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Nitric oxide, cytochrome c and mitochondria.
1Department of Biochemistry, University of Cambridge, U.K.
Biochemical Society Symposium
|September 16, 2000
Summary
Nitric oxide (NO) and peroxynitrite inhibit mitochondrial respiration, impacting cellular function and potentially causing neurotoxicity and apoptosis. These molecules affect key respiratory enzymes and mitochondrial integrity.
Area of Science:
- Biochemistry
- Cell Biology
- Neuroscience
Background:
- Nitric oxide (NO) and peroxynitrite (ONOO-) are signaling molecules with significant roles in physiology and pathology.
- Mitochondrial dysfunction is implicated in various diseases, including neurodegenerative disorders.
Purpose of the Study:
- To investigate the inhibitory effects of NO and ONOO- on mitochondrial respiration.
- To elucidate the mechanisms by which NO and ONOO- induce cellular damage and apoptosis.
Main Methods:
- Experiments using isolated enzymes, mitochondria, and cell cultures (astrocytes, macrophages).
- Measurement of mitochondrial respiration, enzyme activity, and apoptosis markers.
- Utilized NO donors and hypoxia/ischemia models.
Main Results:
- NO reversibly inhibits cytochrome oxidase at nanomolar concentrations, affecting cellular respiration.
- Prolonged NO exposure leads to Complex I inhibition, potentially via thiol nitrosylation.
- ONOO- inhibits multiple mitochondrial complexes (I, II, V), aconitase, and creatine kinase, inducing mitochondrial permeability transition pore opening and cytochrome c release.
- Ischemia induces cytochrome c release and caspase activation, suggesting apoptosis.
Conclusions:
- NO and ONOO- are potent inhibitors of mitochondrial respiration, contributing to NO's physiological and cytotoxic effects.
- Mitochondrial dysfunction induced by NO and ONOO- can lead to neurotoxicity and apoptosis.
- Cytochrome c release is a key event in ischemia-induced apoptosis.