Toxic Concentrations of Glutamate Induce Ferroptosis without Affecting Mitochondrial Respiration in Rodent Brain Slice Cultures
Abstract
Many neuronal disorders are characterized by glutamate toxicity, which is closely associated with mitochondrial and neuronal dysfunction. The aim of this study was to investigate the link between mitochondrial function and mechanisms of cell death induced by glutamate. The study was carried out on male (C57BL/6) mice and male Sprague Dawley rat acute brain slices (ABSs), as well as male and female organotypic brain slice cultures (BSCs). Mitochondrial respiration, activities of tricarboxylic acid cycle enzymes, and the cell death rate [assessed by lactate dehydrogenase release and histological analyses] were determined. Memantine was used to inhibit excitotoxicity, while ferrostatin-1, rosiglitazone, and deferoxamine were used as inhibitors of the ferroptotic pathway. In astrocytes, pyruvate dehydrogenase complex and oxoglutarate dehydrogenase complex (OGDHC) showed <1% of the enzymatic activity observed in the whole-brain tissue. In BSCs, glutamate exposure induced a marked increase in oxidative phosphorylation-linked mitochondrial respiration, which was independent of OGDHC activity and disappeared when BSC homogenates were analyzed. Glutamate-induced cell death was not alleviated by memantine but was significantly reduced by ferrostatin-1. The activation of ferroptosis by glutamate was also observed in ABSs, as well as the inhibition of lipid peroxidation induced by ferrostatin-1, rosiglitazone, and deferoxamine. Ferrostatin-1 and rosiglitazone additionally inhibited cell death, while deferoxamine did not. The unusual response to deferoxamine requires further elucidation. In summary, our data suggest that elevated glutamate levels enhance neuronal energy metabolism in brain slices, compensating glutamate-mediated Ca ²⁺ influx and reduce excitotoxicity. In contrast, persistently elevated levels of extracellular glutamate impair the cystine/glutamate antiporter, leading to ferroptosis.
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BibTeX
@article{vagliogarro2026toxic,
title = {{Toxic Concentrations of Glutamate Induce Ferroptosis without Affecting Mitochondrial Respiration in Rodent Brain Slice Cultures}},
author = {Annette Vaglio-Garro and Marco Theuermann and Katharina E. Sweis and Sergejs Zavadskis and Márton Kokas and Zsuzsanna Környei and Miriam Karas and Laszlo Tretter and Tímea Komlódi and Adelheid Weidinger and Andrey V. Kozlov},
journal = {eneuro},
year = {2026},
month = oct,
doi = {10.1523/eneuro.0439-25.2026},
url = {https://www.eneuro.org/lookup/doi/10.1523/ENEURO.0439-25.2026},
note = {CC BY-NC-SA 4.0},
}
RIS
TY - JOUR
TI - Toxic Concentrations of Glutamate Induce Ferroptosis without Affecting Mitochondrial Respiration in Rodent Brain Slice Cultures
AU - Annette Vaglio-Garro
AU - Marco Theuermann
AU - Katharina E. Sweis
AU - Sergejs Zavadskis
AU - Márton Kokas
AU - Zsuzsanna Környei
AU - Miriam Karas
AU - Laszlo Tretter
AU - Tímea Komlódi
AU - Adelheid Weidinger
AU - Andrey V. Kozlov
PY - 2026
DA - 2026/10/14
JO - eneuro
DO - 10.1523/eneuro.0439-25.2026
UR - https://www.eneuro.org/lookup/doi/10.1523/ENEURO.0439-25.2026
AB - Many neuronal disorders are characterized by glutamate toxicity, which is closely associated with mitochondrial and neuronal dysfunction. The aim of this study was to investigate the link between mitochondrial function and mechanisms of cell death induced by glutamate. The study was carried out on male (C57BL/6) mice and male Sprague Dawley rat acute brain slices (ABSs), as well as male and female organotypic brain slice cultures (BSCs). Mitochondrial respiration, activities of tricarboxylic acid cycle enzymes, and the cell death rate [assessed by lactate dehydrogenase release and histological analyses] were determined. Memantine was used to inhibit excitotoxicity, while ferrostatin-1, rosiglitazone, and deferoxamine were used as inhibitors of the ferroptotic pathway. In astrocytes, pyruvate dehydrogenase complex and oxoglutarate dehydrogenase complex (OGDHC) showed <1% of the enzymatic activity observed in the whole-brain tissue. In BSCs, glutamate exposure induced a marked increase in oxidative phosphorylation-linked mitochondrial respiration, which was independent of OGDHC activity and disappeared when BSC homogenates were analyzed. Glutamate-induced cell death was not alleviated by memantine but was significantly reduced by ferrostatin-1. The activation of ferroptosis by glutamate was also observed in ABSs, as well as the inhibition of lipid peroxidation induced by ferrostatin-1, rosiglitazone, and deferoxamine. Ferrostatin-1 and rosiglitazone additionally inhibited cell death, while deferoxamine did not. The unusual response to deferoxamine requires further elucidation. In summary, our data suggest that elevated glutamate levels enhance neuronal energy metabolism in brain slices, compensating glutamate-mediated Ca ²⁺ influx and reduce excitotoxicity. In contrast, persistently elevated levels of extracellular glutamate impair the cystine/glutamate antiporter, leading to ferroptosis.
SN - 2373-2822
ER -