Bioenergetic effects of mitochondrial-targeted coenzyme Q analogs in endothelial cells.
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.
Departments of Internal Medicine/Endocrinology, University of Iowa, Iowa City, Iowa, USA.
Brian D
BD
Fink
Judith A
JA
Herlein
Mark A
MA
Yorek
Amanda M
AM
Fenner
Robert J
RJ
Kerns
William I
WI
Sivitz
D000111:Acetylcysteine / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D002417:Cattle; D019069:Cell Respiration / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D004734:Energy Metabolism / Q000187:drug effects; D006019:Glycolysis / Q000187:drug effects / Q000502:physiology; D006861:Hydrogen Peroxide / Q000378:metabolism; D008665:Metalloporphyrins / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology*; D009861:Onium Compounds / Q000494:pharmacology; D009943:Organophosphorus Compounds / Q000494:pharmacology; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D010101:Oxygen Consumption / Q000187:drug effects / Q000502:physiology; D010971:Plastoquinone / Q000031:analogs & derivatives / Q000494:pharmacology; D011522:Protons; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D014320:Triphenylmethyl Compounds / Q000494:pharmacology; D014451:Ubiquinone / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology
C532038:10-(6'-plastoquinonyl)decyltriphenylphosphonium; D008665:Metalloporphyrins; D009861:Onium Compounds; D009943:Organophosphorus Compounds; D011522:Protons; D017382:Reactive Oxygen Species; D014320:Triphenylmethyl Compounds; D013481:Superoxides; D014451:Ubiquinone; C011561:triphenylmethylphosphonium; C429015:mitoquinol; C050950:tetrakis(N-methyl-4-pyridiniumyl)porphine manganese(III) complex; D000255:Adenosine Triphosphate; D006861:Hydrogen Peroxide; D013482:Superoxide Dismutase; D010971:Plastoquinone; D000111:Acetylcysteine