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Type of publication: Journal Article
Type of document: Full Paper

Year: 2021

Authors: Žuna, K; Jovanović, O; Khailova, LS; Škulj, S; Brkljača, Z; Kreiter, J; Kotova, EA; Vazdar, M; Antonenko, YN; Pohl, EE

Title: Mitochondrial uncoupling proteins (UCP1-UCP3) and adenine nucleotide translocase (ANT1) enhance the protonophoric action of 2,4-dinitrophenol in mitochondria and planar bilayer membranes.

Source: Biomolecules. 2021; 11(8):1178



Authors Vetmeduni Vienna:

Jovanovic Olga
Kreiter Jürgen
Pohl Elena
Zuna Kristina

Vetmed Research Units
Institute of Physiology, Pathohysiology and Biophysics, Unit of Physiology and Biophysics


Data are deposited in Zenodo | DataLink: https://doi.org/10.5281/zenodo.5113039


Project(s): Proton leak through Adenine Nucleotide Translocase

PROTON – Proton transport and proton-coupled transport


Abstract:
2,4-Dinitrophenol (DNP) is a classic uncoupler of oxidative phosphorylation in mitochondria which is still used in "diet pills", despite its high toxicity and lack of antidotes. DNP increases the proton current through pure lipid membranes, similar to other chemical uncouplers. However, the molecular mechanism of its action in the mitochondria is far from being understood. The sensitivity of DNP's uncoupling action in mitochondria to carboxyatractyloside, a specific inhibitor of adenine nucleotide translocase (ANT), suggests the involvement of ANT and probably other mitochondrial proton-transporting proteins in the DNP's protonophoric activity. To test this hypothesis, we investigated the contribution of recombinant ANT1 and the uncoupling proteins UCP1-UCP3 to DNP-mediated proton leakage using the well-defined model of planar bilayer lipid membranes. All four proteins significantly enhanced the protonophoric effect of DNP. Notably, only long-chain free fatty acids were previously shown to be co-factors of UCPs and ANT1. Using site-directed mutagenesis and molecular dynamics simulations, we showed that arginine 79 of ANT1 is crucial for the DNP-mediated increase of membrane conductance, implying that this amino acid participates in DNP binding to ANT1.


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