Neuronal Mitochondrial Calcium Uniporter (MCU) Deficiency Is Neuroprotective in Hyperexcitability by Modulation of Metabolic Pathways and ROS Balance

• DOI: 10.1007/s12035-024-04148-x
• Publication Date: 2024-04-23T14:01:27Z
• Authors: Laura Bierhansl; Lukas Gola; Venu Narayanan; Andre Dik; Sven G. Meuth; Heinz Wiendl; Stjepana Kovac
• Keywords: Uniporter

Abstract Epilepsy is one of the most common neurological disorders in world. Common epileptic drugs generally affect ion channels or neurotransmitters and prevent emergence seizures. However, up to a third patients suffer from drug-resistant epilepsy, there an urgent need develop new therapeutic strategies that go beyond acute antiepileptic (antiseizure) therapies towards therapeutics also might have effects on chronic epilepsy comorbidities such as cognitive decline depression. The mitochondrial calcium uniporter (MCU) mediates rapid Ca 2+ transport through inner membrane. influx essential for functions, but longer elevations intracellular levels are closely associated with seizure-induced neuronal damage, which underlying mechanisms Using neuronal-specific MCU knockout mice (MCU −/−ΔN ), we demonstrate deficiency reduced hippocampal excitability vivo. Furthermore, vitro analyses glioneuronal cells reveal no change total differences handling. reduces ROS production, declines metabolic fluxes, consequently prevents cell death. This effect was observed under pathological conditions, low magnesium culture model seizure-like activity excitotoxic glutamate stimulation, whereby suppresses overload seen WT cells. study highlights importance at interface handling metabolism mediator stress-related dysfunction, indicates modulation potential target future antiepileptogenic therapy.