The lipophilic weak base (Z)-5-methyl-2-[2-(1-naphthyl)ethenyl]-4-piperidinopyridine (AU-1421) is a potent protonophore type cationic uncoupler of oxidative phosphorylation in mitochondria

• Published in: Biochimica et biophysica acta Vol. 1141; no. 2-3; pp. 231 - 237
• Main Authors: Nagamune, H, Fukushima, Y, Takada, J, Yoshida, K, Unami, A, Shimooka, T, Terada, H
• Format: Journal Article
• Language: English
• Published: Netherlands 01.03.1993
• Subjects: Adenosine Triphosphate - biosynthesis; Adenosine Triphosphate - metabolism; Animals; Electron Transport; Hydrolysis; Male; Mitochondria, Liver - drug effects; Mitochondria, Liver - metabolism; Naphthalenes - pharmacology; Oxidative Phosphorylation; Oxygen - metabolism; Protons; Pyridines - pharmacology; Rats; Rats, Wistar; Uncoupling Agents - pharmacology
• ISSN: 0006-3002; 1878-2434
• DOI: 10.1016/0005-2728(93)90047-J

The lipophilic weak base AU-1421 acts as a simple protonophoric uncoupler of oxidative phosphorylation in rat liver mitochondria judging from the following observations. In the absence of any carrier lipophilic anions or P(i), AU-1421 stimulated the rate of state 4 respiration maximally about 7-fold at a concentration of 30 nmol/mg mitochondrial protein. At the same maximum effective concentration, it also inhibited ATP synthesis, released oligomycin-inhibited state 3 respiration, dissipated the proton motive force in the energized state, and activated latent H(+)-ATPase. AU-1421 also allowed proton conduction in both mitochondrial membranes and liposomes. These actions of AU-1421 resemble those of the typical anionic uncoupler SF6847. A marked difference between the two was, however, that ATPase activation by AU-1421 was not suppressed at higher concentrations of AU-1421, whereas ATPase activated by SF6847 was suppressed on increase of the SF6847 concentration. The finding that this simple protonophoric cation acts as an uncoupler at a micromolar concentration is significant, because all true (i.e., protonophore type) uncouplers known so far are anionic not cationic. Thus, AU-1421 is a unique uncoupler of the protonophore type.