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<jats:title>Abstract</jats:title><jats:p>Epilepsy is one of the most common neurological disorders in the world. Common epileptic drugs generally affect ion channels or neurotransmitters and prevent the emergence of seizures. However, up to a third of the patients suffer from drug-resistant epilepsy, and there is an urgent need to develop new therapeutic strategies that go beyond acute antiepileptic (antiseizure) therapies towards therapeutics that also might have effects on chronic epilepsy comorbidities such as cognitive decline and depression. The mitochondrial calcium uniporter (MCU) mediates rapid mitochondrial Ca<jats:sup>2+</jats:sup> transport through the inner mitochondrial membrane. Ca<jats:sup>2+</jats:sup> influx is essential for mitochondrial functions, but longer elevations of intracellular Ca<jats:sup>2+</jats:sup> levels are closely associated with seizure-induced neuronal damage, which are underlying mechanisms of cognitive decline and depression. Using neuronal-specific MCU knockout mice (MCU<jats:sup>−/−ΔN</jats:sup>), we demonstrate that neuronal MCU deficiency reduced hippocampal excitability in vivo. Furthermore, in vitro analyses of hippocampal glioneuronal cells reveal no change in total Ca<jats:sup>2+</jats:sup> levels but differences in intracellular Ca<jats:sup>2+</jats:sup> handling. MCU<jats:sup>−/−ΔN</jats:sup> reduces ROS production, declines metabolic fluxes, and consequently prevents glioneuronal cell death. This effect was also observed under pathological conditions, such as the low magnesium culture model of seizure-like activity or excitotoxic glutamate stimulation, whereby MCU<jats:sup>−/−ΔN</jats:sup> reduces ROS levels and suppresses Ca<jats:sup>2+</jats:sup> overload seen in WT cells. This study highlights the importance of MCU at the interface of Ca<jats:sup>2+</jats:sup> handling and metabolism as a mediator of stress-related mitochondrial dysfunction, which indicates the modulation of MCU as a potential target for future antiepileptogenic therapy.</jats:p>
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DeepGreen-ID: 7e029b7a847f4246812df438188ee99c ; metadata provieded by: DeepGreen (https://www.oa-deepgreen.de/api/v1/), LIVIVO search scope life sciences (http://z3950.zbmed.de:6210/livivo), Crossref Unified Resource API (https://api.crossref.org/swagger-ui/index.html), to.science.api (https://frl.publisso.de/), ZDB JSON-API (beta) (https://zeitschriftendatenbank.de/api/), lobid - Dateninfrastruktur für Bibliotheken (https://lobid.org/resources/search)
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