Rapid uptake of lipophilic triphenylphosphonium cations by mitochondria in vivo following intravenous injection: implications for mitochondria-specific therapies and probes.

TitleRapid uptake of lipophilic triphenylphosphonium cations by mitochondria in vivo following intravenous injection: implications for mitochondria-specific therapies and probes.
Publication TypeJournal Article
Year of Publication2010
AuthorsPorteous, CM, Logan, A, Evans, C, Ledgerwood, EC, Menon, DK, Aigbirhio, F, Smith, RAJ, Murphy, MP
JournalBiochim Biophys Acta
Volume1800
Issue9
Pagination1009-17
Date Published2010 Sep
ISSN0006-3002
KeywordsAnimals, Antioxidants, Cations, Drug Delivery Systems, Female, Injections, Intravenous, Membrane Potential, Mitochondrial, Mice, Mitochondria, Mitochondrial Diseases, Organophosphorus Compounds
Abstract

BACKGROUND: Mitochondrial 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.CONCLUSIONS: Oral 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.METHODS: To see if this was possible we investigated how rapidly TPP cations were taken up by mitochondria in vivo following intravenous (iv) administration.RESULTS: AlkylTPP 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 SIGNIFICANCE: These findings greatly extend the utility of mitochondria-targeted lipophilic cations as therapies and probes.

DOI10.1016/j.bbagen.2010.06.001
Alternate JournalBiochim. Biophys. Acta
Citation Key10.1016/j.bbagen.2010.06.001
PubMed ID20621583
Grant ListG0001237 / / Medical Research Council / United Kingdom
G0600986 / / Medical Research Council / United Kingdom
G9439390 / / Medical Research Council / United Kingdom
MC_U105663142 / / Medical Research Council / United Kingdom