title: Accumulation of lipophilic dications by mitochondria and cells.
abstract: Lipophilic monocations can pass through phospholipid bilayers and accumulate in negatively-charged compartments such as the mitochondrial matrix, driven by the membrane potential. This property is used to visualize mitochondria, to deliver therapeutic molecules to mitochondria and to measure the membrane potential. In theory, lipophilic dications have a number of advantages over monocations for these tasks, as the double charge should lead to a far greater and more selective uptake by mitochondria, increasing their therapeutic potential. However, the double charge might also limit the movement of lipophilic dications through phospholipid bilayers and little is known about their interaction with mitochondria. To see whether lipophilic dications could be taken up by mitochondria and cells, we made a series of bistriphenylphosphonium cations comprising two triphenylphosphonium moieties linked by a 2-, 4-, 5-, 6- or 10-carbon methylene bridge. The 5-, 6- and 10-carbon dications were taken up by energized mitochondria, whereas the 2- and 4-carbon dications were not. The accumulation of the dication was greater than that of the monocation methyltriphenylphosphonium. However, the uptake of dications was only described by the Nernst equation at low levels of accumulation, and beyond a threshold membrane potential of 90-100 mV there was negligible increase in dication uptake. Interestingly, the 5- and 6-carbon dications were not accumulated by cells, due to lack of permeation through the plasma membrane. These findings indicate that conjugating compounds to dications offers only a minor increase over monocations in delivery to mitochondria. Instead, this suggests that it may be possible to form dications within mitochondria that then remain within the cell.
authors.affiliation: Medical Research Council Dunn Human Nutrition Unit, Wellcome Trust/MRC Building, Hills Road, Cambridge CB2 2XY, UK.
authors.forename: Meredith F
authors.initials: MF
authors.lastname: Ross
authors.forename: Tatiana
authors.initials: T
authors.lastname: Da Ros
authors.forename: Frances H
authors.initials: FH
authors.lastname: Blaikie
authors.forename: Tracy A
authors.initials: TA
authors.lastname: Prime
authors.forename: Carolyn M
authors.initials: CM
authors.lastname: Porteous
authors.forename: Inna I
authors.initials: II
authors.lastname: Severina
authors.forename: Vladimir P
authors.initials: VP
authors.lastname: Skulachev
authors.forename: Henrik G
authors.initials: HG
authors.lastname: Kjaergaard
authors.forename: Robin A J
authors.initials: RA
authors.lastname: Smith
authors.forename: Michael P
authors.initials: MP
authors.lastname: Murphy
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000465:Algorithms; D000818:Animals; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone / Q000494:pharmacology; D002413:Cations, Divalent / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007425:Intracellular Membranes / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D007476:Ionophores / Q000494:pharmacology; D019169:Jurkat Cells; D008051:Lipid Bilayers / Q000378:metabolism; D008055:Lipids / Q000737:chemistry*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D009550:Nigericin / Q000494:pharmacology; D009861:Onium Compounds / Q000737:chemistry / Q000378:metabolism; D009943:Organophosphorus Compounds / Q000737:chemistry / Q000378:metabolism*; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D012402:Rotenone / Q000494:pharmacology; D012414:Rubidium Radioisotopes / Q000378:metabolism; D013730:Terphenyl Compounds / Q000737:chemistry / Q000378:metabolism*; D014316:Tritium / Q000378:metabolism; D014320:Triphenylmethyl Compounds / Q000737:chemistry / Q000378:metabolism; D014475:Uncoupling Agents / Q000494:pharmacology
chemical_list: D002413:Cations, Divalent; D007476:Ionophores; D008051:Lipid Bilayers; D008055:Lipids; D009861:Onium Compounds; D009943:Organophosphorus Compounds; D012414:Rubidium Radioisotopes; D013730:Terphenyl Compounds; D014320:Triphenylmethyl Compounds; D014475:Uncoupling Agents; D012402:Rotenone; D014316:Tritium; C011561:triphenylmethylphosphonium; C062574:1,6-hexanediylbis(triphenylphosphonium); D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; D011189:Potassium Chloride; D000255:Adenosine Triphosphate; D009550:Nigericin