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Neuronal excitotoxicity: the role of mitochondria
1Department of Pharmacology and Neuroscience, University of Dundee, Scotland, UK. d.g.nicholls@dundee.ac.uk
Abstract:
Chronic activation of NMDA receptors by glutamate is toxic to cultured neurons. The extensive Ca2+ entry accompanying receptor activation is largely accumulated by the intracellular mitochondria, with resultant effects on mitochondrial membrane potential, ATP synthesis, glycolysis, reactive oxygen species generation and ultimately failure of cytoplasmic Ca2+ homeostasis and cell death. Each of these parameters is inter-related and in this review we describe attempts to separate out each factor to establish the sequence of events following NMDA-receptor activation. The conclusion is that mitochondrial Ca2+ accumulation is a key event in glutamate excitotoxicity, and that cells maintained by glycolysis in the absence of a mitochondrial membrane potential are highly resistant to glutamate excitotoxicity.
Insights
Chronic glutamate exposure is toxic to neurons. Mitochondrial calcium accumulation is key to this excitotoxicity, while glycolysis protects cells.
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Glutamate-induced excitotoxicity via N-methyl-D-aspartate (NMDA) receptors is a significant threat to neuronal survival.
- This excitotoxicity involves extensive calcium (Ca2+) influx, impacting mitochondrial function and cellular homeostasis.
Purpose of the Study:
- To elucidate the sequence of events following NMDA receptor activation in cultured neurons.
- To identify the critical role of mitochondrial Ca2+ accumulation in glutamate excitotoxicity.
Main Methods:
- Review of studies examining the effects of NMDA receptor activation on cellular parameters.
- Analysis of intracellular Ca2+ dynamics, mitochondrial membrane potential, ATP synthesis, and glycolysis.
Main Results:
- Mitochondrial Ca2+ accumulation is a central event in the cascade leading to excitotoxicity.
- Disruption of mitochondrial membrane potential and subsequent effects on ATP synthesis and reactive oxygen species (ROS) generation are consequences of Ca2+ overload.
- Failure of cytoplasmic Ca2+ homeostasis ultimately results in neuronal cell death.
Conclusions:
- Mitochondrial Ca2+ accumulation is a pivotal factor in glutamate excitotoxicity.
- Neuronal resistance to excitotoxicity is significantly enhanced in cells relying on glycolysis, particularly when mitochondrial membrane potential is compromised.