mitoquinone and triphenylmethylphosphonium

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