An attempt to prevent senescence: A mitochondrial approach

Skulachev, Vladimir P.; Anisimov, Vladimir N.; Antonenko, Yuri N.; Bakeeva, L. E.; Chernyak, Boris V.; Еричев, В. П.; Filenko, О. F.; Ni, Kalinina; Kapelko, V. I.; Kolosova, N. G.; Копнин, Б. П.; Коршунова, Г. А.; Lichinitser, Mikhail; Obukhova, L. A.; Pasyukova, Elena G.; Писаренко, О. И.; Roginsky, Vitaly A.; Ruuge, E. K.; Senin, Ivan I.; Severina, Inna I.; Скулачев, М. В.; Spivak, I. M.; Tashlitsky, Vadim N.; Tkachuk, Vsevolod A.; Vysokikh, Mikhail; Yaguzhinsky, L. S.; Zorov, Dmitry B.

doi:10.1016/j.bbabio.2008.12.008

Cited by 374 publications

(273 citation statements)

References 133 publications

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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: 71%

“…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%

“…For this purpose, we used a novel oral mitochondria-specific antioxidant, the Skulachev ion (plastoquinonyl decyltriphenylphosphonium) (SkQ). SkQ is a small cationic molecule that targets and accumulates in the inner mitochondrial membrane [12]. 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.…”

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: 71%

Section: Introductionmentioning

confidence: 99%

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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“…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.…”

mentioning

confidence: 62%

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

Severin

Severina

Antonenko

et al. 2009

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

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173

106

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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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“…In addition, the study of the molecular mechanisms of mitochondrial damaging agents in lung cancer cells will aid in the development of drugs related to mitochondrial damage for the treatment of lung cancer. The production of reactive oxygen species (ROS) by the mitochondria is considered to be a major factor in the process of senescence [28] .…”

Section: Wwwchinapharcom LI Y Et Almentioning

confidence: 99%

Novel ferrocenyl derivatives exert anti-cancer effect in human lung cancer cells in vitro via inducing G1-phase arrest and senescence

Han

et al. 2013

Acta Pharmacol Sin

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Aim: To investigate the effects of 7 novel 1-ferrocenyl-2-(5-phenyl-1H-1,2,4-triazol-3-ylthio) ethanone derivatives on human lung cancer cells in vitro and to determine the mechanisms of action. Methods: A549 human lung cancer cells were examined. Cell viability was analyzed with MTT assay. Cell apoptosis and senescence were examined using Hoechst 33258 and senescence-associated-β-galactosidase (SA-β-gal) staining, respectively. LDH release was measured using a detection kit. Cell cycle was analyzed using a flow cytometer. Intracellular ROS level was measured with the 2′,7′-dichlorodihydrofluorescein probe. Phosphorylation of p38 was determined using Western blot. Results: Compounds 5b, 5d, and 5e (40 and 80 µmol/L) caused significant decrease of A549 cell viability, while other 4 compounds had no effect on the cells. Compounds 5b, 5d, and 5e (80 µmol/L) induced G 1 -phase arrest (increased the G 1 population by 22.6%, 24.23%, and 26.53%, respectively), and markedly increased SA-β-gal-positive cells. However, the compounds did not cause nuclear DNA frag mentation and chromatin condensation in A549 cells. Nor did they affect the release of LDH from the cells. The compounds significantly elevated the intracellular ROS level, decreased the mitochondrial membrane potential, and increased p38 phosphorylation in the cells. In the presence of the antioxidant and free radical scavenger N-acetyl-L-cysteine (10 mmol/L), above effects of compounds 5b, 5d, and 5e were abolished. Conclusion: The compounds 5b, 5d, and 5e cause neither apoptosis nor necrosis of A549 cells, but exert anti-cancer effect via inducing G 1 -phase arrest and senescence through ROS/p38 MAP-kinase pathway.

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An attempt to prevent senescence: A mitochondrial approach

Cited by 374 publications

References 133 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

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

Novel ferrocenyl derivatives exert anti-cancer effect in human lung cancer cells in vitro via inducing G1-phase arrest and senescence

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