Mitochondrial uncouplers with an extraordinary dynamic range
Open accessAbstract
We have discovered that some weak uncouplers (typified by butylated hydroxytoluene) have a dynamic range of more than 106in 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.
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A new class of molecules that includes butylated hydroxytoluene utilizes the mitochondrial adenine nucleotide translocase to induce limited uncoupling at low concentrations and can have a dynamic range of more than a million fold in vitro.
“A new class of molecules that includes butylated hydroxytoluene utilizes the mitochondrial adenine nucleotide translocase to induce limited uncoupling at low concentrations and can have a dynamic range of more than a million fold in vitro.”
From Cellular bioenergetics as a target for obesity therapy (2010) · cites this paper as [164]
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- Authors
- Lou, P.-H., Hansen, B. S., Olsen, P. H., Tullin, S., Murphy, M. P., & Brand, M. D.
- Affiliations
- MRC Mitochondrial Biology Unit (GB)
- Novo Nordisk (Denmark) (DK)
- Venue
- Biochemical Journal
- Publisher
- Portland Press Ltd.
- Published
- 2007-09-12
- Volume
- 407
- Issue
- 1
- Pages
- 129-140
- ISSN
- 0264-6021 (ISSN-L)
- 1470-8728
- PMC
- PMC2267406
- OpenAlex
- W2021521297
- Cited by
- 141
- References
- 42
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 5 · 2023: 4 · 2022: 7 · 2021: 9 · 2020: 5 · 2019: 9 · 2018: 10 · 2017: 14 · 2016: 8 · 2015: 8 · 2014: 17 · 2013: 8 · 2012: 9
- FWCI
- 2.12
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Biochemical Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion, other-oa)
- Trinity's Access to Research Output (TARA) (Trinity College Dublin) (submittedVersion, other-oa)
- Funders
- British Federation of Women Graduates
- Cambridge Commonwealth Trust
- Novo Nordisk
- Medical Research Council
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › ATP Synthase and ATPases Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- mitochondrial uncouplers, butylated hydroxytoluene, adenine nucleotide translocase, dynamic range, allosteric activation, proton transport, triphenylphosphonium, membrane potential, obesity treatment, mitochondrial membrane potential
- MeSH terms
- Mitochondrial ADP, ATP Translocases, Animals, Butylated Hydroxytoluene, Dose-Response Relationship, Drug, Female, Kinetics, Mitochondria, Thymus Gland, Uncoupling Agents, Rats, Wistar, Rats
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