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

Gale, Jenna (2023) Insights into the Mechanism of Copper-Ionophore Mediated Toxicity in Glial Cells. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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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.

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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Gale, Jennajeg148@pitt.edujeg1480000-0003-2727-9497
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairSun, Dandansund@upmc.edu
Committee MemberBerman, Sarahbermans@upmc.edu
Committee MemberCunningham, ChristopherCUNNINGC@pitt.edu
Committee MemberHastings, Teresathasting@pitt.edu
Committee MemberThathiah, Amanthaamantha@pitt.edu
Committee MemberRosenberg, Paulpaul.rosenberg@childrens.harvard.edu
Thesis AdvisorAizenman, Eliasredox@pitt.edu
Date: 8 December 2023
Date Type: Publication
Defense Date: 26 June 2023
Approval Date: 8 December 2023
Submission Date: 1 August 2023
Access Restriction: 1 year -- Restrict access to University of Pittsburgh for a period of 1 year.
Number of Pages: 218
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Neurobiology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: copper, glioma, astrocytes, elesclomol, ferrodoxin 1
Date Deposited: 08 Dec 2023 14:50
Last Modified: 08 Dec 2023 14:50
URI: http://d-scholarship.pitt.edu/id/eprint/45205

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