Nitric oxide produced in rat liver mitochondria causes oxidative stress and impairment of respiration after transient hypoxia

ABSTRACT Nitric oxide (NO) is produced in mam‐ mals by different isoforms of NO synthase (NOS), in‐ cluding the constitutive mitochondrial enzyme (mtNOS). Here we demonstrate that the concentration of NO resulting from a mitochondrial NOS activity increases under hypoxic conditions in isolated rat l...

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Bibliographic Details
Published in:The FASEB journal 2003-12, Vol.17 (15), p.2194-2201
Main Authors: Schild, Lorenz, Reinheckel, Thomas, Reiser, Michael, Horn, Thomas F. W., Wolf, Gerald, Augustin, Wolfgang
Format: Article
Language:English
Subjects:
Animals
Cell Hypoxia
Cell Respiration
Enzyme Inhibitors - pharmacology
Mitochondria, Liver - drug effects
Mitochondria, Liver - metabolism
NG-Nitroarginine Methyl Ester - pharmacology
Nitric Oxide - biosynthesis
Nitric Oxide - physiology
Nitric Oxide Synthase - antagonists & inhibitors
oxidative phosphorylation
Oxidative Stress
Oxygen Consumption
protein carbonyls
Rats
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Summary:ABSTRACT Nitric oxide (NO) is produced in mam‐ mals by different isoforms of NO synthase (NOS), in‐ cluding the constitutive mitochondrial enzyme (mtNOS). Here we demonstrate that the concentration of NO resulting from a mitochondrial NOS activity increases under hypoxic conditions in isolated rat liver mitochon‐ dria. We show that mitochondrially derived NO medi‐ ates the impairment of active (state 3) respiration as measured in the presence of the substrates glutamate and malate after reoxygenation. Simultaneously, NO induces oxidative stress in mitochondria, characterized by an increase in the amount of protein carbonyls and a decrease in glutathione (GSH). Both the accumulation of oxidative stress markers during and the im‐ paired respiration after reoxygenation were prevented by blocking NO production with the NOS inhibitor L‐NAME. These observations suggest that mitochon‐ dria are exposed to high amounts of NO generated by a mitochondrial NOS upon hypoxia/reoxygenation. Such increased NO levels, in turn, inhibit mitochon‐ drial respiration and may cause oxidative stress that leads to irreversible impairment of mitochondria.— Schild, L., Reinheckel, T., Reiser, M., Horn, T. F. W., Wolf, G., Augustin, W. Nitric oxide produced in rat liver mitochondria causes oxidative stress and impair‐ ment of respiration after transient hypoxia. FASEB J. 17, 2194‐2201 (2003)
ISSN:0892-6638
1530-6860
DOI:10.1096/fj.02-1170com