• Divakaruni, A. S. & Brand, M. D. The regulation and physiology of mitochondrial proton leak. Physiology 26, 192–205 (2011).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Fedorenko, A., Lishko, P. V. & Kirichok, Y. Mechanism of fatty-acid-dependent UCP1 uncoupling in brown fat mitochondria. Cell 151, 400–413 (2012).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Nicholls, D. G. A history of UCP1. Biochem. Soc. Trans. 29, 751–755 (2001).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Aquila, H., Link, T. A. & Klingenberg, M. The uncoupling protein from brown fat mitochondria is related to the mitochondrial ADP/ATP carrier. Analysis of sequence homologies and of folding of the protein in the membrane. EMBO J. 4, 2369–2376 (1985).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Bouillaud, F., Weissenbach, J. & Ricquier, D. Complete cDNA-derived amino acid sequence of rat brown fat uncoupling protein. J. Biol. Chem. 261, 1487–1490 (1986).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Klingenberg, M. & Huang, S. G. Structure and function of the uncoupling protein from brown adipose tissue. Biochim. Biophys. Acta 1415, 271–296 (1999).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Bertholet, A. M. et al. H+ transport is an integral function of the mitochondrial ADP/ATP carrier. Nature 571, 515–520 (2019).

    ADS 
    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Andreyev, A. et al. The ATP/ADP-antiporter is involved in the uncoupling effect of fatty acids on mitochondria. Eur. J. Biochem. 182, 585–592 (1989).

    PubMed 
    Article 

    Google Scholar
     

  • Brustovetsky, N. & Klingenberg, M. The reconstituted ADP/ATP carrier can mediate H+ transport by free fatty acids, which is further stimulated by mersalyl. J. Biol. Chem. 269, 27329–27336 (1994).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • McLaughlin, S. G. & Dilger, J. P. Transport of protons across membranes by weak acids. Physiol. Rev. 60, 825–863 (1980).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Terada, H. Uncouplers of oxidative phosphorylation. Environ. Health Perspect. 87, 213–218 (1990).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Perry, R. J., Zhang, D., Zhang, X. M., Boyer, J. L. & Shulman, G. I. Controlled-release mitochondrial protonophore reverses diabetes and steatohepatitis in rats. Science 347, 1253–1256 (2015).

    ADS 
    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Perry, R. J. et al. Reversal of hypertriglyceridemia, fatty liver disease, and insulin resistance by a liver-targeted mitochondrial uncoupler. Cell Metab. 18, 740–748 (2013).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Tainter, M. L., Stockton, A. B. & Cutting, W. C. Use of dinitrophenol in obesity and related conditions. J. Am. Med. Assoc. 101, 1472–1475 (1933).

    Article 

    Google Scholar
     

  • Grundlingh, J., Dargan, P. I., El-Zanfaly, M. & Wood, D. M. 2,4-Dinitrophenol (DNP): a weight loss agent with significant acute toxicity and risk of death. J. Med. Toxicol. 7, 205–212 (2011).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Lowell, B. B. & Spiegelman, B. M. Towards a molecular understanding of adaptive thermogenesis. Nature 404, 652–660 (2000).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Krauss, S., Zhang, C. Y. & Lowell, B. B. The mitochondrial uncoupling-protein homologues. Nat. Rev. Mol. Cell Biol. 6, 248–261 (2005).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Skulachev, V. P. Uncoupling: new approaches to an old problem of bioenergetics. Biochim. Biophys. Acta 1363, 100–124 (1998).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Bertholet, A. M. et al. Mitochondrial patch clamp of beige adipocytes reveals UCP1-positive and UCP1-negative cells both exhibiting futile creatine cycling. Cell Metab. 25, 811–822 (2017).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Bertholet, A. M. & Kirichok, Y. Patch-clamp analysis of the mitochondrial H+ leak in brown and beige fat. Front. Physiol. 11, 326 (2020).

    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Levy, S. E., Chen, Y. S., Graham, B. H. & Wallace, D. C. Expression and sequence analysis of the mouse adenine nucleotide translocase 1 and 2 genes. Gene 254, 57–66 (2000).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Rodic, N. et al. DNA methylation is required for silencing of ant4, an adenine nucleotide translocase selectively expressed in mouse embryonic stem cells and germ cells. Stem Cells 23, 1314–1323 (2005).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Cho, J. et al. Mitochondrial ATP transporter Ant2 depletion impairs erythropoiesis and B lymphopoiesis. Cell Death Differ. 22, 1437–1450 (2015).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Graham, B. H. et al. A mouse model for mitochondrial myopathy and cardiomyopathy resulting from a deficiency in the heart/muscle isoform of the adenine nucleotide translocator. Nat. Genet. 16, 226–234 (1997).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Childress, E. S., Alexopoulos, S. J., Hoehn, K. L. & Santos, W. L. Small molecule mitochondrial uncouplers and their therapeutic potential. J. Med. Chem. 61, 4641–4655 (2018).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Kenwood, B. M. et al. Identification of a novel mitochondrial uncoupler that does not depolarize the plasma membrane. Mol. Metab. 3, 114–123 (2014).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Bernardi, P. Mitochondrial transport of cations: channels, exchangers, and permeability transition. Physiol. Rev. 79, 1127–1155 (1999).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Klingenberg, M. The ADP and ATP transport in mitochondria and its carrier. Biochim. Biophys. Acta 1778, 1978–2021 (2008).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Alexopoulos, S. J. et al. Mitochondrial uncoupler BAM15 reverses diet-induced obesity and insulin resistance in mice. Nat. Commun. 11, 2397 (2020).

    ADS 
    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Axelrod, C. L. et al. BAM15-mediated mitochondrial uncoupling protects against obesity and improves glycemic control. EMBO Mol. Med. 12, e12088 (2020).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Cannon, B. & Nedergaard, J. Brown adipose tissue: function and physiological significance. Physiol. Rev. 84, 277–359 (2004).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Bertholet, A. M. & Kirichok, Y. UCP1: a transporter for H+ and fatty acid anions. Biochimie 134, 28–34 (2017).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Nicholls, D. G. & Lindberg, O. Brown-adipose-tissue mitochondria. The influence of albumin and nucleotides on passive ion permeabilities. Eur. J. Biochem. 37, 523–530 (1973).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Klingenberg, M. UCP1—a sophisticated energy valve. Biochimie 134, 19–27 (2017).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Pebay-Peyroula, E. et al. Structure of mitochondrial ADP/ATP carrier in complex with carboxyatractyloside. Nature 426, 39–44 (2003).

    ADS 
    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Nury, H. et al. Structural basis for lipid-mediated interactions between mitochondrial ADP/ATP carrier monomers. FEBS Lett. 579, 6031–6036 (2005).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Ruprecht, J. J. et al. Structures of yeast mitochondrial ADP/ATP carriers support a domain-based alternating-access transport mechanism. Proc. Natl Acad. Sci. USA 111, E426–E434 (2014).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Kunji, E. R. & Robinson, A. J. The conserved substrate binding site of mitochondrial carriers. Biochim. Biophys. Acta 1757, 1237–1248 (2006).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Dehez, F., Pebay-Peyroula, E. & Chipot, C. Binding of ADP in the mitochondrial ADP/ATP carrier is driven by an electrostatic funnel. J. Am. Chem. Soc. 130, 12725–12733 (2008).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Ruprecht, J. J. et al. The molecular mechanism of transport by the mitochondrial ADP/ATP carrier. Cell 176, 435–447 (2019).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Bielawski, J., Thompson, T. E. & Lehninger, A. L. The effect of 2,4-dinitrophenol on the electrical resistance of phospholipid bilayer membranes. Biochem. Biophys. Res. Commun. 24, 948–954 (1966).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Skulachev, V. P., Sharaf, A. A. & Liberman, E. A. Proton conductors in the respiratory chain and artificial membranes. Nature 216, 718–719 (1967).

    ADS 
    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Skulachev, V. P. et al. The effect of uncouplers on mitochondria, respiratory enzyme complexes and artificial phospholipid membranes. Curr. Mod. Biol. 2, 98–105 (1968).

    CAS 
    PubMed 

    Google Scholar
     

  • Mitchell, P. & Moyle, J. Stoichiometry of proton translocation through the respiratory chain and adenosine triphosphatase systems of rat liver mitochondria. Nature 208, 147–151 (1965).

    ADS 
    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Mitchell, P. Chemiosmotic coupling in oxidative and photosynthetic phosphorylation. Biol. Rev. Camb. Philos. Soc. 41, 445–502 (1966).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Betz, M. J. & Enerback, S. Human brown adipose tissue: what we have learned so far. Diabetes 64, 2352–2360 (2015).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Reynafarje, B., Costa, L. E. & Lehninger, A. L. O2 solubility in aqueous media determined by a kinetic method. Anal. Biochem. 145, 406–418 (1985).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Olsson, M. H., Sondergaard, C. R., Rostkowski, M. & Jensen, J. H. PROPKA3: consistent treatment of internal and surface residues in empirical pKa predictions. J. Chem. Theory Comput. 7, 525–537 (2011).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Grimme, S., Antony, J., Ehrlich, S. & Krieg, H. A consistent and accurate ab initio parametrization of density functional dispersion correction (DFT-D) for the 94 elements H-Pu. J. Chem. Phys. 132, 154104 (2010).

    ADS 
    PubMed 
    Article 
    CAS 

    Google Scholar
     

  • Roos, K. et al. OPLS3e: extending force field coverage for drug-like small molecules. J. Chem. Theory Comput. 15, 1863–1874 (2019).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Friesner, R. A. et al. Extra precision glide: docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes. J. Med. Chem. 49, 6177–6196 (2006).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Waterhouse, A. et al. SWISS-MODEL: homology modelling of protein structures and complexes. Nucleic Acids Res. 46, W296–W303 (2018).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Jo, S., Kim, T. & Im, W. Automated builder and database of protein/membrane complexes for molecular dynamics simulations. PLoS ONE 2, e880 (2007).

    ADS 
    PubMed 
    PubMed Central 
    Article 
    CAS 

    Google Scholar
     

  • Comte, J., Maisterrena, B. & Gautheron, D. C. Lipid composition and protein profiles of outer and inner membranes from pig heart mitochondria. Comparison with microsomes. Biochim. Biophys. Acta 419, 271–284 (1976).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Huang, J. et al. CHARMM36m: an improved force field for folded and intrinsically disordered proteins. Nat. Methods 14, 71–73 (2017).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Klauda, J. B. et al. Update of the CHARMM all-atom additive force field for lipids: validation on six lipid types. J. Phys. Chem. B 114, 7830–7843 (2010).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Jorgensen, W. L., Chandrasekhar, J., Madura, J. D., Impey, R. W. & Klein, M. L. Comparison of simple potential functions for simulating liquid water. J. Chem. Phys. 79, 926–935 (1983).

    ADS 
    CAS 
    Article 

    Google Scholar
     

  • Beglov, D. & Roux, B. Finite representation of an infinite bulk system: solvent boundary potential for computer simulations. J. Chem. Phys. 100, 9050–9063 (1994).

    ADS 
    CAS 
    Article 

    Google Scholar
     

  • Vanommeslaeghe, K. et al. CHARMM general force field: a force field for drug-like molecules compatible with the CHARMM all-atom additive biological force fields. J. Comput. Chem. 31, 671–690 (2010).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Mayne, C. G., Saam, J., Schulten, K., Tajkhorshid, E. & Gumbart, J. C. Rapid parameterization of small molecules using the Force Field Toolkit. J. Comput. Chem. 34, 2757–2770 (2013).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Frisch, M. J. et al. Gaussian 16 rev. C.01 (Gaussian, 2016).

  • Abraham, M. J. et al. GROMACS: high performance molecular simulations through multi-level parallelism from laptops to supercomputers. SoftwareX 1–2, 19–25 (2015).

    ADS 
    Article 

    Google Scholar
     

  • Hoover, W. G. Canonical dynamics: equilibrium phase-space distributions. Phys. Rev. A Gen. Phys. 31, 1695–1697 (1985).

    ADS 
    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Nosé, S. A molecular dynamics method for simulations in the canonical ensemble. Mol. Phys. 52, 255–268 (1984).

    ADS 
    Article 

    Google Scholar
     

  • Bussi, G., Donadio, D. & Parrinello, M. Canonical sampling through velocity rescaling. J. Chem. Phys. 126, 014101 (2007).

    ADS 
    PubMed 
    Article 
    CAS 

    Google Scholar
     

  • Parrinello, M. & Rahman, A. Polymorphic transitions in single crystals: a new molecular dynamics method. J. Appl. Phys. 52, 7182–7190 (1981).

    ADS 
    CAS 
    Article 

    Google Scholar
     

  • Darden, T., York, D. & Pedersen, L. Particle mesh Ewald: an Nlog(N) method for Ewald sums in large systems. J. Chem. Phys. 98, 10089–10092 (1993).

    ADS 
    CAS 
    Article 

    Google Scholar
     

  • Hess, B., Bekker, H., Berendsen, H. J. C. & Fraaije, J. G. E. M. LINCS. J. Comput. Chem. 18, 1463–1472 (1997).

    CAS 
    Article 

    Google Scholar
     

  • Gumbart, J., Khalili-Araghi, F., Sotomayor, M. & Roux, B. Constant electric field simulations of the membrane potential illustrated with simple systems. Biochim. Biophys. Acta 1818, 294–302 (2012).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Michaud-Agrawal, N., Denning, E. J., Woolf, T. B. & Beckstein, O. MDAnalysis: a toolkit for the analysis of molecular dynamics simulations. J. Comput. Chem. 32, 2319–2327 (2011).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Humphrey, W., Dalke, A. & Schulten, K. VMD: visual molecular dynamics. J. Mol. Graph. 14, 33–38 (1996). 27-38.

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Marcoline, F. V., Bethel, N., Guerriero, C. J., Brodsky, J. L. & Grabe, M. Membrane protein properties revealed through data-rich electrostatics calculations. Structure 23, 1526–1537 (2015).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Baker, N. A., Sept, D., Joseph, S., Holst, M. J. & McCammon, J. A. Electrostatics of nanosystems: application to microtubules and the ribosome. Proc. Natl Acad. Sci. USA 98, 10037–10041 (2001).

    ADS 
    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     



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