ETD

Insights into the Mechanism of Copper-Ionophore Mediated Toxicity in Glial Cells

Public Deposited
Analytics

218 pages

Title
  • Insights into the Mechanism of Copper-Ionophore Mediated Toxicity in Glial Cells
Date modified
  • 11/17/2025
Creator
Abstract
  • Copper is an essential enzyme cofactor in oxidative metabolism, iron homeostasis, antioxidant defenses and neurotransmitter synthesis. Copper also has other important biological functions such as modulation of synaptic transmission, involvement in the innate immune response and erythropoiesis. However, due to copper’s ability to redox cycle, it can also lead to the formation of reactive species and cell death. Given the growing interest in the use of copper, in the presence of the ionophore elesclomol (CuES) for the treatment of gliomas, we investigated the effect of CuES on the surround parenchyma – namely neurons and astrocytes in vitro. We show that astrocytes were highly sensitive to CuES toxicity, while neurons were surprisingly resistant, a vulnerability profile that is opposite of what has been described for zinc. Bolstering these findings, a human astrocytic cell line was similarly sensitive to CuES. Modifications of cellular metabolic pathways implicated in cupropotosis, a form of CuES-regulated cell death, namely inhibition of mitochondrial respiration and knock-down of ferredoxin 1 (FDX1), were insufficient to abrogate CuES toxicity to astrocytes. CuES toxicity was also unaffected by inhibitors of apoptosis, necrosis or ferroptosis. However, we did detect the presence of lipid peroxidation products in CuES-treated astrocytes, indicating the generation of reactive oxygen species following metal exposure. Indeed, treatment with antioxidants mitigated CuES induced cell death in astrocytes, demostrating that oxidative stress is a principal mediator of CuES-induced glial toxicity. Lastly, prior induction of metallothioneins 1 and 2 in astrocytes using zinc plus pyrithione was strikingly protective against CuES toxicity. These results demonstrate a unique toxic response to copper in glial cells, but not neurons, which differs in cell selectivity profile of other biologically relevant metals such as zinc.
Administrative Note
Date created
Identifier
Keyword
Language
Resource type
Degree discipline
  • Neurobiology
Degree grantor
  • University of Pittsburgh
Degree level
  • Doctoral
Degree name
  • Doctor of Philosophy
Rights statement

MLA citation style (9th ed.)

Gale, Jenna. Insights Into the Mechanism of Copper-ionophore Mediated Toxicity In Glial Cells. . 2023. d-scholarship.pitt.edu/concern/etds/08aa4220-d832-4841-a99f-fa8092a159b0.

APA citation style (7th ed.)

G. Jenna. (2023). Insights into the Mechanism of Copper-Ionophore Mediated Toxicity in Glial Cells. https://d-scholarship.pitt.edu/concern/etds/08aa4220-d832-4841-a99f-fa8092a159b0

Chicago citation style (CMOS 17, author-date)

Gale, Jenna. Insights Into the Mechanism of Copper-Ionophore Mediated Toxicity In Glial Cells. 2023. https://d-scholarship.pitt.edu/concern/etds/08aa4220-d832-4841-a99f-fa8092a159b0.

Note: These citations are programmatically generated and may be incomplete.

In Collection:
Thumbnail Title Date Uploaded Visibility Actions
45205_Jenna_Gale_ETD_Final.pdf 45205_Jenna_Gale_ETD_Final.pdf 2025-11-17 Public Download