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Mitochondrial Uncoupling Proteins (UCP1-UCP3) and Adenine Nucleotide Translocase (ANT1) Enhance the Protonophoric Action of 2,4-Dinitrophenol in Mitochondria and Planar Bilayer Membranes

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Institute of Physiology, Pathophysiology and Biophysics, University of Veterinary Medicine, A-1210 Vienna, Austria
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Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Leninskie Gory 1/40, 119991 Moscow, Russia
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Department of Chemistry, Faculty of Science, University of Zagreb, Horvatovac 102a, 10000 Zagreb, Croatia
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Division of Organic Chemistry and Biochemistry, Ruđer Bošković Institute, Bijenička 54, 10000 Zagreb, Croatia
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Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo nám. 2, 16610 Prague, Czech Republic
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Authors to whom correspondence should be addressed.
Academic Editor: Brigita Urbanc
Biomolecules 2021, 11(8), 1178; https://doi.org/10.3390/biom11081178
Received: 21 June 2021 / Revised: 30 July 2021 / Accepted: 4 August 2021 / Published: 9 August 2021
(This article belongs to the Special Issue Proton and Proton-Coupled Transport)
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. View Full-Text
Keywords: mitochondrial uncoupler; protonophore; membrane potential; proton conductance; artificial membranes; molecular dynamics simulations mitochondrial uncoupler; protonophore; membrane potential; proton conductance; artificial membranes; molecular dynamics simulations
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MDPI and ACS Style

Žuna, K.; Jovanović, O.; Khailova, L.S.; Škulj, S.; Brkljača, Z.; Kreiter, J.; Kotova, E.A.; Vazdar, M.; Antonenko, Y.N.; Pohl, E.E. Mitochondrial Uncoupling Proteins (UCP1-UCP3) and Adenine Nucleotide Translocase (ANT1) Enhance the Protonophoric Action of 2,4-Dinitrophenol in Mitochondria and Planar Bilayer Membranes. Biomolecules 2021, 11, 1178. https://doi.org/10.3390/biom11081178

AMA Style

Žuna K, Jovanović O, Khailova LS, Škulj S, Brkljača Z, Kreiter J, Kotova EA, Vazdar M, Antonenko YN, Pohl EE. Mitochondrial Uncoupling Proteins (UCP1-UCP3) and Adenine Nucleotide Translocase (ANT1) Enhance the Protonophoric Action of 2,4-Dinitrophenol in Mitochondria and Planar Bilayer Membranes. Biomolecules. 2021; 11(8):1178. https://doi.org/10.3390/biom11081178

Chicago/Turabian Style

Žuna, Kristina, Olga Jovanović, Ljudmila S. Khailova, Sanja Škulj, Zlatko Brkljača, Jürgen Kreiter, Elena A. Kotova, Mario Vazdar, Yuri N. Antonenko, and Elena E. Pohl 2021. "Mitochondrial Uncoupling Proteins (UCP1-UCP3) and Adenine Nucleotide Translocase (ANT1) Enhance the Protonophoric Action of 2,4-Dinitrophenol in Mitochondria and Planar Bilayer Membranes" Biomolecules 11, no. 8: 1178. https://doi.org/10.3390/biom11081178

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