Mitochondria-targeted plastoquinone derivatives as tools to interrupt execution of the aging program. 2. Treatment of some ROS- and Age-related diseases (heart arrhythmia, heart infarctions, kidney ischemia, and stroke)

Bakeeva, L. E.; Барсков, И. В.; Egorov, Maxim; Isaev, N. K.; Kapelko, V. I.; Kazachenko, A.V.; Kirpatovskiy, V.I.; Kozlovsky, Stanislav V.; Лакомкин, В. Л.; Levina, S. B.; Писаренко, О. И.; Plotnikov, Egor Y.; Saprunova, V. B.; Serebryakova, L. I.; Скулачев, М. В.; Stelmashook, E. V.; Студнева, И. М.; Tskitishvili, O. V.; Vasilyeva, A. K.; Victorov, Ilya V.; Zorov, Dmitry B.; Skulachev, Vladimir P.

doi:10.1134/s000629790812002x

Cited by 155 publications

(94 citation statements)

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“…SkQ treatment normalised H 2 O 2 levels in HF+SkQ mice to those of the LF controls (Fig. 2c), thus confirming the efficacy of the mitochondrial-specific ROS scavenger as shown above and previously reported [12][13][14]. In addition, SOD2 (the mitochondrial SOD) activity was significantly elevated in HF mice (twofold vs LF, p<0.01) (Fig.…”

Section: Resultssupporting

confidence: 88%

“…SkQ mainly scavenges superoxide radicals arising from complex I, but can also sequester ROS generated from complex III [13], thus preventing excessive production of mitochondria-generated ROS. In vitro studies have shown that SkQ has a wide concentration range of antioxidant capacity [13], and in vivo studies have demonstrated that SkQ treatment effectively reduced oxidative damage in several models of oxidative stress [12][13][14].…”

Section: Introductionmentioning

confidence: 99%

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Targeting of mitochondrial reactive oxygen species production does not avert lipid-induced insulin resistance in muscle tissue from mice

et al. 2012

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Aims/hypothesis High-fat, high-sucrose diet (HF)-induced reactive oxygen species (ROS) levels are implicated in skeletal muscle insulin resistance and mitochondrial dysfunction. Here we investigated whether mitochondrial ROS sequestering can circumvent HF-induced oxidative stress; we also determined the impact of any reduced oxidative stress on muscle insulin sensitivity and mitochondrial function. Methods The Skulachev ion (plastoquinonyl decyltriphenylphosphonium) (SkQ), a mitochondria-specific antioxidant, was used to target ROS production in C2C12 muscle cells as well as in HF-fed (16 weeks old) male C57Bl/6 mice, compared with mice on low-fat chow diet (LF) or HF alone. Oxidative stress was measured as protein carbonylation levels. Glucose tolerance tests, glucose uptake assays and insulin-stimulated signalling were determined to assess muscle insulin sensitivity. Mitochondrial function was determined by high-resolution respirometry. Results SkQ treatment reduced oxidative stress in muscle cells (−23% p<0.05), but did not improve insulin sensitivity and glucose uptake under insulin-resistant conditions. In HF mice, oxidative stress was elevated (56% vs LF p<0.05), an effect completely blunted by SkQ. However, HF and HF+SkQ mice displayed impaired glucose tolerance (AUC HF up 33%, p<0.001; HF+SkQ up 22%; p<0.01 vs LF) and disrupted skeletal muscle insulin signalling. ROS sequestering did not improve mitochondrial function. Conclusions/interpretation SkQ treatment reduced muscle mitochondrial ROS production and prevented HF-induced oxidative stress. Nonetheless, whole-body glucose tolerance, insulin-stimulated glucose uptake, muscle insulin signalling and mitochondrial function were not improved. These results suggest that HF-induced oxidative stress is not a prerequisite for the development of muscle insulin resistance.

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Section: Resultssupporting

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Targeting of mitochondrial reactive oxygen species production does not avert lipid-induced insulin resistance in muscle tissue from mice

et al. 2012

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“…However, the existence of ⌬ on the inner mitochondrial membrane being negative inside makes cationic compounds capable of being accumulated inside mitochondria, which should increase their efficiency. It has been shown that SkQR1 accumulates effectively in mitochondria (experiments on isolated mitochondria, mammalian cell cultures, yeast cells, and intact organisms (7,53,54).…”

Section: Discussionmentioning

confidence: 99%

Derivatives of Rhodamine 19 as Mild Mitochondria-targeted Cationic Uncouplers

Antonenko

Avetisyan

Cherepanov

et al. 2011

Journal of Biological Chemistry

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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.Transport of electrons along the mitochondrial respiratory chain is accompanied by the formation of an electrochemical gradient of hydrogen ions (⌬ H ϩ) 3 at the inner mitochondrial membrane. ⌬ H ϩ is used for ATP production and other energyconsuming processes. However, high values of ⌬ H ϩ can increase the production of dangerous reactive oxygen species (ROS) (1, 2). Although mitochondria are able to control ⌬ H ϩ by adjusting the activity of natural uncoupling mechanisms (i.e. free fatty acids, anion carriers, and uncoupling proteins) (3), there is considerable interest in finding pharmacological agents to increase mitochondrial proton leak and, as a consequence, to prevent obesity and to decrease ROS production (4 -7).Uncouplers, or protonophores, are small organic compounds capable of carrying hydrogen ions across artificial and biological membranes. The strategy of "mild uncoupling" (2) relies on the fact that partial decrease in ⌬ H ϩ can be beneficial for cells especially under some pathological conditions, suggesting that uncouplers are good candidates for therapeutic uses. Apparently, such applications are hindered by high toxicity, as in the case of 2,4-dinitrophenol (DNP), which was temporarily used at the beg...

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“…This effect was accompanied by retardation of the development of many age-related diseases and traits (2,14,(18)(19)(20)(21). When studying the molecular mechanism of the effects of SkQs, we usually employed C 12 TPP as the control compound.…”

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confidence: 99%

Penetrating cation/fatty acid anion pair as a mitochondria-targeted protonophore

Severin

Severina

Antonenko

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

180

115

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A unique phenomenon of mitochondria-targeted protonophores is described.ItconsistsinatransmembraneH þ -conductingfattyacidcycling mediated by penetrating cations such as 10-(6'-plastoquinonyl) decyltriphenylphosphonium (SkQ1) or dodecyltriphenylphosphonium (C 12 TPP). The phenomenon has been modeled by molecular dynamics and directly proved by experiments on bilayer planar phospholipid membrane, liposomes, isolated mitochondria, and yeast cells. In bilayer planar phospholipid membrane, the concerted action of penetrating cations and fatty acids is found to result in conversion of a pH gradient (ΔpH) to a membrane potential (Δψ) of the Nernstian value (about 60 mV Δψ at ΔpH ¼ 1). A hydrophobic cation with localized charge (cetyltrimethylammonium) failed to substitute for hydrophobic cations with delocalized charge. In isolated mitochondria, SkQ1 and C 12 TPP, but not cetyltrimethylammonium, potentiatedfattyacid-induced(i)uncouplingofrespirationandphosphorylation, and (ii) inhibition of H 2 O 2 formation. In intact yeast cells, C 12 TPP stimulated respiration regardless of the extracellular pH value, whereas a nontargeted protonophorous uncoupler (trifluoromethoxycarbonylcyanidephenylhydrazone)stimulatedrespiration at pH 5 but not at pH 3. Hydrophobic penetrating cations might be promising to treat obesity, senescence, and some kinds of cancer that require mitochondrial hyperpolarization.mild uncoupling | membrane | Mitochondria-targeted uncoupler | penetrating ion | antioxidant S ome decrease in mitochondrial membrane potential (Δψ) in the resting state may be favorable in treating obesity and hypothyroidism as well as in preventing senescence and certain types of cancer [for reviews, see refs. 1, 2]. In the first two cases, Δψ lowering stimulates respiratory metabolism. As to senescence and cancer, such an effect seems to be related to a decrease in production of reactive oxygen species (ROS) in mitochondria. ROS, in turn, were assumed to mediate senescence and some steps of cancerogenesis (2, 3). As was shown in our group (4), there is a very steep dependence of mitochondrial ROS formation on Δψ. Small (10-15%) lowering of Δψ resulted in ten-fold decrease in the ROS production rate (4). In isolated mitochondria, this can be achieved by adding a low concentration of a protonophorous uncoupler (4-6). This approach, called "mild uncoupling" (4, 6), was recently used by Padalko (7) and by Kowaltowski and coworkers (8) to prolong the lifespan of Drosophila and mice, respectively. However, long-term treatment of animals with uncouplers results in toxic side effects (9).In this paper, we put forward an alternative approach based on the use of synthetic cations that easily penetrate through biological membranes. Penetrating ions were suggested by our group to reveal electric potential difference across mitochondrial membrane (9, 10). In tetraphenylphosphonium (TPP), a typical representative of such ions, the positive charge is strongly displaced over four phenyl residues. As a result, water dipoles cannot be held by t...

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Mitochondria-targeted plastoquinone derivatives as tools to interrupt execution of the aging program. 2. Treatment of some ROS- and Age-related diseases (heart arrhythmia, heart infarctions, kidney ischemia, and stroke)

Cited by 155 publications

References 25 publications

Targeting of mitochondrial reactive oxygen species production does not avert lipid-induced insulin resistance in muscle tissue from mice

Targeting of mitochondrial reactive oxygen species production does not avert lipid-induced insulin resistance in muscle tissue from mice

Derivatives of Rhodamine 19 as Mild Mitochondria-targeted Cationic Uncouplers

Penetrating cation/fatty acid anion pair as a mitochondria-targeted protonophore

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