title: Mitochondrial calcium uniporter Mcu controls excitotoxicity and is transcriptionally repressed by neuroprotective nuclear calcium signals.
abstract: 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.
authors.affiliation: Centre for Integrative Physiology, University of Edinburgh, Edinburgh, UK.
authors.forename: Jing
authors.initials: J
authors.lastname: Qiu
authors.forename: Yan-Wei
authors.initials: YW
authors.lastname: Tan
authors.forename: Anna M
authors.initials: AM
authors.lastname: Hagenston
authors.forename: Marc-Andre
authors.initials: MA
authors.lastname: Martel
authors.forename: Niclas
authors.initials: N
authors.lastname: Kneisel
authors.forename: Paul A
authors.initials: PA
authors.lastname: Skehel
authors.forename: David J A
authors.initials: DJ
authors.lastname: Wyllie
authors.forename: Hilmar
authors.initials: H
authors.lastname: Bading
authors.forename: Giles E
authors.initials: GE
authors.lastname: Hardingham
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009498:Neurotoxins / Q000633:toxicity*; D034741:RNA, Small Interfering / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D013569:Synapses / Q000187:drug effects / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D002118:Calcium; D015220:Calcium Channels; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D018696:Neuroprotective Agents; D009498:Neurotoxins; D034741:RNA, Small Interfering; D016194:Receptors, N-Methyl-D-Aspartate; D012097:Repressor Proteins; C533005:Npas4 protein, mouse; C034703:mitochondrial calcium uniporter