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

Nat Commun. 2013;4:2034. doi: 10.1038/ncomms3034.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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 / drug effects
  • Cell Nucleus / drug effects
  • Cell Nucleus / enzymology
  • Cell Nucleus / metabolism*
  • Gene Knockdown Techniques
  • Membrane Potential, Mitochondrial / drug effects
  • Mice
  • Mice, Inbred C57BL
  • Neuroprotective Agents / pharmacology*
  • Neurotoxins / toxicity*
  • RNA, Small Interfering / metabolism
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Repressor Proteins / metabolism*
  • Synapses / drug effects
  • Synapses / metabolism
  • Transcription, Genetic / drug effects*

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Calcium Channels
  • Neuroprotective Agents
  • Neurotoxins
  • Npas4 protein, mouse
  • RNA, Small Interfering
  • Receptors, N-Methyl-D-Aspartate
  • Repressor Proteins
  • mitochondrial calcium uniporter
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Calcium