Abstract
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 Fe2+ with metal and oxidation state specificity. The probe can detect physiological changes in labile Fe2+ 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.
Keywords:
infectious disease; labile iron; luciferin; metal homeostasis; molecular imaging.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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2,2'-Dipyridyl / pharmacology
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Acinetobacter Infections / genetics
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Acinetobacter Infections / metabolism*
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Acinetobacter Infections / microbiology
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Acinetobacter Infections / pathology
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Acinetobacter baumannii / pathogenicity
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Acinetobacter baumannii / physiology
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Anemia, Iron-Deficiency / genetics
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Anemia, Iron-Deficiency / metabolism*
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Anemia, Iron-Deficiency / pathology
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Animals
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Cation Transport Proteins / genetics
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Cation Transport Proteins / metabolism
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Cations, Divalent
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Disease Models, Animal
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Ferric Compounds / pharmacology
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Firefly Luciferin / analogs & derivatives
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Firefly Luciferin / analysis*
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Firefly Luciferin / chemical synthesis
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Fluorescent Dyes / analysis*
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Fluorescent Dyes / chemical synthesis
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Gene Expression Regulation
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Hepcidins / genetics
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Hepcidins / metabolism
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Homeostasis / genetics
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Iron / metabolism*
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Iron Overload / genetics
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Iron Overload / metabolism*
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Iron Overload / pathology
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Iron Regulatory Protein 1 / genetics
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Iron Regulatory Protein 1 / metabolism
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Iron Regulatory Protein 2 / genetics
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Iron Regulatory Protein 2 / metabolism
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Luminescent Measurements
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Mice
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Mice, Transgenic
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Quaternary Ammonium Compounds / pharmacology
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Receptors, Transferrin / genetics
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Receptors, Transferrin / metabolism
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Signal Transduction
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Transferrin / genetics
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Transferrin / metabolism
Substances
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Cation Transport Proteins
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Cations, Divalent
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Ferric Compounds
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Fluorescent Dyes
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Hepcidins
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Quaternary Ammonium Compounds
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Receptors, Transferrin
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Transferrin
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metal transporting protein 1
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solute carrier family 11- (proton-coupled divalent metal ion transporters), member 2
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2,2'-Dipyridyl
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Firefly Luciferin
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Iron
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Iron Regulatory Protein 1
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Iron Regulatory Protein 2
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ferric ammonium citrate