Copper Nanoparticles Enable Multi-Compartment Cuproenzyme Metalation in Cellular Models of Copper Deficiency.
5 affiliations
- 1Department of Biochemistry and Biophysics, Texas A&M University, College Station, Texas77843, United States.
- 2Department of Biomedical Engineering, Texas A&M University, College Station, Texas77843, United States.
- 3Interdisciplinary Program in Genetics and Genomics, Texas A&M University, College Station, Texas77843, United States.
- 4Department of Biochemistry, University of Missouri, Columbia, Missouri65211, United States.
- 5Department of Ophthalmology, University of Missouri, Columbia, Missouri65211, United States.
Abstract
Copper (Cu) is an essential trace element that serves as a cofactor for enzymes involved in diverse metabolic pathways and processes across multiple subcellular compartments. Mutations that cause systemic or subcellular Cu deficiency result in fatal pediatric disorders, including Menkes disease and related mitochondrial disorders. Treatment of these disorders requires pharmacological agents that can transport Cu across membranes; however, the only approved drug, Cu histidinate, shows limited efficacy. Using genetic models of Menkes disease, we recently demonstrated that the Cu ionophore elesclomol (ES) efficiently restores the activity of mitochondrial and cytosolic cuproenzymes, but its ability to metalate cuproenzymes within secretory compartments is low. To overcome this limitation, we investigated Cu nanoparticles (Cu-NPs) as a facile means of delivering Cu to multiple subcellular compartments simultaneously. Cu-NPs were synthesized by chemical reduction to produce spherical nanoparticles with an average size of 80 nm. Biophysical characterization of Cu-NPs revealed zero-valent Cu and a neutral zeta potential, compatible with biological interactions and in vivo circulation. In cellular models of Cu deficiency, Cu-NPs were shown to internalize via clathrin-mediated endocytosis and restore the activity of cuproenzymes in mitochondrial, cytosolic, and secretory compartments. Importantly, biomarkers of Cu toxicity were not activated under these conditions, indicating a favorable therapeutic index. Overall, these findings highlight Cu-NPs as versatile Cu delivery agents with therapeutic potential for Cu deficiency disorders.
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BibTeX
@article{kaur2026copper,
title = {{Copper Nanoparticles Enable Multi-Compartment Cuproenzyme Metalation in Cellular Models of Copper Deficiency.}},
author = {Harman Kaur and John Soukar and Nikita Gudekar and Vinit C Shanbhag and Michael J Petris and Akhilesh K Gaharwar and Vishal M Gohil},
journal = {ACS chemical biology},
year = {2026},
month = sep,
doi = {10.1021/acschembio.6c00564},
url = {https://europepmc.org/article/MED/42906013},
note = {CC BY},
}
RIS
TY - JOUR
TI - Copper Nanoparticles Enable Multi-Compartment Cuproenzyme Metalation in Cellular Models of Copper Deficiency.
AU - Harman Kaur
AU - John Soukar
AU - Nikita Gudekar
AU - Vinit C Shanbhag
AU - Michael J Petris
AU - Akhilesh K Gaharwar
AU - Vishal M Gohil
PY - 2026
DA - 2026/09/01
JO - ACS chemical biology
DO - 10.1021/acschembio.6c00564
UR - https://europepmc.org/article/MED/42906013
AB - Copper (Cu) is an essential trace element that serves as a cofactor for enzymes involved in diverse metabolic pathways and processes across multiple subcellular compartments. Mutations that cause systemic or subcellular Cu deficiency result in fatal pediatric disorders, including Menkes disease and related mitochondrial disorders. Treatment of these disorders requires pharmacological agents that can transport Cu across membranes; however, the only approved drug, Cu histidinate, shows limited efficacy. Using genetic models of Menkes disease, we recently demonstrated that the Cu ionophore elesclomol (ES) efficiently restores the activity of mitochondrial and cytosolic cuproenzymes, but its ability to metalate cuproenzymes within secretory compartments is low. To overcome this limitation, we investigated Cu nanoparticles (Cu-NPs) as a facile means of delivering Cu to multiple subcellular compartments simultaneously. Cu-NPs were synthesized by chemical reduction to produce spherical nanoparticles with an average size of 80 nm. Biophysical characterization of Cu-NPs revealed zero-valent Cu and a neutral zeta potential, compatible with biological interactions and in vivo circulation. In cellular models of Cu deficiency, Cu-NPs were shown to internalize via clathrin-mediated endocytosis and restore the activity of cuproenzymes in mitochondrial, cytosolic, and secretory compartments. Importantly, biomarkers of Cu toxicity were not activated under these conditions, indicating a favorable therapeutic index. Overall, these findings highlight Cu-NPs as versatile Cu delivery agents with therapeutic potential for Cu deficiency disorders.
SN - 1554-8929
SN - 1554-8937
ER -