Accumulation of lipophilic dications by mitochondria and cells

M F Ross , T da Ros , F H Blaikie , T A Prime , C M Porteous , I I Severina , V P Skulachev , H G Kjaergaard , R A Smith , M P Murphy , M P Murphy (1)

1 MRC-Dunn Human Nutrition Unit

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 visualise 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. 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 if lipophilic dications could be taken up by mitochondria and cells, we made a series of bistriphenylphosphonium (bisTPP) cations comprising two TPP moieties linked by a 2-, 4-, 5-, 6-, or 10-carbon methylene bridge. The 5-, 6-, and 10-carbon dications were taken up by energised mitochondria, while the 2- and 4-carbon dications were not. The accumulation of the dication was greater than that of the monocation methyltriphenylphosphonium (TPMP). 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.

Mots clés: Life Sciences

M F Ross, T da Ros, F H Blaikie, T A Prime, C M Porteous, et al.. Accumulation of lipophilic dications by mitochondria and cells. Biochemical Journal, 2006, 400 (1), pp.199-208. ⟨10.1042/BJ20060919⟩. ⟨hal-00478621⟩