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

• Published in: Nature communications Vol. 4; no. 1; p. 2034
• Main Authors: Qiu, Jing, Tan, Yan-Wei, Hagenston, Anna M., Martel, Marc-Andre, Kneisel, Niclas, Skehel, Paul A., Wyllie, David J. A., Bading, Hilmar, Hardingham, Giles E.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 18.06.2013; Nature Publishing Group; Nature Pub. Group
• Subjects: 631/378; 631/80/86/1999; Animals; Basic Helix-Loop-Helix Transcription Factors - metabolism; Biological Transport - drug effects; Calcium - metabolism; Calcium Channels - metabolism; Calcium Signaling - drug effects; Calcium-Calmodulin-Dependent Protein Kinases - metabolism; Cell death; Cell Death - drug effects; Cell Nucleus - drug effects; Cell Nucleus - enzymology; Cell Nucleus - metabolism; Gene Knockdown Techniques; Humanities and Social Sciences; Investigations; Kinases; Membrane Potential, Mitochondrial - drug effects; Mice; Mice, Inbred C57BL; Mitochondria; multidisciplinary; Neurons; Neuroprotective Agents - pharmacology; Neurosciences; Neurotoxins - toxicity; Physiology; Receptors, N-Methyl-D-Aspartate - metabolism; Repressor Proteins - metabolism; RNA, Small Interfering - metabolism; Science; Science (multidisciplinary); Synapses - drug effects; Synapses - metabolism; Transcription, Genetic - drug effects
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms3034

The recent identification of the mitochondrial Ca 2+ uniporter gene (Mcu/Ccdc109a) has enabled us to address its role, and that of mitochondrial Ca 2+ uptake, in neuronal excitotoxicity. Here we show that exogenously expressed Mcu is mitochondrially localized and increases mitochondrial Ca 2+ 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 Ca 2+ , 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 Ca 2+ overload when cytoplasmic Ca 2+ levels are high. Specifically, synaptic activity transcriptionally represses Mcu, via a mechanism involving the nuclear Ca 2+ and CaM kinase-mediated induction of Npas4, resulting in the inhibition of NMDA receptor-induced mitochondrial Ca 2+ 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. Calcium uptake by the mitochondrial calcium uniporter is implicated in excitotoxicity. This study shows that the uniporter gene product mediates mitochondrial calcium uptake and depolarisation in neurons during excitotoxicity, and is transcriptionally repressed by neuroprotective nuclear calcium signals.