Novel Penetrating Cations for Targeting Mitochondria

Title:Novel Penetrating Cations for Targeting Mitochondria

Volume: 19 Issue: 15

Author(s): Boris V. Chernyak, Yuri N. Antonenko, Lidia V. Domnina, Olga Yu. Ivanova, Konstantin G. Lyamzaev, Antonina V. Pustovidko, Tatiana I. Rokitskaya, Inna I. Severina, Ruben A. Simonyan, Tatiana A. Trendeleva and Renata A. Zvyagilskaya

Affiliation:

Keywords: Mitochondria, penetrating cations, antioxidants, uncouplers, berberine, palmatine, rhodamine, SkQ family

Abstract: Novel penetrating cations were used for the design of mitochondria-targeted compounds and tested in model lipid membranes, in isolated mitochondria and in living human cells in culture. Rhodamine-19, berberine and palmatine were conjugated by aliphatic linkers with plastoquinone possessing antioxidant activity. These conjugates (SkQR1,SkQBerb, SkQPalm) and their analogs lacking plastoquinol moiety (C12R1,C10Berb and C10Palm) penetrated bilayer phospholipid membrane in their cationic forms and accumulated in isolated mitochondria or in mitochondria of living cells due to membrane potential negative inside. Reduced forms of SkQR1, SkQBerb and SkQPalm inhibited lipid peroxidation in isolated mitochondria at nanomolar concentrations. In human fibroblasts SkQR1, SkQBerb and SkQPalm prevented fragmentation of mitochondria and apoptosis induced by hydrogen peroxide. SkQR1 was effective at subnanomolar concentrations while SkQberb, SkQPalm and SkQ1 (prototypic conjugate of plastoquinone with dodecyltriphenylphosphonium) were effective at 10-times higher concentrations.

The aliphatic conjugates of berberine and palmatine (as well as the conjugates of triphenylphosphonium) induced proton transport mediated by free fatty acids (FA) both in the model and mitochondrial membrane. In mitochondria this process was facilitated by the adenine nucleotide carrier. In contrast to the other cationic conjugates, SkQR1 and C12R1 induced FA-independent proton conductivity due to protonation/deprotonation of the rhodamine residue. This property in combination with the antioxidant activity probably makes rhodamine conjugates highly effective in protection against oxidative stress.

The novel cationic conjugates described here are promising candidates for drugs against various pathologies and aging as mitochondriatargeted antioxidants and selective mild uncouplers.

Cite this article as:

V. Chernyak Boris, N. Antonenko Yuri, V. Domnina Lidia, Yu. Ivanova Olga, G. Lyamzaev Konstantin, V. Pustovidko Antonina, I. Rokitskaya Tatiana, I. Severina Inna, A. Simonyan Ruben, A. Trendeleva Tatiana and A. Zvyagilskaya Renata, Novel Penetrating Cations for Targeting Mitochondria, Current Pharmaceutical Design 2013; 19 (15) . https://dx.doi.org/10.2174/1381612811319150015

DOI https://dx.doi.org/10.2174/1381612811319150015	Print ISSN 1381-6128
Publisher Name Bentham Science Publisher	Online ISSN 1873-4286