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High glucose-induced oxidative stress and mitochondrial dysfunction in neurons
James W Russell1, David Golovoy, Andrea M Vincent
1Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA. jruss@umich.edu
Summary
Mild glucose increases trigger reactive oxygen species (ROS) and mitochondrial swelling, leading to neuronal apoptosis. Inhibiting ROS, mitochondrial depolarization, or caspase activation prevents this glucotoxicity in primary neurons.
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- High glucose levels can induce cellular stress and damage.
- Mitochondria play a critical role in cellular energy production and apoptosis.
- Reactive oxygen species (ROS) are implicated in various pathological processes.
Purpose of the Study:
- To investigate the link between glucose-induced ROS, mitochondrial dysfunction, and programmed cell death in primary neurons.
- To identify key molecular events in glucose-induced neuronal apoptosis.
- To explore potential therapeutic targets for glucotoxicity.
Main Methods:
- Primary dorsal root ganglion (DRG) neurons were treated with high glucose concentrations (45 mM).
- Measurements included ROS levels, mitochondrial size and membrane potential, ATP levels, and caspase activation.
- Specific inhibitors of the mitochondrial electron transport chain (myxothiazole, thenoyltrifluoroacetone) and adenosine nucleotide translocase (bongkrekic acid) were used.
Main Results:
- High glucose rapidly increased ROS and mitochondrial size in DRG neurons.
- This was accompanied by mitochondrial membrane depolarization (MMD), ATP depletion, and activation of caspase-3 and -9.
- Inhibitors of the mitochondrial electron transport chain and ANT blocked glucose-induced ROS, MMD, and caspase activation.
Conclusions:
- Mild elevations in glucose induce ROS and mitochondrial swelling, preceding neuronal apoptosis.
- Glucotoxicity is mediated by ROS production, mitochondrial depolarization, and caspase activation.
- Inhibiting these pathways, or stabilizing the ANT, can protect neurons from glucose-induced cell death.