Selective targeting of an antioxidant to mitochondria

Mitochondrial oxidative damage contributes significantly to a range of huma n disorders, including neurodegenerative diseases, ischaemia-reperfusion in jury and ageing associated dysfunction. To prevent this damage we have deli vered a molecule containing the active antioxidant moiety of vitamin E to m itochondria. This was carried out by covalently coupling the antioxidant mo iety to a lipophilic triphenylphosphonium cation. This mitochondrially targ eted antioxidant, 2-[2-(triphenylphosphonio)ethyl]-3,4-dihydro-2,5,7,8-tetr amethyl-2H-1-benzopyran-6-ol bromide (TPPB), accumulated several-hundred fo ld within the mitochondrial matrix, driven by the organelle's large membran e potential. When cells were incubated with micromolar concentrations of TP PB, they accumulated millimolar concentrations within their mitochondria. T he amount of TPPB taken up by mitochondria was approximate to 80-fold great er than endogenous levels of vitamin E. Consequently the targeted derivativ e of vitamin E protected mitochondrial function from oxidative damage far m ore effectively than vitamin E itself. The mitochondrially targeted antioxi dant TPPB has potential as an antioxidant therapy for disorders involving m itochondrial oxidative damage. It also suggests a new family of mitochondri ally targeted antioxidants, redox-active and pharmacologically active molec ules designed to prevent damage or manipulate mitochondrial function.