title: A mitochondria-targeted derivative of ascorbate: MitoC.
abstract: Mitochondrial oxidative damage contributes to a wide range of pathologies. One therapeutic strategy to treat these disorders is targeting antioxidants to mitochondria by conjugation to the lipophilic triphenylphosphonium (TPP) cation. To date only hydrophobic antioxidants have been targeted to mitochondria; however, extending this approach to hydrophilic antioxidants offers new therapeutic and research opportunities. Here we report the development and characterization of MitoC, a mitochondria-targeted version of the hydrophilic antioxidant ascorbate. We show that MitoC can be taken up by mitochondria, despite the polarity and acidity of ascorbate, by using a sufficiently hydrophobic link to the TPP moiety. MitoC reacts with a range of reactive species, and within mitochondria is rapidly recycled back to the active ascorbate moiety by the glutathione and thioredoxin systems. Because of this accumulation and recycling MitoC is an effective antioxidant against mitochondrial lipid peroxidation and also decreases aconitase inactivation by superoxide. These findings show that the incorporation of TPP function can be used to target polar and acidic compounds to mitochondria, opening up the delivery of a wide range of bioactive compounds. Furthermore, MitoC has therapeutic potential as a new mitochondria-targeted antioxidant, and is a useful tool to explore the role(s) of ascorbate within mitochondria.
authors.affiliation: MRC Mitochondrial Biology Unit, Wellcome Trust/MRC Building, Cambridge CB2 0XY, UK.
authors.forename: Peter G
authors.initials: PG
authors.lastname: Finichiu
authors.affiliation: Department of Chemistry, University of Otago, P.O. Box 56, Dunedin 9054, New Zealand.
authors.forename: David S
authors.initials: DS
authors.lastname: Larsen
authors.affiliation: Department of Chemistry, University of Otago, P.O. Box 56, Dunedin 9054, New Zealand.
authors.forename: Cameron
authors.initials: C
authors.lastname: Evans
authors.affiliation: Department of Chemistry, University of Otago, P.O. Box 56, Dunedin 9054, New Zealand.
authors.forename: Lesley
authors.initials: L
authors.lastname: Larsen
authors.affiliation: MRC Mitochondrial Biology Unit, Wellcome Trust/MRC Building, Cambridge CB2 0XY, UK.
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Bright
authors.affiliation: MRC Mitochondrial Biology Unit, Wellcome Trust/MRC Building, Cambridge CB2 0XY, UK.
authors.forename: Ellen L
authors.initials: EL
authors.lastname: Robb
authors.affiliation: Laboratory for Metabolism and Bioenergetics, Third Faculty of Medicine, Charles University, 100 00 Prague 10, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Trnka
authors.affiliation: MRC Mitochondrial Biology Unit, Wellcome Trust/MRC Building, Cambridge CB2 0XY, UK.
authors.forename: Tracy A
authors.initials: TA
authors.lastname: Prime
authors.affiliation: MRC Mitochondrial Biology Unit, Wellcome Trust/MRC Building, Cambridge CB2 0XY, UK.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: James
authors.affiliation: Department of Chemistry, University of Otago, P.O. Box 56, Dunedin 9054, New Zealand.
authors.forename: Robin A J
authors.initials: RA
authors.lastname: Smith
authors.affiliation: MRC Mitochondrial Biology Unit, Wellcome Trust/MRC Building, Cambridge CB2 0XY, UK. Electronic address: mpm@mrc-mbu.cam.ac.uk.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Murphy
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000737:chemistry* / Q000494:pharmacology*; D001205:Ascorbic Acid / Q000737:chemistry* / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000975:Antioxidants; D001205:Ascorbic Acid
keywords: Ascorbic acid; Lipid peroxidation; Lipophilic cation; MitoC; MitoPerox; Mitochondria; Mitochondrial targeting