as illustrated by the direct identification of elevations in LIPs during ferroptosis (26,27), an emerging form of cell death, using the ratiometric iron indicator FIP-1 (15).…”

mentioning

confidence: 99%

In vivo bioluminescence imaging of labile iron accumulation in a murine model of Acinetobacter baumannii infection

Aron

Heffern

Lonergan

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

118

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Iron is an essential metal for all organisms, yet disruption of its homeostasis, particularly in labile forms that can contribute to oxidative stress, is connected to diseases ranging from infection to cancer to neurodegeneration. Iron deficiency is also among the most common nutritional deficiencies worldwide. To advance studies of iron in healthy and disease states, we now report the synthesis and characterization of iron-caged luciferin-1 (ICL-1), a bioluminescent probe that enables longitudinal monitoring of labile iron pools (LIPs) in living animals. ICL-1 utilizes a bioinspired endoperoxide trigger to release D-aminoluciferin for selective reactivity-based detection of Fe 2+ with metal and oxidation state specificity. The probe can detect physiological changes in labile Fe 2+ levels in live cells and mice experiencing iron deficiency or overload. Application of ICL-1 in a model of systemic bacterial infection reveals increased iron accumulation in infected tissues that accompany transcriptional changes consistent with elevations in both iron acquisition and retention. The ability to assess iron status in living animals provides a powerful technology for studying the contributions of iron metabolism to physiology and pathology.labile iron | molecular imaging | luciferin | metal homeostasis | infectious disease I ron is an essential mineral for nearly every form of life, owing in large part to its ability to cycle between different oxidation states for processes such as nucleotide synthesis, oxygen transport, and respiration (1, 2). At the same time, the potent redox activity of iron is potentially toxic, particularly in unregulated labile forms that can trigger aberrant production of reactive oxygen species via Fenton chemistry (3). Indeed, iron deficiency remains one of the most common nutritional deficiencies in the world (4), and aberrant iron levels have been linked to various ailments, including cancer (5-7), cardiovascular (8), and neurodegenerative (9) disorders, as well as aging (10). The situation is especially complex in infectious diseases, where the requirement for iron by both host organism and invading pathogen leads to an intricate chemical tug-of-war for this metal nutrient during various stages of the immune response (11,12).The foregoing examples provide motivation for developing technologies to monitor biological iron status, with particular interest in methods to achieve in vivo iron imaging in live animal models that go beyond current state-of-the-art assays that are limited primarily to cell culture specimens. In this regard, detection of iron with both metal and oxidation state specificity is of central importance, because while iron is stored primarily in the ferric oxidation state, a ferrous iron pool loosely bound to cellular ligands, defined as the labile iron pool (LIP), exists at the center of highly regulated networks that control iron acquisition, trafficking, and excretion. Indeed, as a weak binder on the Irving-Williams stability series (13), Fe 2+ provides a challenge for d...

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A new class of high-contrast Fe(ii) selective fluorescent probes based on spirocyclized scaffolds for visualization of intracellular labile iron delivered by transferrin

Cited by 90 publications

References 70 publications

Manganese causes neurotoxic iron accumulation via translational repression of amyloid precursor protein and H‐Ferritin

Manganese causes neurotoxic iron accumulation via translational repression of amyloid precursor protein and H‐Ferritin

Hyperglycemia promotes microvillus membrane expression of DMT1 in intestinal epithelial cells in a PKCα‐dependent manner

In vivo bioluminescence imaging of labile iron accumulation in a murine model of Acinetobacter baumannii infection

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