ubiquinone and triphenylmethylphosphonium

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.

Topics: Acetylcysteine; Adenosine Triphosphate; Animals; Aorta; Cattle; Cell Respiration; Cells, Cultured; Endothelial Cells; Energy Metabolism; Glycolysis; Hydrogen Peroxide; Metalloporphyrins; Mitochondria; Onium Compounds; Organophosphorus Compounds; Oxidation-Reduction; Oxidative Stress; Oxygen Consumption; Plastoquinone; Protons; Reactive Oxygen Species; Superoxide Dismutase; Superoxides; Trityl Compounds; Ubiquinone

We used the fruit fly Drosophila melanogaster to test the effects of feeding the superoxide dismutase (SOD) mimetic drugs Euk-8 and -134 and the mitochondria-targeted mitoquinone (MitoQ) on lifespan and oxidative stress resistance of wild type and SOD-deficient flies. Our results reaffirm the findings by other workers that exogenous antioxidant can rescue pathology associated with compromised defences to oxidative stress, but fail to extend the lifespan of normal, wild type animals. All three drugs showed a dose-dependent increase in toxicity in wild type flies, an effect that was exacerbated in the presence of the redox-cycling drug paraquat. However, important findings from this study were that in SOD-deficient flies, where the antioxidant drugs increased lifespan, the effects were sex-specific and, for either sex, the effects were also variable depending on (1) the stage of development from which the drugs were given, and (2) the magnitude of the dose. These findings place significant constraints on the role of oxidative stress in normal ageing.

Topics: Aging; Animals; Animals, Genetically Modified; Antioxidants; Dose-Response Relationship, Drug; Drosophila melanogaster; Female; Free Radicals; Genes, Insect; Homozygote; Longevity; Male; Models, Statistical; Onium Compounds; Organophosphorus Compounds; Oxidative Stress; Paraquat; RNA Interference; Sex Factors; Superoxide Dismutase; Temperature; Time Factors; Trityl Compounds; Ubiquinone

Mitochondrial-targeted antioxidants that selectively block mitochondrial oxidative damage and prevent some types of cell death have been developed. These antioxidants are ubiquinone and tocopherol derivatives and are targeted to mitochondria by covalent attachment to a lipophilic triphenylphosphonium cation. Because of the large mitochondrial membrane potential, these cations accumulated within mitochondria inside cells, where the antioxidant moiety prevents lipid peroxidation and protects mitochondria from oxidative damage. The mitochondrially localized ubiquinone also protected mammalian cells from hydrogen peroxide-induced apoptosis while an untargeted ubiquinone analogue was ineffective against apoptosis. When fed to mice these compounds accumulated within the brain, heart, and liver; therefore, using these mitochondrial-targeted antioxidants may help investigations of the role of mitochondrial oxidative damage in animal models of aging.

Topics: Animals; Antioxidants; Apoptosis; Electron Transport; Female; Humans; Indicators and Reagents; Jurkat Cells; Mice; Mitochondria, Liver; Molecular Structure; Onium Compounds; Organophosphorus Compounds; Oxidation-Reduction; Rats; Thiobarbituric Acid Reactive Substances; Trityl Compounds; Ubiquinone

In the present study we investigated the changes in the hepatic mitochondrial respiratory system in the transition from weaning to adulthood in the rat. We conceptually divided the system into blocks of reactions that produced or consumed mitochondrial membrane potential and then measured the kinetic responses of these blocks of reactions to changes in this potential in isolated liver mitochondria from 25- and 60-day-old rats using succinate as substrate. Moreover, we considered the mitochondrial membrane potential producers to be divided into blocks of reactions that reduced or oxidized ubiquinone-2 (Q-2) and then measured the kinetic responses of these two blocks to changes in Q-2 redox state as well as the flux control coefficients and the cytochrome content. We found that adult rats exhibited significantly higher state 3 respiratory rates with increased kinetic response of the substrate oxidation pathway to the mitochondrial membrane potential, slightly decreased activity of the phosphorylating system, increased kinetic responses of both Q-2 reducers and oxidizers to Q-2 redox state, and increased cytochrome content. Our results indicate that important changes in the hepatic mitochondrial respiratory system occur in the transition from weaning to adulthood in rats.

Topics: Age Factors; Animals; Cell Respiration; Cytochromes; Kinetics; Male; Membrane Potentials; Mitochondria, Liver; Oligomycins; Onium Compounds; Oxidation-Reduction; Oxygen Consumption; Phosphorylation; Rats; Rats, Wistar; Rubidium; Trityl Compounds; Ubiquinone