Copper induces neuron‐sparing, ferredoxin 1‐independent astrocyte toxicity mediated by oxidative stress

Abstract

Copper is an essential enzyme cofactor in oxidative metabolism, anti‐oxidant defenses, and neurotransmitter synthesis. However, intracellular copper, when improperly buffered, can also lead to 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 this compound on the surround parenchyma—namely neurons and astrocytes in vitro. Here, 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 and other toxins. Bolstering these findings, a human astrocytic cell line was similarly sensitive to CuES. Modifications of cellular metabolic pathways implicated in cuproptosis, a form of copper‐regulated cell death, such as inhibition of mitochondrial respiration or knock‐down of ferredoxin 1 (FDX1), did not block 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 that oxidative stress is a mediator of CuES‐induced glial toxicity. Indeed, treatment with anti‐oxidants mitigated CuES‐induced cell death in astrocytes indicating that oxidative stress is a mediator of CuES‐induced glial toxicity. Lastly, prior induction of metallothioneins 1 and 2 in astrocytes with zinc plus pyrithione was strikingly protective against CuES toxicity. As neurons express high levels of metallothioneins basally, these results may partially account for their resistance to CuES toxicity. These results demonstrate a unique toxic response to copper in glial cells which contrasts with the cell selectivity profile of zinc, another biologically relevant metal.image

The physiological and pathophysiological roles of copper in the nervous system

“…Two additional abnormal astrocytic cell are observed in WD patient brains—Alzheimers's type I and type II astrocytes, both of which are misshapen and characterized as reactive astrocytes (Goldman, 2022; Meenakshi‐Sundaram et al, 2008; Mikol et al, 2005; Poujois et al, 2017; Sosunov et al, 2020). Although Alzheimer's type II astrocytes are associated with hepatic encephalopathy (Poujois et al, 2017), the cause of Alzheimer's type I astrocytes, which are present in a number of neurodegenerative disorders, remains a mystery (Goldman, 2022), although evidence suggests that copper induces astrocyte toxicity in an oxidative stress dependent manner (Gale et al, 2023; Hu et al, 2016; Reddy et al, 2008). Unfortunately, although several animal models for WD exist (Hadrian & Przybyłkowski, 2021; Reed et al, 2018), most poorly recapitulate the neurological manifestations of disease and are better suited for investigation of hepatic pathology, making it difficult to investigate the causes of neuronal and glial cell death and injury in this disease.…”