Abstract |
NO-mediated toxicity contributes to neuronal damage after hypoxia; however, the molecular mechanisms involved are still a matter of controversy. Since mitochondria play a key role in signalling neuronal death, we aimed to determine the role of nitrative stress in hypoxia-induced mitochondrial damage. Therefore, we analysed the biochemical and ultrastructural impairment of these organelles in the optic lobe of chick embryos after in vivo hypoxia-reoxygenation. Also, we studied the NO-dependence of damage and examined modulation of mitochondrial nitric oxide synthase (mtNOS) after the hypoxic event. A transient but substantial increase in mtNOS content and activity was observed at 0-2 h posthypoxia, resulting in accumulation of nitrated mitochondrial proteins measured by immunoblotting. However, no variations in nNOS content were observed in the homogenates, suggesting an increased translocation to mitochondria and not a general de novo synthesis. In parallel with mtNOS kinetics, mitochondria exhibited prolonged inhibition of maximal complex I activity and ultrastructural phenotypes associated with swelling, namely, fading of cristae, intracristal dilations and membrane disruption. Administration of the selective nNOS inhibitor 7-nitroindazole 20 min before hypoxia prevented complex I inhibition and most ultrastructural damage. In conclusion, we show here for the first time that hypoxia induces NO-dependent complex I inhibition and ultrastructural damage by increasing mitochondrial NO in the developing brain.
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Authors | Sebastián Giusti, Daniela P Converso, Juan J Poderoso, Sara Fiszer de Plazas |
Journal | The European journal of neuroscience
(Eur J Neurosci)
Vol. 27
Issue 1
Pg. 123-31
(Jan 2008)
ISSN: 1460-9568 [Electronic] France |
PMID | 18184317
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Enzyme Inhibitors
- Indazoles
- Nitric Oxide
- Nitric Oxide Synthase
- Electron Transport Complex I
- 7-nitroindazole
- NG-Nitroarginine Methyl Ester
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Topics |
- Animals
- Central Nervous System
(embryology, metabolism, ultrastructure)
- Chick Embryo
- Dose-Response Relationship, Drug
- Electron Transport Complex I
(metabolism)
- Enzyme Inhibitors
(pharmacology)
- Gene Expression Regulation, Developmental
(physiology)
- Hypoxia
(metabolism, pathology, physiopathology)
- Indazoles
(pharmacology)
- Microscopy, Electron, Transmission
- Mitochondria
(drug effects, enzymology, ultrastructure)
- NG-Nitroarginine Methyl Ester
(pharmacology)
- Nitric Oxide
(metabolism)
- Nitric Oxide Synthase
(metabolism)
- Time Factors
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