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 overmonocations
in delivery to mitochondria. Instead, this suggests that it may be
possible to form dications within mitochondria that then remain
within the cell.
