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Redox control of hepatic cell death
Hannes Hentze1, Markus Latta, Gerald Künstle
1Faculty of Biology, M-668, University of Konstanz, Universitätsstrasse 10, D-78457 Konstanz, Germany.
Toxicology Letters
|March 12, 2003
Summary
Glutathione depletion prevents liver cell death from death receptor overstimulation. A healthy glutathione status is critical for initiating apoptosis in liver cells.
Area of Science:
- Hepatology
- Cellular Biology
- Biochemistry
Background:
- Necrotic liver failure, such as from acetaminophen overdose, is linked to glutathione depletion.
- Fulminant apoptotic liver destruction via death receptors (TNFR1, CD95) occurs without reduced glutathione levels.
Purpose of the Study:
- To investigate the impact of glutathione depletion on liver sensitivity to CD95- or TNFR1-mediated hepatotoxicity.
- To determine if glutathione status is essential for receptor-mediated apoptosis.
Main Methods:
- In vivo studies using phorone to induce enzymatic glutathione (GSH) depletion in mice.
- In vitro mechanistic studies in lymphoid cell lines to examine caspase activation pathways.
Main Results:
- Glutathione depletion significantly disabled receptor-mediated hepatic apoptosis in vivo.
- Pro-caspase-8 activation at the CD95 death receptor and pro-caspase-9 activation in mitochondria require sufficient intracellular reduced glutathione for activation.
Conclusions:
- An intact glutathione status is a critical determinant for the execution of receptor-mediated apoptosis in the liver.
- Reduced glutathione is essential for the activation of key caspases involved in apoptosis signaling.