Mitochondrial calcium uniporter Mcu controls excitotoxicity and is transcriptionally repressed by neuroprotective nuclear calcium signals

Jing Qiu, Yan-Wei Tan, Anna M. Hagenston, Marc-Andre Martel, Niclas Kneisel, Paul A. Skehel, David J. A. Wyllie, Hilmar Bading () and Giles E. Hardingham ()
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Jing Qiu: Centre for Integrative Physiology, University of Edinburgh
Yan-Wei Tan: Interdisciplinary Center for Neurosciences (IZN)
Anna M. Hagenston: Interdisciplinary Center for Neurosciences (IZN)
Marc-Andre Martel: Centre for Integrative Physiology, University of Edinburgh
Niclas Kneisel: Interdisciplinary Center for Neurosciences (IZN)
Paul A. Skehel: Centre for Integrative Physiology, University of Edinburgh
David J. A. Wyllie: Centre for Integrative Physiology, University of Edinburgh
Hilmar Bading: Interdisciplinary Center for Neurosciences (IZN)
Giles E. Hardingham: Centre for Integrative Physiology, University of Edinburgh

Nature Communications, 2013, vol. 4, issue 1, 1-12

Abstract: Abstract 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 induction of Npas4, resulting in the inhibition of NMDA receptor-induced mitochondrial Ca2+ uptake and preventing excitotoxic death. This establishes Mcu and the pathways regulating its expression as important determinants of excitotoxicity, which may represent therapeutic targets for excitotoxic disorders.

Date: 2013
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DOI: 10.1038/ncomms3034

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