Uncouplers of Oxidative Phosphorylation

Abstract

Uncouplers of Oxidative Phosphorylationby Hiroshi Terada* Uncouplers of oxidative phosphorylation in mitochondria inhibit the coupling between the electron transport and phosphorylation reactions and thus inhibit ATP synthesis without affecting the respiratory chain and ATP synthase (H+-ATPase). Miscellaneous compounds are known to be uncouplers, but weakly acidic uncouplers are representative because they show very potent activities. The most potent uncouplers discovered so far are the hindered phenol SF 6847, and hydrophobic salicylanilide S-13, which are active in vitro at concentrations in the 10 nM range. For induction of uncoupling, an acid dissociable group, bulky hydrophobic moiety and strong electron-withdrawing group are required. Weakly acidic uncouplers are considered to produce uncoupling by their protonophoric action in the H+-impermeable mitochondrial membrane. For exerting these effects, the stability of the respective uncoupler anions in the hydrophobic membrane is very important. High stability is achieved by delocalization of the polar ionic charge through uncoupler (chemical)-specific mechanisms. Such an action of weakly acidic uncouplers is characteristic of the highly efficient membrane targeting action of a nonsite-specific type of bioactive compound.

Structure-Activity Analysis of Niclosamide Reveals Potential Role for Cytoplasmic pH in Control of Mammalian Target of Rapamycin Complex 1 (mTORC1) Signaling

“…Niclosamide resembles the well characterized protonophore S13 (77)(78)(79). Based on a model for S13 (80), the structural groups that confer protonophoric activity to niclosamide are the weakly acidic OH group with a pK a in the physiological pH range and a number of chemical features that help delocalize the negative charge of the anionic form of the molecule to maintain its hydrophobicity and membrane association, such as the electron-withdrawing NO 2 moiety and the NH group that participates in an intramolecular H-bond ( Fig.…”

“…Niclosamide did not inhibit mTORC1 or 95 other protein kinases in vitro, indicating that it must inhibit mTORC1 indirectly, unlike recently developed active site mTOR inhibitors. Examination of the chemical properties of niclosamide showed that it possesses distinctive features of protonophores, including a weakly acidic OH group that can reversibly bind protons in the physiological pH range, a bulky hydrophobic moiety for membrane solubility, and electron-withdrawing moieties that delocalize the negative charge of the anionic form of the protonophore, allowing it to remain associated with membranes (78,79). These properties enable such chemicals to embed themselves into the plasma membrane and intracellular membranes and carry out rapid cycles of proton binding and release, thereby decreasing proton gradients across membranes.…”

SR4 Uncouples Mitochondrial Oxidative Phosphorylation, Modulates AMP-dependent Kinase (AMPK)-Mammalian Target of Rapamycin (mTOR) Signaling, and Inhibits Proliferation of HepG2 Hepatocarcinoma Cells

“…This is followed by the translocation of their deprotonated form to the outer side of the membrane to bind another proton, thus "short circuiting" the coupling between the electron transport and phosphorylation reactions and preventing ATP synthesis. For induction of protonophore (protein-independent) uncoupling, an acid-dissociable group, bulky hydrophobic moiety, and strong electronwithdrawing groups are required (28). Based on our mitochondria swelling experiments on potassium acetate medium treated with the K ϩ ionophore valinomycin, SR4 exhibited "protonophoric" properties similarly with the structurally different FCCP, a prototype protonophore.…”

“…In particular, pharmacological use of synthetic and naturally occurring uncouplers, with their potential to compromise mitochondrial functions and affect cellular bioenergetics and metabolism, have lately shown promising anticancer effects (23)(24)(25)(26)(27). Mitochondrial uncouplers generally belong to one of two general classes: (a) protonophore uncouplers (protein-independent uncoupling) that transport protons across the inner mitochondrial membrane, dissipating the transmembrane proton gradient required for the coupling between electron transport and OxPhos, and (b) non-protonophores (protein-mediated uncoupling) that activate proton leak through protein complexes such as the adenine nucleotide translocase (ANT) or uncoupling proteins (UCPs) (28,29).…”

Structure—activity relationships for chloro‐ and nitrophenol toxicity in the pollen tube growth test

“…For a certain range of pK a values, uncoupling of oxidative phosphorylation becomes the dominating mode of toxic action in aquatic organisms [3]. Uncoupling activity results from increased proton transport across energy-transducing membranes, where moderately acidic chemicals may function as particularly efficient carriers [4]. Classic examples of uncoupling agents are pentachlorophenol and 2,4-dinitrophenol.…”