Mitochondrial uncouplers with an extraordinary dynamic range.

TitleMitochondrial uncouplers with an extraordinary dynamic range.
Publication TypeJournal Article
Year of Publication2007
AuthorsLou, P-H, Hansen, BS, Olsen, PH, Tullin, S, Murphy, MP, Brand, MD
JournalBiochem J
Date Published2007 Oct 01
KeywordsAnimals, Butylated Hydroxytoluene, Dose-Response Relationship, Drug, Female, Kinetics, Mitochondria, Mitochondrial ADP, ATP Translocases, Rats, Rats, Wistar, Thymus Gland, Uncoupling Agents

We have discovered that some weak uncouplers (typified by butylated hydroxytoluene) have a dynamic range of more than 10(6) in vitro: the concentration giving measurable uncoupling is less than one millionth of the concentration causing full uncoupling. They achieve this through a high-affinity interaction with the mitochondrial adenine nucleotide translocase that causes significant but limited uncoupling at extremely low uncoupler concentrations, together with more conventional uncoupling at much higher concentrations. Uncoupling at the translocase is not by a conventional weak acid/anion cycling mechanism since it is also caused by substituted triphenylphosphonium molecules, which are not anionic and cannot protonate. Covalent attachment of the uncoupler to a mitochondrially targeted hydrophobic cation sensitizes it to membrane potential, giving a small additional effect. The wide dynamic range of these uncouplers in isolated mitochondria and intact cells reveals a novel allosteric activation of proton transport through the adenine nucleotide translocase and provides a promising starting point for designing safer uncouplers for obesity therapy.

Alternate JournalBiochem. J.
Citation Key10.1042/BJ20070606
PubMed ID17608618
PubMed Central IDPMC2267406
Grant ListMC_U105663137 / / Medical Research Council / United Kingdom
MC_U105663142 / / Medical Research Council / United Kingdom