Nature communications, 2013-06, Vol.4 (1), p.2034, Article 2034
2013
Details
- Autor(en) / Beteiligte
- Titel
- Mitochondrial calcium uniporter Mcu controls excitotoxicity and is transcriptionally repressed by neuroprotective nuclear calcium signals
- Ist Teil von
- Nature communications, 2013-06, Vol.4 (1), p.2034, Article 2034
- Ort / Verlag
- England: Nature Publishing Group
- Erscheinungsjahr
- 2013
- Link zum Volltext
- Quelle
- Elektronische Zeitschriftenbibliothek - Freely accessible e-journals
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 2041-1723eISSN: 2041-1723DOI: 10.1038/ncomms3034Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3709514
- Format
- –
- Schlagworte
- 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, Investigations, Kinases, Membrane Potential, Mitochondrial - drug effects, Mice, Mice, Inbred C57BL, Mitochondria, Neurons, Neuroprotective Agents - pharmacology, Neurosciences, Neurotoxins - toxicity, Physiology, Receptors, N-Methyl-D-Aspartate - metabolism, Repressor Proteins - metabolism, RNA, Small Interfering - metabolism, Synapses - drug effects, Synapses - metabolism, Transcription, Genetic - drug effects