Mitochondrial calcium uniporter Mcu controls excitotoxicity and is transcriptionally repressed by neuroprotective nuclear calcium signals.
Nat Commun
; 4: 2034, 2013.
Article
in En
| MEDLINE
| ID: mdl-23774321
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Repressor Proteins
/
Transcription, Genetic
/
Calcium Channels
/
Cell Nucleus
/
Neuroprotective Agents
/
Calcium Signaling
/
Neurotoxins
Type of study:
Prognostic_studies
Limits:
Animals
Language:
En
Journal:
Nat Commun
Journal subject:
BIOLOGIA
/
CIENCIA
Year:
2013
Document type:
Article
Affiliation country:
United kingdom