title: Derivatives of rhodamine 19 as mild mitochondria-targeted cationic uncouplers.
abstract: 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 (C(12)R1) 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 C(12)R1 and SkQR1. These compounds induced pH equilibration in liposomes loaded with the pH probe pyranine. C(12)R1 and SkQR1 partially stimulated respiration of rat liver mitochondria in State 4 and decreased their membrane potential. Also, C(12)R1 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 C(12)R1 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.
authors: Belozersky Institute of Physico-Chemical Biology, Moscow State University, Leninskie Gory 1, Moscow 119991, Russia. antonen@genebee.msu.ru
authors: Yuri N
authors: YN
authors: Antonenko
authors: Armine V
authors: AV
authors: Avetisyan
authors: Dmitry A
authors: DA
authors: Cherepanov
authors: Dmitry A
authors: DA
authors: Knorre
authors: Galina A
authors: GA
authors: Korshunova
authors: Olga V
authors: OV
authors: Markova
authors: Silvia M
authors: SM
authors: Ojovan
authors: Irina V
authors: IV
authors: Perevoshchikova
authors: Antonina V
authors: AV
authors: Pustovidko
authors: Tatyana I
authors: TI
authors: Rokitskaya
authors: Inna I
authors: II
authors: Severina
authors: Ruben A
authors: RA
authors: Simonyan
authors: Ekaterina A
authors: EA
authors: Smirnova
authors: Alexander A
authors: AA
authors: Sobko
authors: Natalia V
authors: NV
authors: Sumbatyan
authors: Fedor F
authors: FF
authors: Severin
authors: Vladimir P
authors: VP
authors: Skulachev
mesh_terms: D000818:Animals; D005456:Fluorescent Dyes / Q000737:chemistry / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D008051:Lipid Bilayers / Q000737:chemistry / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects*; D008930:Mitochondria, Liver / Q000378:metabolism*; D051381:Rats; D012235:Rhodamines / Q000737:chemistry / Q000494:pharmacology; D012441:Saccharomyces cerevisiae / Q000378:metabolism*; D014475:Uncoupling Agents / Q000737:chemistry / Q000494:pharmacology
chemical_list: D005456:Fluorescent Dyes; D008051:Lipid Bilayers; D012235:Rhodamines; D014475:Uncoupling Agents