Rapid and extensive uptake and activation of hydrophobic triphenylphosphonium cations within cells.

TitleRapid and extensive uptake and activation of hydrophobic triphenylphosphonium cations within cells.
Publication TypeJournal Article
Year of Publication2008
AuthorsRoss, MF, Prime, TA, Abakumova, I, James, AM, Porteous, CM, Smith, RAJ, Murphy, MP
JournalBiochem J
Volume411
Issue3
Pagination633-45
Date Published2008 May 01
ISSN1470-8728
KeywordsAnimals, Biological Transport, Cations, Cell Membrane, Fibroblasts, Humans, Hydrophobic and Hydrophilic Interactions, Jurkat Cells, Mitochondria, Liver, Molecular Structure, Onium Compounds, Oxidation-Reduction, Rats, Time Factors, Trityl Compounds
Abstract

Mitochondria-targeted molecules comprising the lipophilic TPP (triphenylphosphonium) cation covalently linked to a hydrophobic bioactive moiety are used to modify and probe mitochondria in cells and in vivo. However, it is unclear how hydrophobicity affects the rate and extent of their uptake into mitochondria within cells, making it difficult to interpret experiments because their intracellular concentration in different compartments is uncertain. To address this issue, we compared the uptake into both isolated mitochondria and mitochondria within cells of two hydrophobic TPP derivatives, [3H]MitoQ (mitoquinone) and [3H]DecylTPP, with the more hydrophilic TPP cation [3H]TPMP (methyltriphenylphosphonium). Uptake of MitoQ by mitochondria and cells was described by the Nernst equation and was approximately 5-fold greater than that for TPMP, as a result of its greater binding within the mitochondrial matrix. DecylTPP was also taken up extensively by cells, indicating that increased hydrophobicity enhanced uptake. Both MitoQ and DecylTPP were taken up very rapidly into cells, reaching a steady state within 15 min, compared with approximately 8 h for TPMP. This far faster uptake was the result of the increased rate of passage of hydrophobic TPP molecules through the plasma membrane. Within cells MitoQ was predominantly located within mitochondria, where it was rapidly reduced to the ubiquinol form, consistent with its protective effects in cells and in vivo being due to the ubiquinol antioxidant. The strong influence of hydrophobicity on TPP cation uptake into mitochondria within cells facilitates the rational design of mitochondria-targeted compounds to report on and modify mitochondrial function in vivo.

DOI10.1042/BJ20080063
Alternate JournalBiochem. J.
Citation Key10.1042/BJ20080063
PubMed ID18294140
Grant ListMC_U105663142 / / Medical Research Council / United Kingdom