Rapid uptake of lipophilic triphenylphosphonium cations by mitochondria in vivo following intravenous injection: Implications for mitochondria-specific therapies and probes |
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Authors: | Carolyn M. Porteous Angela Logan Cameron Evans Elizabeth C. Ledgerwood David K. Menon Franklin Aigbirhio Robin A.J. Smith Michael P. Murphy |
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Affiliation: | 1. Department of Chemistry, University of Otago, P.O. Box 56, Dunedin 9054, New Zealand;2. Department of Biochemistry, University of Otago, P.O. Box 56, Dunedin 9054, New Zealand;3. MRC Mitochondrial Biology Unit, Hills Road, Cambridge, CB2 0XY, UK;4. Division of Anaesthesia, University of Cambridge, Box 93, Addenbrooke''s Hospital, Hills Road, Cambridge CB2 0QQ, UK;5. Wolfson Brain Imaging Centre, Department of Clinical Neurosciences, University of Cambridge, Addenbrooke''s Hospital, Hills Road, Cambridge CB2 0QQ, UK |
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Abstract: | BackgroundMitochondrial dysfunction contributes to a range of pathologies, consequently there is a need to monitor mitochondrial function and to intervene pharmacologically to prevent mitochondrial damage. One approach to this is to deliver antioxidants, probes and pharmacophores to mitochondria by conjugation to the lipophilic triphenylphosphonium (TPP) cation that is taken up selectively by mitochondria driven by the membrane potential.ConclusionsOral administration of TPP-conjugated antioxidants protects against mitochondrial damage in vivo. However, there is also a need to deliver molecules rapidly to mitochondria to respond quickly to pathologies and for the real-time assessment of mitochondrial function.MethodsTo see if this was possible we investigated how rapidly TPP cations were taken up by mitochondria in vivo following intravenous (iv) administration.ResultsAlkylTPP cations were accumulated selectively by mitochondria within mice within 5 min of iv injection. The extent of uptake was enhanced 10–30-fold relative to simple alkylTPP cations by attaching functional groups to the TPP cation via long, hydrophobic alkyl chains. Conclusions: Mitochondria-targeted antioxidants, probes and pharmacophores can be delivered into mitochondria within minutes of iv administration.General significanceThese findings greatly extend the utility of mitochondria-targeted lipophilic cations as therapies and probes. |
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Keywords: | DecylTPP, decyltriphenylphosphonium bromide FluoroUndecylTPP, 11-fluoroundecyltriphenylphosphonium mesylate IAM, iodoacetamide IBTP, 4-iodobutylTPP IDTP, 10-iododecylTPP iv, intravenous LC/MS/MS, liquid chromatography&ndash tandem mass spectrometry MitoQ, [10-(4,5-dimethoxy-2-methyl-3,6-dioxo-1,4-cyclohexadien-1-yl)decyl]triphenylphosphonium PET, positron emission tomography TPP, triphenylphosphonium cation ROS, reactive oxygen species TPMP, methyltriphenylphosphonium IAM-TPP, [5-(2-iodo-acetylamino-pentyl]-triphenylphosphoni mesylate |
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