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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 &lt;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\n                    <jats:sup>2+<\/jats:sup>\n                    influx and reduce excitotoxicity. In contrast, persistently elevated levels of extracellular glutamate impair the cystine\/glutamate antiporter, leading to ferroptosis.\n                  <\/jats:p>","DOI":"10.1523\/eneuro.0439-25.2026","type":"journal-article","created":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T17:50:22Z","timestamp":1792000222000},"page":"ENEURO.0439-25.2026","update-policy":"https:\/\/doi.org\/10.1523\/eneuro.crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Toxic Concentrations of Glutamate Induce Ferroptosis without Affecting Mitochondrial Respiration in Rodent Brain Slice 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