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The recent identification of the mitochondrial Ca²⁺ uniporter gene (Mcu/Ccdc109a) has enabled us to address its role, and that of mitochondrial Ca²⁺ uptake, in neuronal excitotoxicity. Here we show that exogenously expressed Mcu is mitochondrially localized and increases mitochondrial Ca²⁺ levels following NMDA receptor activation, leading to increased mitochondrial membrane depolarization and excitotoxic cell death. Knockdown of endogenous Mcu expression reduces NMDA-induced increases in mitochondrial Ca²⁺, resulting in lower levels of mitochondrial depolarization and resistance to excitotoxicity. Mcu is subject to dynamic regulation as part of an activity-dependent adaptive mechanism that limits mitochondrial Ca²⁺ overload when cytoplasmic Ca²⁺ levels are high. Specifically, synaptic activity transcriptionally represses Mcu, via a mechanism involving the nuclear Ca²⁺ and CaM kinase-mediated …