ArticleProceedings of the National Academy of Sciences of the United States of America2019
Ratiometric two-photon microscopy reveals attomolar copper buffering in normal and Menkes mutant cells.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 48 papers.
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Who cites it
48 citing papers in PubMed, 90 citations in OpenAlex.
- Cuproptosis and the bioinorganic basis of copper-induced cell death.Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry · 2026Review
- Site-Specific Labeling of PD-L1 Fab through Disulfide Rebridging for ImmunoPET Imaging.Chemical & biomedical imaging · 2026Article
- TPEN, a Well-Known Zinc Chelator, Sequesters Attomolar-Buffered Cellular Cu(I) Through an Oxygen-Dependent Mechanism.ACS chemical neuroscience · 2026Article
- Copper homeostasis and cuproptosis in cancer: mitochondrial metabolic dependency and nanomedicine-based therapeutic strategies.Apoptosis : an international journal on programmed cell death · 2026Review
- Simultaneous Imaging of CuAngewandte Chemie (International ed. in English) · 2026Article
- POLARIS is a copper-binding peptide that interacts with ETR1 to negatively regulate ethylene signaling in Arabidopsis.Plant communications · 2025Article
- Copper homeostasis and cuproptosis in Alzheimer's disease (Review).International journal of molecular medicine · 2025Review
- An Alkyne-Directed Cleavage Approach for Activity-Based Cu(I) Sensing Reveals Manganese-Promoted Sensitization of Cuproptosis.Journal of the American Chemical Society · 2025Article
- A primer on copper biology in the brain.Neurobiology of disease · 2025Review
- Activity-based sensing reveals elevated labile copper promotes liver aging via hepatic ALDH1A1 depletion.Nature communications · 2025Article
- Metals in Motion: Understanding Labile Metal Pools in Bacteria.Biochemistry · 2025Review
- A histochemical approach to activity-based copper sensing reveals cuproplasia-dependent vulnerabilities in cancer.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- A metal-trap tests and refines blueprints to engineer cellular protein metalation with different elements.Nature communications · 2025Article
- Mammalian copper homeostasis: physiological roles and molecular mechanisms.Physiological reviews · 2025Review
- An Activity-Based Sensing Approach to Multiplex Mapping of Labile Copper Pools by Stimulated Raman Scattering.Journal of the American Chemical Society · 2024Article
- Balancing Brightness and Photobasicity: Modulating Excited-State Proton Transfer Pathways in Push-Pull Fluorophores for Biological Two-Photon Imaging.The journal of physical chemistry. A · 2024Article
- Selective removal of copper from complex biological media with an agarose-immobilized high-affinity PSP ligand.Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry · 2024Article
- The physiological and pathophysiological roles of copper in the nervous system.The European journal of neuroscience · 2024Review
- Reducing Heavy Metal Contamination in Soil and Water Using Phytoremediation.Plants (Basel, Switzerland) · 2024Review
- Small-Molecule Fluorescent Probes for Binding- and Activity-Based Sensing of Redox-Active Biological Metals.Chemical reviews · 2024Review
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Authors and funding
9 authors at 3 institutions in 1 country.
Funding
Abstract
Copper is controlled by a sophisticated network of transport and storage proteins within mammalian cells, yet its uptake and efflux occur with rapid kinetics. Present as Cu(I) within the reducing intracellular environment, the nature of this labile copper pool remains elusive. While glutathione is involved in copper homeostasis and has been assumed to buffer intracellular copper, we demonstrate with a ratiometric fluorescent indicator, crisp-17, that cytosolic Cu(I) levels are buffered to the vicinity of 1 aM, where negligible complexation by glutathione is expected. Enabled by our phosphine sulfide-stabilized phosphine (PSP) ligand design strategy, crisp-17 offers a Cu(I) dissociation constant of 8 aM, thus exceeding the binding affinities of previous synthetic Cu(I) probes by four to six orders of magnitude. Two-photon excitation microscopy with crisp-17 revealed rapid, reversible increases in intracellular Cu(I) availability upon addition of the ionophoric complex CuGTSM or the thiol-selective oxidant 2,2'-dithiodipyridine (DTDP). While the latter effect was dramatically enhanced in 3T3 cells grown in the presence of supplemental copper and in cultured Menkes mutant fibroblasts exhibiting impaired copper efflux, basal Cu(I) availability in these cells showed little difference from controls, despite large increases in total copper content. Intracellular copper is thus tightly buffered by endogenous thiol ligands with significantly higher affinity than glutathione. The dual utility of crisp-17 to detect normal intracellular buffered Cu(I) levels as well as to probe the depth of the labile copper pool in conjunction with DTDP provides a promising strategy to characterize perturbations of cellular copper homeostasis.
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