Coenzyme Q<sub>1</sub>as a probe for mitochondrial complex I activity in the intact perfused hyperoxia-exposed wild-type and<i>Nqo1</i>-null mouse lung

Bongard, Robert D.; Myers, Charles R.; Lindemer, Brian; Baumgardt, Shelley; Gonzalez, Frank J.; Merker, Marilyn P.

doi:10.1152/ajplung.00251.2011

Cited by 4 publications

(2 citation statements)

References 54 publications

(87 reference statements)

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“…Multiple endogenous and exogenous oxidants activate NADPH, and many have been used to induce cellular injury in animal and in vitro models. Examples include hyperoxia, hypoxia, inhaled particles, xanthine oxidase, cigarette smoke, and other ROS themselves, all of which contribute to mitochondrial dysfunction by overwhelming enzymes within the OXPHOS metabolic pathway (9,18,69,158). For example, Ghouleh et al (57) recently demonstrated increased expression of Nox-1 in the pulmonary endothelium of patients with PH.…”

Section: Metabolic Pathways and Mitochondria In Pulmonary Hypertension-the "Metabolic Theory"mentioning

confidence: 99%

Mitochondrial dysfunction and pulmonary hypertension: cause, effect, or both

Marshall

Bazán

Zhang

et al. 2018

American Journal of Physiology-Lung Cellular and Molecular Phys

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Pulmonary hypertension describes a heterogeneous disease defined by increased pulmonary artery pressures, and progressive increase in pulmonary vascular resistance due to pathologic remodeling of the pulmonary vasculature involving pulmonary endothelial cells, pericytes, and smooth muscle cells. This process occurs under various conditions, and although these populations vary, the clinical manifestations are the same: progressive dyspnea, increases in right ventricular (RV) afterload and dysfunction, RV-pulmonary artery uncoupling, and right-sided heart failure with systemic circulatory collapse. The overall estimated 5-yr survival rate is 72% in highly functioning patients, and as low as 28% for those presenting with advanced symptoms. Metabolic theories have been suggested as underlying the pathogenesis of pulmonary hypertension with growing evidence of the role of mitochondrial dysfunction involving the major proteins of the electron transport chain, redox-related enzymes, regulators of the proton gradient and calcium homeostasis, regulators of apoptosis, and mitophagy. There remain more studies needed to characterize mitochondrial dysfunction leading to impaired vascular relaxation, increase proliferation, and failure of regulatory mechanisms. The effects on endothelial cells and resulting interactions with their microenvironment remain uncharted territory for future discovery. Additionally, on the basis of observations that the "plexigenic lesions" of pulmonary hypertension resemble the unregulated proliferation of tumor cells, similarities between cancer pathobiology and pulmonary hypertension have been drawn, suggesting interactions between mitochondria and angiogenesis. Recently, mitochondria targeting has become feasible, which may yield new therapeutic strategies. We present a state-of-the-art review of the role of mitochondria in both the pathobiology of pulmonary hypertension and potential therapeutic targets in pulmonary vascular processes.

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Section: Metabolic Pathways and Mitochondria In Pulmonary Hypertension-the "Metabolic Theory"mentioning

confidence: 99%

Mitochondrial dysfunction and pulmonary hypertension: cause, effect, or both

Marshall

Bazán

Zhang

et al. 2018

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…The NQO1 in the lung has been investigated in several studies ( 11 , 15 , 16 ). Recently, Bongard et al have shown that alterations in CoQ1 redox metabolism, either by addition of the complex I inhibitor rotenone or exposure of the animal to hyperoxia, can reveal a decrease in mitochondrial complex I activity ( 18 ). In addition, by using bovine pulmonary arterial EC, they have demonstrated that the cytoplasmic redox status, as reflected in the NADH/NAD + and NADPH/NADP + ratios, affects t-PMET reduction of thiazine compounds and NQO1-mediated quinone reduction ( 16 ).…”

Section: Redox Buffer Systemsmentioning

confidence: 99%

Redox Regulation of Ion Channels in the Pulmonary Circulation

Olschewski

Weir

2015

Antioxidants & Redox Signaling

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Significance: The pulmonary circulation is a low-pressure, low-resistance, highly compliant vasculature. In contrast to the systemic circulation, it is not primarily regulated by a central nervous control mechanism. The regulation of resting membrane potential due to ion channels is of integral importance in the physiology and pathophysiology of the pulmonary vasculature. Recent Advances: Redox-driven ion conductance changes initiated by direct oxidation, nitration, and S-nitrosylation of the cysteine thiols and indirect phosphorylation of the threonine and serine residues directly affect pulmonary vascular tone. Critical Issues: Molecular mechanisms of changes in ion channel conductance, especially the identification of the sites of action, are still not fully elucidated. Future Directions: Further investigation of the interaction between redox status and ion channel gating, especially the physiological significance of S-glutathionylation and S-nitrosylation, could result in a better understanding of the physiological and pathophysiological importance of these mediators in general and the implications of such modifications in cellular functions and related diseases and their importance for targeted treatment strategies. Antioxid. Redox Signal. 22, 465–485.

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Depleted energy charge and increased pulmonary endothelial permeability induced by mitochondrial complex I inhibition are mitigated by coenzyme Q1 in the isolated perfused rat lung

Bongard

Yan

Hoffmann

et al. 2013

Free Radical Biology and Medicine

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Mitochondrial dysfunction is associated with various forms of lung injury and disease that also involve alterations in pulmonary endothelial permeability, but the relationship, if any, between the two is not well understood. This question was addressed by perfusing the isolated intact rat lung with a buffered physiological saline solution in the absence or presence of the mitochondrial complex I inhibitor rotenone (20 uM). As compared to control, rotenone depressed whole lung tissue ATP from 5.66 ± 0.46 (SEM) to 2.34 ± 0.15 (SEM) μmol·gram−1 dry lung, with concomitant increases in the ADP:ATP and AMP:ATP ratios. Rotenone also increased lung perfusate lactate (from 12.36 ± 1.64 (SEM) to 38.62 ± 3.14 μmol·15 min−1 perfusion·gm−1 dry lung) and the lactate:pyruvate ratio, but had no detectable impact on lung tissue GSH:GSSG redox status. The amphipathic quinone, coenzyme Q1 (CoQ1; 50 μM) mitigated the impact of rotenone on the adenine nucleotide balance, wherein mitigation was blocked by NAD(P)H:quinone oxidoreductase 1 (NQO1) or mitochondrial complex III inhibitors. In separate studies, rotenone increased the pulmonary vascular endothelial filtration coefficient (Kf) from 0.043 ± 0.010 (SEM) to 0.156 ± 0.037 (SEM) ml·min−1·cm H2O−1·gm−1 dry lung weight, and CoQ1 protected against the effect of rotenone on Kf. A second complex I inhibitor, piericidin A, qualitatively reproduced the impact of rotenone on Kf and the lactate/pyruvate ratio. Taken together, the observations imply that pulmonary endothelial barrier integrity depends on mitochondrial bioenergetics as reflected in lung tissue ATP levels and that compensatory activation of whole lung glycolysis cannot protect against pulmonary endothelial hyperpermeability in response to mitochondrial blockade. The study further suggests that low molecular weight amphipathic quinones may have therapeutic utility in protecting lung barrier function in mitochondrial insufficiency.

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Coenzyme Q₁as a probe for mitochondrial complex I activity in the intact perfused hyperoxia-exposed wild-type andNqo1-null mouse lung

Cited by 4 publications

References 54 publications

Mitochondrial dysfunction and pulmonary hypertension: cause, effect, or both

Mitochondrial dysfunction and pulmonary hypertension: cause, effect, or both

Redox Regulation of Ion Channels in the Pulmonary Circulation

Depleted energy charge and increased pulmonary endothelial permeability induced by mitochondrial complex I inhibition are mitigated by coenzyme Q1 in the isolated perfused rat lung

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Coenzyme Q1as a probe for mitochondrial complex I activity in the intact perfused hyperoxia-exposed wild-type andNqo1-null mouse lung

Cited by 4 publications

References 54 publications

Mitochondrial dysfunction and pulmonary hypertension: cause, effect, or both

Mitochondrial dysfunction and pulmonary hypertension: cause, effect, or both

Redox Regulation of Ion Channels in the Pulmonary Circulation

Depleted energy charge and increased pulmonary endothelial permeability induced by mitochondrial complex I inhibition are mitigated by coenzyme Q1 in the isolated perfused rat lung

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Product

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Coenzyme Q₁as a probe for mitochondrial complex I activity in the intact perfused hyperoxia-exposed wild-type andNqo1-null mouse lung