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 ∼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 ∼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.
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Research Article|
April 14 2008
Rapid and extensive uptake and activation of hydrophobic triphenylphosphonium cations within cells
Meredith F. Ross;
Meredith F. Ross
*Medical Research Council Dunn Human Nutrition Unit, Wellcome Trust/MRC Building, Hills Road, Cambridge CB2 0XY, U.K.
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Tracy A. Prime;
Tracy A. Prime
*Medical Research Council Dunn Human Nutrition Unit, Wellcome Trust/MRC Building, Hills Road, Cambridge CB2 0XY, U.K.
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Irina Abakumova;
Irina Abakumova
*Medical Research Council Dunn Human Nutrition Unit, Wellcome Trust/MRC Building, Hills Road, Cambridge CB2 0XY, U.K.
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Andrew M. James;
Andrew M. James
*Medical Research Council Dunn Human Nutrition Unit, Wellcome Trust/MRC Building, Hills Road, Cambridge CB2 0XY, U.K.
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Carolyn M. Porteous;
Carolyn M. Porteous
§Department of Biochemistry, University of Otago, PO Box 56, Dunedin, New Zealand
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Robin A. J. Smith;
Robin A. J. Smith
†Department of Chemistry, University of Otago, PO Box 56, Dunedin, New Zealand
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Michael P. Murphy
Michael P. Murphy
1
*Medical Research Council Dunn Human Nutrition Unit, Wellcome Trust/MRC Building, Hills Road, Cambridge CB2 0XY, U.K.
1To whom correspondence should be addressed (email mpm@mrc-dunn.cam.ac.uk).
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Publisher: Portland Press Ltd
Received:
January 08 2008
Revision Received:
February 22 2008
Accepted:
February 25 2008
Accepted Manuscript online:
February 25 2008
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2008 Biochemical Society
2008
Biochem J (2008) 411 (3): 633–645.
Article history
Received:
January 08 2008
Revision Received:
February 22 2008
Accepted:
February 25 2008
Accepted Manuscript online:
February 25 2008
Citation
Meredith F. Ross, Tracy A. Prime, Irina Abakumova, Andrew M. James, Carolyn M. Porteous, Robin A. J. Smith, Michael P. Murphy; Rapid and extensive uptake and activation of hydrophobic triphenylphosphonium cations within cells. Biochem J 1 May 2008; 411 (3): 633–645. doi: https://doi.org/10.1042/BJ20080063
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