Targeting dinitrophenol to mitochondria: limitations to the development of a self-limiting mitochondrial protonophore.

TitleTargeting dinitrophenol to mitochondria: limitations to the development of a self-limiting mitochondrial protonophore.
Publication TypeJournal Article
Year of Publication2006
AuthorsBlaikie, FH, Brown, SE, Samuelsson, LM, Brand, MD, Smith, RAJ, Murphy, MP
JournalBiosci Rep
Volume26
Issue3
Pagination231-43
Date Published2006 Jun
ISSN0144-8463
KeywordsAnimals, Cell Respiration, Dinitrophenols, Ionophores, Membrane Potentials, Mitochondria, Liver, Molecular Structure, Protons, Rats, Uncoupling Agents
Abstract

The protonmotive force (Deltap) across the mitochondrial inner membrane drives ATP synthesis. In addition, the energy stored in Deltap can be dissipated by proton leak through the inner membrane, contributing to basal metabolic rate and thermogenesis. Increasing mitochondrial proton leak pharmacologically should decrease the efficiency of oxidative phosphorylation and counteract obesity by enabling fatty acids to be oxidised with decreased ATP production. While protonophores such as 2,4-dinitrophenol (DNP) increase mitochondrial proton leak and have been used to treat obesity, a slight increase in DNP concentration above the therapeutically effective dose disrupts mitochondrial function and leads to toxicity. Therefore we set out to develop a less toxic protonophore that would increase proton leak significantly at high Deltap but not at low Deltap. Our design concept for a potential self-limiting protonophore was to couple the DNP moiety to the lipophilic triphenylphosphonium (TPP) cation and this was achieved by the preparation of 3-(3,5-dinitro-4-hydroxyphenyl)propyltriphenylphosphonium methanesulfonate (MitoDNP). TPP cations accumulate within mitochondria driven by the membrane potential (Deltapsi), the predominant component of Deltap. Our hypothesis was that MitoDNP would accumulate in mitochondria at high Deltapsi where it would act as a protonophore, but that at lower Deltapsi the accumulation and uncoupling would be far less. We found that MitoDNP was extensively taken into mitochondria driven by Deltapsi. However MitoDNP did not uncouple mitochondria as judged by its inability to either increase respiration rate or decrease Deltapsi. Therefore MitoDNP did not act as a protonophore, probably because the efflux of deprotonated MitoDNP was inhibited.

DOI10.1007/s10540-006-9018-8
Alternate JournalBiosci. Rep.
Citation Key10.1007/s10540-006-9018-8
PubMed ID16850251
Grant ListMC_U105663137 / / Medical Research Council / United Kingdom
MC_U105663142 / / Medical Research Council / United Kingdom