Faculty Collaboration Database

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. Free Radic Biol Med 2013 Dec;65:1455-1463

Date

08/06/2013

Pubmed ID

23912160

Pubmed Central ID

PMC3924785

DOI

10.1016/j.freeradbiomed.2013.07.040

Scopus ID

2-s2.0-84890437171 (requires institutional sign-in at Scopus site)   21 Citations

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.

Author List

Bongard RD, Yan K, Hoffmann RG, Audi SH, Zhang X, Lindemer BJ, Townsley MI, Merker MP

Authors

Said Audi PhD Professor in the Biomedical Engineering department at Marquette University
Ke Yan PhD Associate Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adenosine Triphosphate
Animals
Anti-Bacterial Agents
Blood-Air Barrier
Capillary Permeability
Electron Transport Complex I
Electron Transport Complex III
Endothelium, Vascular
Energy Metabolism
Glycolysis
Lactic Acid
Lung
Lung Injury
Male
Mitochondria
NAD(P)H Dehydrogenase (Quinone)
Oxidation-Reduction
Pyridines
Pyruvic Acid
Rats
Rats, Sprague-Dawley
Reperfusion
Rotenone
Ubiquinone
Uncoupling Agents