Analytical Methods for Imaging Metals in Biology: From Transition Metal Metabolism to Transition Metal Signaling

Ackerman, Cheri M.; Lee, Sumin; Chang, Christopher J.

doi:10.1021/acs.analchem.6b04631

Cited by 137 publications

(115 citation statements)

References 212 publications

Supporting

Mentioning

106

Contrasting

Unclassified

Order By: Relevance

“…A modest response is observed with free copper salts, as is similarly observed for the related fluorescence probe FIP-1 (15). However, as a typical eukaryotic cell exhibits a ∼10-fold higher level of iron over copper coupled with the high buffering capacity of copper with glutathione and metallochaperones (picomolar to femtomolar K d values) (55)(56)(57)(58)(59)(60), the modest response to free copper salts suggests that ICL-1 should have sufficient selectivity to detect alterations in biological ferrous iron levels. ICL-1 is also selective for labile Fe 2+ over other biologically relevant forms of iron that are tightly bound to proteins and cofactors, such as transferrin, ferritin, hemin, and hemoglobin, as well as Fe 3+ , along with reductants glutathione, N-acetyl cysteine, β-mercaptoethanol, and ascorbic acid (Fig.…”

Section: Resultsmentioning

confidence: 70%

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.

Self Cite

112

View full text Add to dashboard Cite

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...

show abstract

Section: Resultsmentioning

confidence: 70%

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.

Self Cite

112

View full text Add to dashboard Cite

show abstract

“…Other storage sites for copper, which may serve as the origin of copper signals, include the copper chaperones (96) or small molecules such as glutathione (6). Continued efforts to develop new technologies to image and characterize copper pools in living systems will aid in addressing these outstanding questions (14,18,97,98).…”

Section: Resultsmentioning

confidence: 99%

“…Additionally, copper ionophores, such as clioquinol and other 8-hydroxyquinoline (8HQ) derivatives, redistribute copper across cell and organelle membranes, altering the labile copper pool without adding or removing copper from the system (16,17). Changes to the labile copper pool may be assessed by the use of fluorescent small-molecule indicators that can equilibrate with kinetically accessible copper in the cytosol, enabling one to distinuguish labile copper from total copper, the latter of which is typically measured using direct techniques including X-ray fluorescence microscopy (XFM) or mass spectrometry imaging (14,18).…”

Section: Acquisition and Trafficking Of Copper In Mammalsmentioning

confidence: 99%

Copper signaling in the brain and beyond

Ackerman

Chang

2018

Journal of Biological Chemistry

Self Cite

130

124

View full text Add to dashboard Cite

Transition metals have been recognized and studied primarily in the context of their essential roles as structural and metabolic cofactors for biomolecules that compose living systems. More recently, an emerging paradigm of transition metal signaling, where dynamic changes in transition metal pools can modulate protein function, cell fate, and organism health and disease, has broadened our view of the potential contributions of these essential nutrients in biology. Using copper as a canonical example of transition metal signaling, we highlight key experiments where direct measurement and/or visualization of dynamic copper pools, in combination with biochemical, physiological, and behavioral studies, have deciphered sources, targets, and physiological effects of copper signals.

show abstract

“…[86] We suggest that by exchanging the ion sensor,t his or closely related assays could be used to visualize metal ion transport into vesicles by fluorescence microscopy in real time (Figure 2b). [88][89][90] Small-molecule ion sensors,although subject to constant improvements,are notoriously unselective between ions and can exert nonrelated secondary effects; [91] this calls for caution if they are employed for analysis of ion transport in cellular systems.Despite these challenges,highly selective ion sensors for, for example,C u + and Cu 2+ have been developed and rigorously characterized in cells and in vivo. [87] Metal ion sensors and their use in cells have been reviewed in detail.…”

Section: Assessing Ionophore Activity In Vitro and In Cellsmentioning

confidence: 99%

Chemical Syntheses and Chemical Biology of Carboxyl Polyether Ionophores: Recent Highlights

2019

View full text Add to dashboard Cite

show abstract

Analytical Methods for Imaging Metals in Biology: From Transition Metal Metabolism to Transition Metal Signaling

Cited by 137 publications

References 212 publications

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

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

Copper signaling in the brain and beyond

Chemical Syntheses and Chemical Biology of Carboxyl Polyether Ionophores: Recent Highlights

Contact Info

Product

Resources

About