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Identification of an inducible nitric oxide synthase in diaphragm mitochondria from septic mice: its relation with
Luis C López1, Germaine Escames, Víctor Tapias
1Departamento de Fisiología, Facultad de Medicina, Instituto de Biotecnología, Universidad de Granada, Avenida de Madrid, 11, E-18012 Granada, Spain. luisca@ugr.es
Abstract:
Sepsis provokes an induction of inducible nitric oxide synthase (iNOS) and melatonin down-regulates its expression and activity. Looking for an inducible mtNOS isoform, we induced sepsis by cecal ligation and puncture in both normal and iNOS knockout mice and studied the changes in mtNOS activity. We also studied the effects of mtNOS induction in mitochondrial function, and the role of melatonin against induced mtNOS and mitochondrial dysfunction. The activity of mtNOS and nitrite levels significantly increased after sepsis in iNOS+/+ mice. These animals showed a significant inhibition of the respiratory chain activity and an increase in mitochondrial oxidative stress, reflected in the disulfide/glutathione ratio, glutathione redox cycling enzymes activity and lipid peroxidation levels. Interestingly, mtNOS activity remained unchanged in iNOS-/- septic mice, and mitochondria of these animals were unaffected by sepsis. Melatonin administration to iNOS+/+ mice counteracted mtNOS induction and respiratory chain failure, restoring the redox status. The results support the existence of an inducible mtNOS that is likely coded by the same gene as iNOS. The results also suggest that sepsis-induced mtNOS is responsible for the increase of mitochondrial impairment due to oxidative stress in sepsis, perhaps due to the high production of NO. Melatonin treatment prevents mitochondrial failure at the same extend as the lack of iNOS gene.
Insights
Sepsis induces mitochondrial nitric oxide synthase (mtNOS), impairing cellular respiration and increasing oxidative stress. Melatonin treatment or the absence of inducible nitric oxide synthase (iNOS) protects against these sepsis-induced mitochondrial dysfunctions.
Area of Science:
- Biochemistry
- Molecular Biology
- Pathophysiology
Background:
- Sepsis is associated with inducible nitric oxide synthase (iNOS) induction, and melatonin is known to down-regulate its expression.
- The existence and role of a mitochondrial isoform of inducible nitric oxide synthase (mtNOS) in sepsis remain less understood.
Purpose of the Study:
- To investigate the presence and activity of an inducible mtNOS isoform during sepsis.
- To determine the impact of mtNOS induction on mitochondrial function and oxidative stress.
- To evaluate the protective role of melatonin against sepsis-induced mtNOS activity and mitochondrial dysfunction.
Main Methods:
- Sepsis was induced in wild-type and iNOS knockout mice using cecal ligation and puncture.
- Mitochondrial nitric oxide synthase (mtNOS) activity, nitrite levels, respiratory chain function, and oxidative stress markers were measured.
- The effects of melatonin administration on these parameters were assessed.
Main Results:
- Sepsis significantly increased mtNOS activity and nitrite levels in wild-type mice, accompanied by impaired respiratory chain function and elevated oxidative stress.
- Mitochondria in iNOS knockout mice remained unaffected by sepsis, with no significant change in mtNOS activity.
- Melatonin treatment in wild-type septic mice reversed the mtNOS induction, restored respiratory chain function, and normalized redox status.
Conclusions:
- Results support the existence of an inducible mtNOS, likely encoded by the same gene as iNOS.
- Sepsis-induced mtNOS contributes to mitochondrial dysfunction and oxidative stress, potentially via excessive nitric oxide production.
- Melatonin effectively prevents sepsis-induced mitochondrial failure, similar to the protective effect observed in iNOS knockout mice.
