Details

Autor(en) / Beteiligte

• Antonenko, Yuri N.
• Avetisyan, Armine V.
• Cherepanov, Dmitry A.
• Knorre, Dmitry A.
• Korshunova, Galina A.
• Markova, Olga V.
• Ojovan, Silvia M.
• Perevoshchikova, Irina V.
• Pustovidko, Antonina V.
• Rokitskaya, Tatyana I.
• Severina, Inna I.
• Simonyan, Ruben A.
• Smirnova, Ekaterina A.
• Sobko, Alexander A.
• Sumbatyan, Natalia V.
• Severin, Fedor F.
• Skulachev, Vladimir P.

Titel

Derivatives of Rhodamine 19 as Mild Mitochondria-targeted Cationic Uncouplers

Ist Teil von

• The Journal of biological chemistry, 2011-05, Vol.286 (20), p.17831-17840

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2011

Quelle

MEDLINE

Beschreibungen/Notizen

• A limited decrease in mitochondrial membrane potential can be beneficial for cells, especially under some pathological conditions, suggesting that mild uncouplers (protonophores) causing such an effect are promising candidates for therapeutic uses. The great majority of protonophores are weak acids capable of permeating across membranes in their neutral and anionic forms. In the present study, protonophorous activity of a series of derivatives of cationic rhodamine 19, including dodecylrhodamine (C12R1) and its conjugate with plastoquinone (SkQR1), was revealed using a variety of assays. Derivatives of rhodamine B, lacking dissociable protons, showed no protonophorous properties. In planar bilayer lipid membranes, separating two compartments differing in pH, diffusion potential of H+ ions was generated in the presence of C12R1 and SkQR1. These compounds induced pH equilibration in liposomes loaded with the pH probe pyranine. C12R1 and SkQR1 partially stimulated respiration of rat liver mitochondria in State 4 and decreased their membrane potential. Also, C12R1 partially stimulated respiration of yeast cells but, unlike the anionic protonophore FCCP, did not suppress their growth. Loss of function of mitochondrial DNA in yeast (grande-petite transformation) is known to cause a major decrease in the mitochondrial membrane potential. We found that petite yeast cells are relatively more sensitive to the anionic uncouplers than to C12R1 compared with grande cells. Together, our data suggest that rhodamine 19-based cationic protonophores are self-limiting; their uncoupling activity is maximal at high membrane potential, but the activity decreases membrane potentials, which causes partial efflux of the uncouplers from mitochondria and, hence, prevents further membrane potential decrease.