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Mitochondrial uncouplers with an extraordinary dynamic range.

Phing-How Lou1, Birgit S Hansen, Preben H Olsen

  • 1MRC Dunn Human Nutrition Unit, Hills Road, Cambridge CB2 2XY, UK.

The Biochemical Journal
|July 5, 2007
PubMed
Summary

Weak uncouplers, like butylated hydroxytoluene, show a vast dynamic range by interacting with mitochondrial adenine nucleotide translocase. This interaction reveals a novel allosteric activation of proton transport, crucial for developing safer obesity therapies.

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Area of Science:

  • Biochemistry
  • Mitochondrial Physiology
  • Pharmacology

Background:

  • Mitochondrial uncouplers are investigated for potential therapeutic applications, such as obesity treatment.
  • Understanding the mechanism and dynamic range of weak uncouplers is crucial for drug development.

Purpose of the Study:

  • To investigate the mechanism and dynamic range of weak uncouplers.
  • To explore the interaction of weak uncouplers with mitochondrial adenine nucleotide translocase.
  • To identify potential starting points for designing safer uncouplers for obesity therapy.

Main Methods:

  • In vitro studies using isolated mitochondria and intact cells.
  • Assessing uncoupling concentrations and dynamic ranges.
  • Investigating interactions with mitochondrial adenine nucleotide translocase using various chemical structures.

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Last Updated: Jul 14, 2026

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Main Results:

  • Weak uncouplers exhibit a dynamic range exceeding 10^6 in vitro.
  • Uncouplers interact with mitochondrial adenine nucleotide translocase, causing limited uncoupling at low concentrations and conventional uncoupling at higher concentrations.
  • The uncoupling mechanism at the translocase does not involve conventional weak acid/anion cycling and can be mediated by non-anionic molecules.

Conclusions:

  • A novel allosteric activation of proton transport through the adenine nucleotide translocase by weak uncouplers has been discovered.
  • The wide dynamic range and unique mechanism offer a promising avenue for developing safer obesity therapeutics.