Mitochondrial Nitric-Oxide Synthase: Enzyme Expression, Characterization, and Regulation

Haynes, Virginia; Elfering, Sarah; Traaseth, Nathaniel J.; Giulivi, Cecilia R

doi:10.1023/b:jobb.0000041765.27145.08

Cited by 82 publications

(60 citation statements)

References 63 publications

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“…It has been shown that NOS is located in mitochondria (16,17). Zaobornyj et al (35) reported that NO is produced in the myocardium in physiologically relevant quantities by two isoforms of NOS: i) an isoenzyme located in the mitochondria, which accounts for ~55-62% of total heart NO production, and ii) an isoenzyme located in caveolae of the sarcoplasmic reticulum and plasma membrane, which accounts for the remaining 38-45%.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, uncoupling of NOS3 by decreased BH4 appears to mediate cardiac hypertrophy and remodeling by pressure overload. Interestingly, accumulated evidence has shown the presence of NOS in mitochondria (16)(17)(18). The mitochondrial NOS isoenzyme is a constitutive protein of the mitochondrial inner membrane that generates NO in a Ca 2+ -dependent reaction (19).…”

Section: Introductionmentioning

confidence: 99%

“…The mitochondrial NOS isoenzyme is a constitutive protein of the mitochondrial inner membrane that generates NO in a Ca 2+ -dependent reaction (19). Although the role of NO in mitochondria remains to be elucidated, mitochondrial events such as oxygen consumption and ROS production appear to be regulated by NO (17,20,21). Notably, mitochondrial NOS also seems to cause uncoupling (22).…”

Section: Introductionmentioning

confidence: 99%

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Decreased cardiac mitochondrial tetrahydrobiopterin in a rat model of pressure overload

Shimizu

Ishibashi

Kumagai

et al. 2013

International Journal of Molecular Medicine

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Abstract. Sustained cardiac pressure overload induces mitochondrial dysfunction and apoptosis of cardiomyocytes leading to pathological cardiac hypertrophy and dysfunction. Mitochondrial nitric oxide synthase (NOS) appears to cause uncoupling, which produces reactive oxygen species (ROS) instead of nitric oxide (NO), by a decrease in the cofactor tetrahydrobiopterin (BH4). This study focused on examining the changes in mitochondrial BH4 levels during cardiac pressure overload. Chronic cardiac pressure overload was generated by abdominal aortic banding in rats. Levels of BH4 and its oxidized form were measured in the mitochondria isolated from the left ventricle (LV) and the post-mitochondrial supernatants. Chronic aortic banding increased blood pressure, and induced cardiac hypertrophy and fibrosis. Notably, the BH4 levels were decreased while its oxidized forms were increased in LV mitochondria, but not in the post-mitochondrial supernatants containing the cytosol and microsome. Anti-neuronal NOS antibody-sensitive protein was detected in the cardiac mitochondria. Moreover, continuous administration of BH4 to rats with pressure overload increased mitochondrial BH4 levels and reduced cardiac fibrosis and matrix metallopeptidase activity, but not cardiac hypertrophy. These findings show the possibility that NOS uncoupling by decreased cardiac mitochondrial BH4 levels is implicated, at least in part, in the development of cardiac fibrosis, leading to cardiac dysfunction induced by pressure overload.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Decreased cardiac mitochondrial tetrahydrobiopterin in a rat model of pressure overload

Shimizu

Ishibashi

Kumagai

et al. 2013

International Journal of Molecular Medicine

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“…good or bad NO, the complex interplay between NO and mitochondria remains to be defined in the context of fatty liver disease from alcohol and obesity. Moreover, the critical importance of understanding the regulation of the mitochondrial respiratory chain by NO in hepatic physiology and pathophysiology is supported by several studies demonstrating that localized NO production can occur within the organelle through a specific mitochondrial NOS isoform or via metabolism of nitrite to NO [119][120][121].…”

Section: Interplay Between Nitric Oxide and Mitochondria In Fatty LIVmentioning

confidence: 99%

Mitochondrial dysfunction and oxidative stress in the pathogenesis of alcohol- and obesity-induced fatty liver diseases

Mantena

King

Andringa

et al. 2008

Free Radical Biology and Medicine

388

302

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Fatty liver disease associated with chronic alcohol consumption or obesity/type 2 diabetes has emerged as a serious public health problem. Steatosis, accumulation of triglyceride in hepatocytes, is now recognized as a critical "first-hit" in the pathogenesis of liver disease. It is proposed that steatosis "primes" the liver to progress to more severe liver pathologies when individuals are exposed to subsequent metabolic and/or environmental stressors or "second-hits". Genetic risk factors can also influence the susceptibility and severity of fatty liver disease. Furthermore, oxidative stress, disrupted nitric oxide (NO) signaling, and mitochondrial dysfunctional are proposed to be key molecular events that accelerate or worsen steatosis and initiate progression to steatohepatitis and fibrosis. This review article will discuss the following topics regarding the pathobiology and molecular mechanisms responsible for fatty liver disease: 1) the "two-hit" or "multi-hit" hypothesis; 2) the role of mitochondrial bioenergetic defects and oxidant stress; 3) interplay between NO and mitochondria in fatty liver disease; 4) genetic risk factors and oxidative stress responsive genes; and 5) the feasibility of antioxidants for treatment.

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“…One established mechanism of this regulatory function is reversible inhibition of cytochrome c oxidase (17). The discovery of mitochondrial nitric-oxide synthase emphasized the significance of NO in mitochondrial functions (18,19), although NO can also reach mitochondria from external sources because of its hydrophobic nature and facile diffusion in biomembranes (20,21). An increased production of NO has been demonstrated during early stages of apoptosis indicating its potential involvement in regulation of programmed cell death (22,23).…”

Section: Cyt Cmentioning

confidence: 99%

Nitric Oxide Inhibits Peroxidase Activity of Cytochrome c· Cardiolipin Complex and Blocks Cardiolipin Oxidation

Vlasova

Tyurin

Kapralov

et al. 2006

Journal of Biological Chemistry

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The increased production of NO during the early stages of apoptosis indicates its potential involvement in the regulation of programmed cell death through yet to be identified mechanisms. Recently, an important role for catalytically competent peroxidase form of pentacoordinate cytochrome c (cyt c) in a complex with a mitochondriaspecific phospholipid, cardiolipin (CL), has been demonstrated during execution of the apoptotic program. Because the cyt c⅐CL complex acts as CL oxygenase and selectively oxidizes CL in apoptotic cells in a reaction dependent on the generation of protein-derived (tyrosyl) radicals, we hypothesized that binding and nitrosylation of cyt c regulates CL oxidation. Here we demonstrate by low temperature electron paramagnetic resonance spectroscopy that CL facilitated interactions of ferro-and ferri-states of cyt c with NO and NO ؊ , respectively, to yield a mixture of penta-and hexa-coordinate nitrosylated cyt c. In the nitrosylated cyt c⅐CL complex, NO chemically reacted with H 2 O 2 -activated peroxidase intermediates resulting in their reduction. A dose-dependent quenching of H 2 O 2 -induced protein-derived radicals by NO donors was shown using direct electron paramagnetic resonance measurements as well as immuno-spin trapping with antibodies against protein 5,5-dimethyl-1-pyrroline N-oxide-nitrone adducts. In the presence of NO donors, H 2 O 2 -induced oligomeric forms of cyt c positively stained for 3-nitrotyrosine confirming the reactivity of NO toward tyrosyl radicals of cyt c. Interaction of NO with the cyt c⅐CL complex inhibited its peroxidase activity with three different substrates: CL, etoposide, and 3,3-diaminobenzidine. Given the importance of CL oxidation in apoptosis, mass spectrometry analysis was utilized to assess the effects of NO on oxidation of 1,12,2-tertalinoleoyl cardiolipin. NO effectively inhibited 1,12,2-tertalinoleoyl cardiolipin oxidation catalyzed by the peroxidase activity of cyt c. Thus, NO can act as a regulator of peroxidase activity of cyt c⅐CL complexes.

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Mitochondrial Nitric-Oxide Synthase: Enzyme Expression, Characterization, and Regulation

Cited by 82 publications

References 63 publications

Decreased cardiac mitochondrial tetrahydrobiopterin in a rat model of pressure overload

Decreased cardiac mitochondrial tetrahydrobiopterin in a rat model of pressure overload

Mitochondrial dysfunction and oxidative stress in the pathogenesis of alcohol- and obesity-induced fatty liver diseases

Nitric Oxide Inhibits Peroxidase Activity of Cytochrome c· Cardiolipin Complex and Blocks Cardiolipin Oxidation

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