Hypoxia induces complex I inhibition and ultrastructural damage by increasing mitochondrial nitric oxide in developing CNS.

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.

• 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)

Chemical References

• Enzyme Inhibitors
• Indazoles
• Nitric Oxide
• Nitric Oxide Synthase
• Electron Transport Complex I
• 7-nitroindazole
• NG-Nitroarginine Methyl Ester

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