Regulation of the rate of synthesis of nitric oxide by Mg 2+ and hypoxia. Studies in rat heart mitochondria

Manzo‐Ávalos, Salvador; Pérez-Vázquez, Victoriano; Ramı́rez, Joel; Aguilera-Aguirre, Leopoldo; González‐Hernández, Juan Carlos; Clemente‐Guerrero, Mónica; Villalobos‐Molina, Rafael; Saavedra‐Molina, Alfredo

doi:10.1007/s007260200022

Cited by 18 publications

(14 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Indeed, heart mtNOS activity is dependent on cation concentration in the reaction medium. Extramitochondrial free Mg 2ϩ , a well-known mitochondrial Ca 2ϩ uniporter blocker, inhibits NO production in rat heart mitochondria by 60% in a dose-dependent manner (91,143). This concept is in agreement with other reports (40,41) showing that blocking the mitochondrial Ca 2ϩ uniporter with ruthenium red inhibits mitochondrial NO production.…”

Section: Heart Nosssupporting

confidence: 82%

“…Interestingly, substrate-energized heart mitochondria produce NO without additional supplementation with Ca 2ϩ (128), indicating that the concentration of Ca 2ϩ in the mitochondrial preparation may be sufficient to sustain a basal mtNOS activity. Nevertheless, the functional studies performed on cardiac mitochondria isolated from mice (70,72) or rats (91,115,126,140,141,143) demonstrated the activation of mitochondrial NO production upon addition of Ca 2ϩ to the reaction medium. Taking into account that heart mitochondrial matrix Ca 2ϩ concentrations differ from cytosolic Ca 2ϩ concentrations (39,85), the existence of a Ca 2ϩ -dependent NOS within mitochondria has significant consequences in terms of the differential regulation of this enzyme.…”

Section: Heart Nossmentioning

confidence: 99%

“…There is a general consensus that iNOS is transiently expressed in the heart during immune responses under stress (8) and, therefore, during pathophysiological conditions of the myocardium such as in ischemia-reperfusion injury (133), septicemia (125), heart failure (146), as well as during aging (138). During the last fifteen years, different groups have used various experimental approaches and reported the presence of mtNOS in the heart (1,10,16,40,45,60,66,72,79,91,115,129,130,140,141,143,147). Regarding the localization of mtNOS, one interesting study provided evidence about the docking of eNOS to the outer mitochondrial membrane in endothelial cells (52).…”

Section: Heart Nossmentioning

confidence: 99%

See 2 more Smart Citations

Strategic localization of heart mitochondrial NOS: a review of the evidence

Zaobornyj

Ghafourifar²

2012

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

chondria play a central role in cell energy provision and in signaling. Nitric oxide (NO) is a free radical with primary regulatory functions in the heart and involved in a broad array of key processes in cardiac metabolism. Specific NO synthase (NOS) isoforms are confined to distinct locations in cardiomyocytes. The present article reviews the chemical reactions through which NO interacts with biomolecules and exerts some of its crucial roles. Specifically, the article discusses the reactions of NO with mitochondrial targets and the subcellular localization of NOS within the myocardium and analyzes the available data about heart mitochondrial NOS activity and identity. The article also describes the regulation of heart mtNOS by the distinctive mitochondrial environment by showing the effects of Ca 2ϩ , O2, L-arginine, mitochondrial transmembrane potential, and the metabolic states on heart mitochondrial NO production. The article depicts the effects of NO on heart function and highlights the relevance of NO production within mitochondria. Finally, the evidence on the functional implications of heart mitochondrial NOS is delineated with emphasis on chronic hypoxia and ischemia-reperfusion studies. mitochondrial nitric oxide synthase; calcium; transmembrane potential; hypoxia; ischemia-reperfusion SINCE THE RECOGNITION OF MITOCHONDRIA as the powerhouses of the cells, numerous studies have shown that these organelles play a central role in various biological processes. Under physiological conditions, mitochondria provide the cell with both the energy and the signals involved in the genetic expression and metabolic regulation (35). About two decades ago, the discovery that nitric oxide (NO) is the endothelium-derived relaxing factor caused a paradigm shift in the understanding of cardiovascular physiology and pathophysiology (68,102). NO is a gaseous uncharged 30-Da molecule. It is highly diffusible in aqueous and lipid phases and possesses a biochemistry that supports its role as one of the most versatile molecules in various biological regulatory and signaling processes (76,86,134).In the cardiovascular system, NO plays integral roles not only in the regulation of vascular smooth muscle tone but also in the function of ion channels, myocyte contraction, O 2 consumption, apoptosis, and hypertrophic myocardial remodeling (36, 92). In cardiac endothelial cells and myocytes, NO is generated by NO synthase (NOS) isozymes: neuronal NOS (nNOS or NOS1), inducible NOS (iNOS or NOS2), and endothelial NOS (eNOS or NOS3) (71, 75). Initially, eNOS was considered to be the only isoform constitutively expressed in myocytes and thus the source of NO involved in the autocrine regulation of myocardial contraction and Ca 2ϩ homeostasis (7, 37). However, subsequent studies showed that NOS is targeted to the cardiac sarcoplasmic reticulum (SR) (137) and localized in cardiac mitochondria (72). Additionally, iNOS has been shown to be expressed in the myocardium upon induction by cytokines (8) during inflammatory responses implicated in...

show abstract

Section: Heart Nosssupporting

confidence: 82%

Section: Heart Nossmentioning

confidence: 99%

Section: Heart Nossmentioning

confidence: 99%

See 1 more Smart Citation

Strategic localization of heart mitochondrial NOS: a review of the evidence

Zaobornyj

Ghafourifar²

2012

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

show abstract

“…In contrast to the nitrotyrosine immunoreactivity intensities, the patterns after reoxygenation in the presence of L-arginine were independent of the duration of hypoxia-anoxia and mirrored the pattern exhibited by mitochondria before hypoxia-anoxia. These results suggest that the same proteins become selectively nitrated during reoxygenation, a condition of oxidative and nitrative stress (23,24,47) generated via excessive superoxide formation (20) along with the full recovery of ⅐ NO production (34). Nevertheless, the high selectivity and rapid turnover of the nitro groups at the target proteins during a "denitration-nitration" cycle suggest that this process is more than simply oxidant damage and clearance.…”

Section: Resultsmentioning

confidence: 99%

Rapid and Selective Oxygen-regulated Protein Tyrosine Denitration and Nitration in Mitochondria

Koeck

Hazen

et al. 2004

Journal of Biological Chemistry

167

133

View full text Add to dashboard Cite

Growing evidence connects a cumulative formation of 3-nitrotyrosyl adducts in proteins as a marker for oxidative damage with the pathogenesis of various diseases and pathological conditions associated with oxidative stress. A physiological signaling role for protein nitration has also been suggested. Controlled "denitration" would be essential for such a contribution of protein nitration to cellular regulatory processes. Thus, we further characterized such a potentially controlled, reversible tyrosine nitration that occurs in respiring mitochondria during oxygen deprivation followed by reoxygenation, which we recently discovered. Mitochondria constitute cellular centers of protein nitration and are leading candidates for a "nitrative" regulation. Mitochondria are capable of completely eliminating 3-nitrotyrosyl adducts during 20 min of hypoxia-anoxia and undergoing a selective partial reduction after only 5 min. This denitration is independent of protein degradation but depends on the oxygen tension. Reoxygenation re-establishes protein tyrosine nitration patterns that are almost identical to the pattern that occurs before hypoxia-anoxia, with nitration levels that depend on the duration of hypoxia-anoxia. The identified mitochondrial targets of this process are critical for energy and antioxidant homeostasis and, therefore, cell and tissue viability. This cycle of protein nitration and denitration shows analogies to protein phosphorylation, and we demonstrate that the cycle meets most of the criteria for a cellular signaling mechanism. Taken together, our data reveal that protein tyrosine nitration in mitochondria can be controlled, is target-selective and rapid, and is dynamic enough to serve as a nitrative regulatory signaling process that likely affects cellular energy, redox homeostasis, and pathological conditions when these features become disturbed.

show abstract

“…Several groups have shown Ca 2+ sensitivity of mtNOS in various organs, tissues, and cells [19,[36][37][38]. However, an earlier study suggested that mtNOS is not Ca 2+ sensitive and its activity is stimulated by supplementing mitochondria with L-arginine [39].…”

Section: Ca 2+ -Dependence Of Heart Mtnosmentioning

confidence: 99%

Hypoxia/Reoxygenation of isolated rat heart mitochondria causes cytochrome c release and oxidative stress; evidence for involvement of mitochondrial nitric oxide synthase

Zenebe

Nazarewicz

Parihar

et al. 2007

Journal of Molecular and Cellular Cardiology

View full text Add to dashboard Cite

The objective of the present study was to delineate the molecular mechanisms for mitochondrial contribution to oxidative stress induced by hypoxia and reoxygenation in the heart. The present study introduces a novel model allowing real-time studying mitochondria under hypoxia and reoxygenation, and describes the significance of intramitochondrial calcium homeostasis and mitochondrial nitric oxide synthase (mtNOS) for oxidative stress. The present study shows that incubating isolated rat heart mitochondria under hypoxia followed by reoxygenation, but not hypoxia per se, causes cytochrome c release from the mitochondria, oxidative modification of mitochondrial lipids and proteins, and inactivation of mitochondrial enzymes susceptible to inactivation by peroxynitrite. Those alterations were prevented when mtNOS was inhibited or mitochondria were supplemented with antioxidant peroxynitrite scavengers. The present study shows mitochondria independent of other cellular components respond to hypoxia/reoxygenation by elevating intramitochondrial ionized calcium and stimulating mtNOS. The present study proposes a crucial role for heart mitochondrial calcium homeostasis and mtNOS in oxidative stress induced by hypoxia/ reoxygenation.

show abstract

Regulation of the rate of synthesis of nitric oxide by Mg 2+ and hypoxia. Studies in rat heart mitochondria

Cited by 18 publications

References 31 publications

Strategic localization of heart mitochondrial NOS: a review of the evidence

Strategic localization of heart mitochondrial NOS: a review of the evidence

Rapid and Selective Oxygen-regulated Protein Tyrosine Denitration and Nitration in Mitochondria

Hypoxia/Reoxygenation of isolated rat heart mitochondria causes cytochrome c release and oxidative stress; evidence for involvement of mitochondrial nitric oxide synthase

Contact Info

Product

Resources

About