title: A short-chain alkyl derivative of Rhodamine 19 acts as a mild uncoupler of mitochondria and a neuroprotector.
abstract: Limited uncoupling of oxidative phosphorylation is known to be beneficial in various laboratory models of diseases. The search for cationic uncouplers is promising as their protonophorous effect is self-limiting because these uncouplers lower membrane potential which is the driving force for their accumulation in mitochondria. In this work, the penetrating cation Rhodamine 19 butyl ester (C4R1) was found to decrease membrane potential and to stimulate respiration of mitochondria, appearing to be a stronger uncoupler than its more hydrophobic analog Rhodamine 19 dodecyl ester (C12R1). Surprisingly, C12R1 increased H(+) conductance of artificial bilayer lipid membranes or induced mitochondria swelling in potassium acetate with valinomycin at concentrations lower than C4R1. This paradox might be explained by involvement of mitochondrial proteins in the uncoupling action of C4R1. In experiments with HeLa cells, C4R1 rapidly and selectively accumulated in mitochondria and stimulated oligomycin-sensitive respiration as a mild uncoupler. C4R1 was effective in preventing oxidative stress induced by brain ischemia and reperfusion in rats: it suppressed stroke-induced brain swelling and prevented the decline in neurological status more effectively than C12R1. Thus, C4R1 seems to be a promising example of a mild uncoupler efficient in treatment of brain pathologies related to oxidative stress.
authors.affiliation: Lomonosov Moscow State University, Belozersky Institute of Physico-Chemical Biology, Vorobyevy Gory 1, Moscow 119991, Russia; Lomonosov Moscow State University, Institute of Mitoengineering, Vorobyevy Gory 1, Moscow 119991, Russia.
authors.forename: Ljudmila S
authors.initials: LS
authors.lastname: Khailova
authors.affiliation: Lomonosov Moscow State University, Belozersky Institute of Physico-Chemical Biology, Vorobyevy Gory 1, Moscow 119991, Russia; Lomonosov Moscow State University, Institute of Mitoengineering, Vorobyevy Gory 1, Moscow 119991, Russia.
authors.forename: Denis N
authors.initials: DN
authors.lastname: Silachev
authors.affiliation: Lomonosov Moscow State University, Belozersky Institute of Physico-Chemical Biology, Vorobyevy Gory 1, Moscow 119991, Russia; Lomonosov Moscow State University, Institute of Mitoengineering, Vorobyevy Gory 1, Moscow 119991, Russia.
authors.forename: Tatyana I
authors.initials: TI
authors.lastname: Rokitskaya
authors.affiliation: Lomonosov Moscow State University, Belozersky Institute of Physico-Chemical Biology, Vorobyevy Gory 1, Moscow 119991, Russia; Lomonosov Moscow State University, Institute of Mitoengineering, Vorobyevy Gory 1, Moscow 119991, Russia.
authors.forename: Armine V
authors.initials: AV
authors.lastname: Avetisyan
authors.affiliation: Lomonosov Moscow State University, Belozersky Institute of Physico-Chemical Biology, Vorobyevy Gory 1, Moscow 119991, Russia; Lomonosov Moscow State University, Institute of Mitoengineering, Vorobyevy Gory 1, Moscow 119991, Russia.
authors.forename: Konstantin G
authors.initials: KG
authors.lastname: Lyamsaev
authors.affiliation: Lomonosov Moscow State University, Belozersky Institute of Physico-Chemical Biology, Vorobyevy Gory 1, Moscow 119991, Russia; Lomonosov Moscow State University, Institute of Mitoengineering, Vorobyevy Gory 1, Moscow 119991, Russia.
authors.forename: Inna I
authors.initials: II
authors.lastname: Severina
authors.affiliation: Lomonosov Moscow State University, Belozersky Institute of Physico-Chemical Biology, Vorobyevy Gory 1, Moscow 119991, Russia; Lomonosov Moscow State University, Institute of Mitoengineering, Vorobyevy Gory 1, Moscow 119991, Russia.
authors.forename: Tatyana M
authors.initials: TM
authors.lastname: Il'yasova
authors.affiliation: Lomonosov Moscow State University, Faculty of Fundamental Medicine, Lomonosovsky Prospect 31/5, Moscow 117192, Russia.
authors.forename: Mikhail V
authors.initials: MV
authors.lastname: Gulyaev
authors.affiliation: Lomonosov Moscow State University, Belozersky Institute of Physico-Chemical Biology, Vorobyevy Gory 1, Moscow 119991, Russia; Lomonosov Moscow State University, Institute of Mitoengineering, Vorobyevy Gory 1, Moscow 119991, Russia.
authors.forename: Vera I
authors.initials: VI
authors.lastname: Dedukhova
authors.affiliation: A. N. Bach Institute of Biochemistry, Russian Academy of Sciences, Leninsky Prospect 33/2, 119071 Moscow, Russia.
authors.forename: Tatyana A
authors.initials: TA
authors.lastname: Trendeleva
authors.affiliation: Lomonosov Moscow State University, Belozersky Institute of Physico-Chemical Biology, Vorobyevy Gory 1, Moscow 119991, Russia; Lomonosov Moscow State University, Institute of Mitoengineering, Vorobyevy Gory 1, Moscow 119991, Russia.
authors.forename: Egor Y
authors.initials: EY
authors.lastname: Plotnikov
authors.affiliation: Lomonosov Moscow State University, Institute of Mitoengineering, Vorobyevy Gory 1, Moscow 119991, Russia; A. N. Bach Institute of Biochemistry, Russian Academy of Sciences, Leninsky Prospect 33/2, 119071 Moscow, Russia.
authors.forename: Renata A
authors.initials: RA
authors.lastname: Zvyagilskaya
authors.affiliation: Lomonosov Moscow State University, Belozersky Institute of Physico-Chemical Biology, Vorobyevy Gory 1, Moscow 119991, Russia; Lomonosov Moscow State University, Institute of Mitoengineering, Vorobyevy Gory 1, Moscow 119991, Russia.
authors.forename: Boris V
authors.initials: BV
authors.lastname: Chernyak
authors.affiliation: Lomonosov Moscow State University, Belozersky Institute of Physico-Chemical Biology, Vorobyevy Gory 1, Moscow 119991, Russia; Lomonosov Moscow State University, Institute of Mitoengineering, Vorobyevy Gory 1, Moscow 119991, Russia.
authors.forename: Dmitry B
authors.initials: DB
authors.lastname: Zorov
authors.affiliation: Lomonosov Moscow State University, Belozersky Institute of Physico-Chemical Biology, Vorobyevy Gory 1, Moscow 119991, Russia; Lomonosov Moscow State University, Institute of Mitoengineering, Vorobyevy Gory 1, Moscow 119991, Russia. Electronic address: antonen@genebee.msu.ru.
authors.forename: Yuri N
authors.initials: YN
authors.lastname: Antonenko
authors.affiliation: Lomonosov Moscow State University, Belozersky Institute of Physico-Chemical Biology, Vorobyevy Gory 1, Moscow 119991, Russia; Lomonosov Moscow State University, Institute of Mitoengineering, Vorobyevy Gory 1, Moscow 119991, Russia; Lomonosov Moscow State University, Faculty of Bioengineering and Bioinformatics, Vorobyevy Gory 1, Moscow 119991, Russia. Electronic address: skulach@belozersky.msu.ru.
authors.forename: Vladimir P
authors.initials: VP
authors.lastname: Skulachev
mesh_terms: D000818:Animals; D006367:HeLa Cells; D006801:Humans; D008051:Lipid Bilayers; D008930:Mitochondria, Liver / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D012235:Rhodamines / Q000737:chemistry / Q000494:pharmacology*; D014475:Uncoupling Agents / Q000494:pharmacology*
chemical_list: D008051:Lipid Bilayers; D018696:Neuroprotective Agents; D012235:Rhodamines; D014475:Uncoupling Agents
keywords: Membrane potential; Mild uncoupler; Mitochondria; Protonophore; Rhodamine