Prevention of mitochondrial oxidative damage using targeted antioxidants.
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.
Kelso
Geoffrey F
GF
Department of Chemistry, University of Otago, Box 56, Dunedin, New Zealand.
Porteous
Carolyn M
CM
Hughes
Gillian
G
Ledgerwood
Elizabeth C
EC
Gane
Alison M
AM
Smith
Robin A J
RA
Murphy
Michael P
MP
D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology*; D017209:Apoptosis / Q000502:physiology; D004579:Electron Transport / Q000502:physiology*; D005260:Female; D006801:Humans; D007202:Indicators and Reagents / Q000378:metabolism; D019169:Jurkat Cells; D051379:Mice; D008930:Mitochondria, Liver / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D015394:Molecular Structure; D009861:Onium Compounds / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D009943:Organophosphorus Compounds / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D010084:Oxidation-Reduction; D051381:Rats; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D014320:Triphenylmethyl Compounds / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D014451:Ubiquinone / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology / Q000031:analogs & derivatives
D000975:Antioxidants; D007202:Indicators and Reagents; D009861:Onium Compounds; D009943:Organophosphorus Compounds; D017392:Thiobarbituric Acid Reactive Substances; D014320:Triphenylmethyl Compounds; D014451:Ubiquinone; C011561:triphenylmethylphosphonium; C429014:mitoquinone; C429015:mitoquinol