Journal article
Bioenergetic effects of mitochondrial-targeted coenzyme Q analogs in endothelial cells
The Journal of pharmacology and experimental therapeutics, Vol.342(3), pp.709-719
09/2012
DOI: 10.1124/jpet.112.195586
PMCID: PMC3422527
PMID: 22661629
Abstract
Mitochondrial-targeted analogs of coenzyme Q (CoQ) are under development to reduce oxidative damage induced by a variety of disease states. However, there is a need to understand the bioenergetic effects of these agents and whether or not these effects are related to redox properties, including their known pro-oxidant effects. We examined the bioenergetic effects of two mitochondrial-targeted CoQ analogs in their quinol forms, mitoquinol (MitoQ) and plastoquinonyl-decyl-triphenylphosphonium (SkQ1), in bovine aortic endothelial cells. We used an extracellular oxygen and proton flux analyzer to assess mitochondrial action at the intact-cell level. Both agents, in dose-dependent fashion, reduced the oxygen consumption rate (OCR) directed at ATP turnover (OCR(ATP)) (IC₅₀ values of 189 ± 13 nM for MitoQ and 181 ± 7 for SKQ1; difference not significant) while not affecting or mildly increasing basal oxygen consumption. Both compounds increased extracellular acidification in the basal state consistent with enhanced glycolysis. Both compounds enhanced mitochondrial superoxide production assessed by using mitochondrial-targeted dihydroethidium, and both increased H₂O₂ production from mitochondria of cells treated before isolation of the organelles. The manganese superoxide dismutase mimetic manganese(III) tetrakis(1-methyl-4-pyridyl)porphyrin did not alter or actually enhanced the actions of the targeted CoQ analogs to reduce OCR(ATP). In contrast, N-acetylcysteine mitigated this effect of MitoQ and SkQ1. In summary, our data demonstrate the important bioenergetic effects of targeted CoQ analogs. Moreover, these effects are mediated, at least in part, through superoxide production but depend on conversion to H₂O₂. These bioenergetic and redox actions need to be considered as these compounds are developed for therapeutic purposes.
Details
- Title: Subtitle
- Bioenergetic effects of mitochondrial-targeted coenzyme Q analogs in endothelial cells
- Creators
- Brian D Fink - Departments of Internal Medicine/Endocrinology, University of Iowa, Iowa City, Iowa, USAJudith A HerleinMark A YorekAmanda M FennerRobert J KernsWilliam I Sivitz
- Resource Type
- Journal article
- Publication Details
- The Journal of pharmacology and experimental therapeutics, Vol.342(3), pp.709-719
- DOI
- 10.1124/jpet.112.195586
- PMID
- 22661629
- PMCID
- PMC3422527
- ISSN
- 0022-3565
- eISSN
- 1521-0103
- Grant note
- T32 GM067795 / NIGMS NIH HHS R01 HL073166 / NHLBI NIH HHS T32GM067795 / NIGMS NIH HHS 5R01HL073166 / NHLBI NIH HHS
- Language
- English
- Date published
- 09/2012
- Academic Unit
- Pharmaceutical Sciences and Experimental Therapeutics; Fraternal Order of Eagles Diabetes Research Center; Endocrinology and Metabolism; Medicinal and Natural Products Chemistry; Internal Medicine
- Record Identifier
- 9984094368702771
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