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Mitochondrial Preparation from Microglia for Glycan Analysis
Published on: May 30, 2025
L-Glutamine-induced apoptosis in microglia is mediated by mitochondrial dysfunction
Nina Svoboda1, Hubert H Kerschbaum
1Department of Cell Biology, University of Salzburg, Salzburg, Austria.
The European Journal of Neuroscience
|July 21, 2009
Summary
High L-glutamine levels in the brain, seen in conditions like hepatic failure, trigger microglial cell death. This occurs via the intrinsic apoptosis pathway, involving mitochondrial dysfunction and caspase activation.
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Astrocytes regulate L-glutamate and L-glutamine metabolism for neuronal function.
- Pathological conditions, such as hepatic failure, lead to elevated brain L-glutamine and ammonium.
- The Trojan horse hypothesis suggests L-glutamine hydrolysis increases local ammonium, causing mitochondrial dysfunction.
Purpose of the Study:
- To investigate the toxic effects of L-glutamine on microglia.
- To elucidate the mechanisms underlying L-glutamine-induced microglial apoptosis.
- To identify key molecular players in L-glutamine toxicity.
Main Methods:
- Exposure of primary murine microglia and BV-2 cells to L-glutamine and ammonium.
- Assessment of apoptotic markers: chromatin condensation, annexin-V labeling, cell shrinkage, fragmentation.
- Inhibition studies using 6-diazo-5-oxo-L-norleucine (glutaminase inhibitor) and L-methionine sulfoximine (glutamine synthetase inhibitor).
- Measurement of reactive oxygen species (ROS) production.
- Apoptosis inhibition studies using alpha-tocopherol, N(G)-methyl-L-arginine, Cyclosporin A, and Z-LEHD-FMK.
Main Results:
- L-glutamine exposure induced microglial apoptosis, characterized by nuclear changes, cell shrinkage, and apoptotic body formation.
- Inhibition of phosphate-activated glutaminase and glutamine synthetase attenuated L-glutamine- and ammonium-induced apoptosis, respectively.
- L-glutamine and ammonium increased ROS production.
- Apoptosis was ameliorated by radical scavengers, nitric oxide synthase blockers, and mitochondrial permeability transition pore inhibitors.
- Blockade of caspase-9 activity prevented L-glutamine-induced apoptosis.
Conclusions:
- Mitochondrial hydrolysis of L-glutamine and subsequent ammonium accumulation trigger the intrinsic apoptosis pathway in microglia.
- Mitochondrial dysfunction and caspase-9 activation are critical events in L-glutamine-induced microglial cell death.
- These findings highlight a novel mechanism of microglial injury relevant to neurological disorders associated with hyperammonemia.
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