Mitochondrial uncouplers with an extraordinary dynamic range.
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.
Lou
Phing-How
PH
MRC Dunn Human Nutrition Unit, Hills Road, Cambridge CB2 2XY, UK.
Hansen
Birgit S
BS
Olsen
Preben H
PH
Tullin
Søren
S
Murphy
Michael P
MP
Brand
Martin D
MD
D000818:Animals; D002084:Butylated Hydroxytoluene / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D007700:Kinetics; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D000226:Mitochondrial ADP, ATP Translocases / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013950:Thymus Gland / Q000378:metabolism; D014475:Uncoupling Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
D014475:Uncoupling Agents; D002084:Butylated Hydroxytoluene; D000226:Mitochondrial ADP, ATP Translocases