Depolarized mitochondrial membrane potential and protection with duroquinone in isolated perfused lungs from rats exposed to hyperoxia. J Appl Physiol (1985) 2022 Feb 01;132(2):346-356
Date
12/24/2021Pubmed ID
34941441Pubmed Central ID
PMC8816614DOI
10.1152/japplphysiol.00565.2021Scopus ID
2-s2.0-85124056241 (requires institutional sign-in at Scopus site) 5 CitationsAbstract
Dissipation of mitochondrial membrane potential (Δψm) is a hallmark of mitochondrial dysfunction. Our objective was to use a previously developed experimental-computational approach to estimate tissue Δψm in intact lungs of rats exposed to hyperoxia and to evaluate the ability of duroquinone (DQ) to reverse any hyperoxia-induced depolarization of lung Δψm. Rats were exposed to hyperoxia (>95% O2) or normoxia (room air) for 48 h, after which lungs were excised and connected to a ventilation-perfusion system. The experimental protocol consisted of measuring the concentration of the fluorescent dye rhodamine 6 G (R6G) during three single-pass phases: loading, washing, and uncoupling, in which the lungs were perfused with and without R6G and with the mitochondrial uncoupler FCCP, respectively. For normoxic lungs, the protocol was repeated with 1) rotenone (complex I inhibitor), 2) rotenone and either DQ or its vehicle (DMSO), and 3) rotenone, glutathione (GSH), and either DQ or DMSO added to the perfusate. Hyperoxic lungs were studied with and without DQ and GSH added to the perfusate. Computational modeling was used to estimate lung Δψm from R6G data. Rat exposure to hyperoxia resulted in partial depolarization (-33 mV) of lung Δψm and complex I inhibition depolarized lung Δψm by -83 mV. Results also demonstrate the efficacy of DQ to fully reverse both rotenone- and hyperoxia-induced lung Δψm depolarization. This study demonstrates hyperoxia-induced Δψm depolarization in intact lungs and the utility of this approach for assessing the impact of potential therapies such as exogenous quinones that target mitochondria in intact lungs.NEW & NOTEWORTHY This study is the first to measure hyperoxia-induced Δψm depolarization in isolated perfused lungs. Hyperoxia resulted in a partial depolarization of Δψm, which was fully reversed with duroquinone, demonstrating the utility of this approach for assessing the impact of potential therapies that target mitochondria such as exogenous quinones.
Author List
Audi SH, Ganesh S, Taheri P, Zhang X, Dash RK, Clough AV, Jacobs ERAuthors
Said Audi PhD Professor in the Biomedical Engineering department at Marquette UniversityRanjan K. Dash PhD Professor in the Biomedical Engineering department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsBenzoquinones
Hyperoxia
Lung
Membrane Potential, Mitochondrial
Rats
