title: 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.
abstract: 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 isolated intact rat lung with a buffered physiological saline solution in the absence or presence of the mitochondrial complex I inhibitor rotenone (20 μM). Compared to control, rotenone depressed whole lung tissue ATP from 5.66 ± 0.46 (SEM) to 2.34 ± 0.15 µmol · g(-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 to 38.62 ± 3.14 µmol · 15 min(-1) perfusion · g(-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 or mitochondrial complex III inhibitors. In separate studies, rotenone increased the pulmonary vascular endothelial filtration coefficient (Kf) from 0.043 ± 0.010 to 0.156 ± 0.037 ml · min(-1) · cm H2O(-1) · g(-1) dry lung, 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.
authors.affiliation: Department of Pulmonary Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Bongard
authors.affiliation: Department of Biostatistics, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
authors.forename: Ke
authors.initials: K
authors.lastname: Yan
authors.affiliation: Department of Biostatistics, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
authors.forename: Raymond G
authors.initials: RG
authors.lastname: Hoffmann
authors.affiliation: Department of Biomedical Engineering, Marquette University, Milwaukee, WI 53201, USA.
authors.forename: Said H
authors.initials: SH
authors.lastname: Audi
authors.affiliation: Department of Biomedical Engineering, Marquette University, Milwaukee, WI 53201, USA.
authors.forename: Xiao
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Lindemer
authors.affiliation: Department of Physiology and Department of Medicine, University of South Alabama, Mobile, AL 36688, USA.
authors.forename: Mary I
authors.initials: MI
authors.lastname: Townsley
authors.affiliation: Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Department of Pharmacology/Toxicology, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Zablocki Veterans Administration Medical Center, Milwaukee, WI 53295, USA. Electronic address: mmerker@mcw.edu.
authors.forename: Marilyn P
authors.initials: MP
authors.lastname: Merker
mesh_terms: D000255:Adenosine Triphosphate / Q000032:analysis; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D015824:Blood-Air Barrier / Q000187:drug effects; D002199:Capillary Permeability; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors*; D014450:Electron Transport Complex III / Q000037:antagonists & inhibitors; D004730:Endothelium, Vascular / Q000378:metabolism; D004734:Energy Metabolism; D006019:Glycolysis; D019344:Lactic Acid / Q000032:analysis; D008168:Lung / Q000098:blood supply*; D055370:Lung Injury; D008297:Male; D008928:Mitochondria / Q000378:metabolism*; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000494:pharmacology; D010084:Oxidation-Reduction / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D019289:Pyruvic Acid / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D015424:Reperfusion; D012402:Rotenone / Q000494:pharmacology*; D014451:Ubiquinone / Q000494:pharmacology*; D014475:Uncoupling Agents / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D011725:Pyridines; D014475:Uncoupling Agents; D012402:Rotenone; D014451:Ubiquinone; D019344:Lactic Acid; D019289:Pyruvic Acid; D000255:Adenosine Triphosphate; C100213:piericidin A; D016660:NAD(P)H Dehydrogenase (Quinone); C507703:NQO1 protein, rat; D042967:Electron Transport Complex I; D014450:Electron Transport Complex III; C025203:Ubiquinone Q1
keywords: Free radicals; Mitochondrial electron transport complex I; Perfused lung; Pulmonary endothelial filtration coefficient; Pulmonary endothelial permeability; Pulmonary endothelium; Quinone
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