The study of uncoupling action mechanism
of SkQ-SkQ3 family compounds
S.A. Eremeyev, K.A. Motovilov, L.S. Yaguzhinsky
A.N. Belozersky Institute of Physico-Chemical Biology, Moscow State University
Earlier in our work it was demonstrated that under conditions of mitochondrial proton
pumps activation on the outer side of inner mitochondrial membrane the special fraction
of protons is formed. These protons are nonequilibrium bounded with membrane and take
part in ATP synthesis directly. Hydrogen ions of this fraction do not interact effectively
with classic uncouplers. It was found out that weak Lewis bases (such as HEPES, MES,
citrate) decrease the volume of the proton fraction discussed dew to catalysis of dissociation
reaction of these protons from membrane surface into aqueous volume. We synthesized
and tested new type of uncouplers (2,4,6-trichloro-3-pentadecylphenol,TCP-C15) with
significantly increased affinity to membrane. It was shown that TCP-C15 selectively
interacts with nonequilibrium membrane bounded protons. Removal of these protons by
catalyst (HEPES) leads to dissipation of TCP-C15 uncoupling effect. However the
uncoupling effect of classical uncoupler pentachlorophenol (PCP) remains unchanged
in same conditions. In actual investigation we have demonstrated that addition of SkQ3
to mitochondria induces increase of respiration like the addition of TCP-C15 it does.
This effect can be significantly decreased by higher concentration of catalyst (HEPES).
The results obtained led us to preliminary conclusion that high membrane-acting properties
of SkQ3 provide this substance with ability to interact with nonequilibrium membrane
bounded protons effectively. In the general case SkQ3 may induce uncoupling effect by
two ways: as single proton carrier and (in accordance to Severin F.F. et al.) as
penetrating complex with fatty acid anions.
References:
Severin F.F., Severina I.I., Antonenko Y.N., Rokitskaya T.I., Cherepanov D.A.,
Mokhova E.N., Vyssokikh M.Y., Pustovidko A.V., Markova O.V., Yaguzhinsky L.S.,
Korshunova G.A., Sumbatyan N.V., Skulachev M.V., Skulachev V.P. Penetrating
cation/fatty acid anion pair as a mitochondria-targeted protonophore. Proc.
Natl. Acad. Sci. USA. (2010);107(2):663-8.
Homo Sapiens Liberatus Workshop, Moscow State University, May 2010