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Peroxynitrite and brain mitochondria: evidence for increased proton leak
P S Brookes1, J M Land, J B Clark
1Department of Neurochemistry, Institute of Neurology, University College London, England, UK.
Journal of Neurochemistry
|May 8, 1998
Summary
Peroxynitrite initially stimulates, then inhibits mitochondrial respiration in brain cells. This effect is linked to lipid peroxidation, increasing proton leak and potentially impacting neurodegenerative diseases.
Area of Science:
- Biochemistry
- Neuroscience
- Mitochondrial Biology
Background:
- Peroxynitrite is known to inhibit mitochondrial respiration.
- The precise mechanisms of peroxynitrite's effects on mitochondria, especially in brain tissue, require further elucidation.
Purpose of the Study:
- To investigate the effects of peroxynitrite on mitochondrial respiration in rat brain mitochondria.
- To explore the role of lipid peroxidation and proton leak in peroxynitrite-induced mitochondrial dysfunction.
Main Methods:
- Exposure of rat brain mitochondria to sequential additions of peroxynitrite.
- Measurement of state 4 and state 3 respiration.
- Assessment of mitochondrial membrane potential.
- Evaluation of the effects of Cyclosporin A and Trolox.
Main Results:
- Peroxynitrite initially stimulated state 4 respiration, indicating increased proton leak.
- Further peroxynitrite exposure inhibited state 4 respiration.
- No stimulation of state 3 respiration or enzyme activity was observed.
- The stimulation was linked to decreased mitochondrial membrane potential and prevented by Trolox, suggesting lipid peroxidation.
Conclusions:
- Peroxynitrite induces a biphasic effect on brain mitochondrial respiration, with initial stimulation mediated by lipid peroxidation-induced proton leak.
- This mechanism may be particularly relevant to neurodegenerative disorders involving mitochondrial oxidative damage.
- The mitochondrial permeability transition pore is not involved in the initial stimulation.