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

Authors

Robert D. Bongard, Medical College of Wisconsin
Ke Yan, Medical College of WisconsinFollow
Raymond G. Hoffmann, Medical College of Wisconsin
Said H. Audi, Marquette UniversityFollow
Xiao Zhang, Marquette UniversityFollow
Brian J. Lindemer, Medical College of Wisconsin
Mary I. Townsley, University of South Alabama
Marilyn P. Merker, Medical College of Wisconsin

Document Type

Article

Language

eng

Format of Original

9 p.

Publication Date

12-2013

Publisher

Elsevier

Source Publication

Free Radical Biology and Medicine

Source ISSN

0891-5849

Original Item ID

doi: 10.1016/j.freeradbiomed.2013.07.040

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 (K_f) 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 K_f. A second complex I inhibitor, piericidin A, qualitatively reproduced the impact of rotenone on K_f 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.

Comments

Accepted version. Free Radical Biology and Medicine, Vol. 65 (December 2013): 1455-1463. DOI. © 2013 Elsevier. Used with permission.

NOTICE: this is the author’s version of a work that was accepted for publication in Free Radical Biology and Medicine. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Free Radical Biology and Medicine, VOL 65, December 2013, DOI.

Recommended Citation

Bongard, Robert D.; Yan, Ke; Hoffmann, Raymond G.; Audi, Said H.; Zhang, Xiao; Lindemer, Brian J.; Townsley, Mary I.; and Merker, Marilyn P., "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" (2013). Biomedical Engineering Faculty Research and Publications. 277.
https://epublications.marquette.edu/bioengin_fac/277