Mitochondria‐targeted antioxidant SkQR1 selectively protects MDR (Pgp 170)‐negative cells against oxidative stress

Fetisova, E. K.; Avetisyan, A. V.; Izyumov, D. S.; Korotetskaya, M. V.; Chernyak, Boris V.; Vp, Skulachev

doi:10.1016/j.febslet.2009.12.002

Cited by 43 publications

(28 citation statements)

References 24 publications

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“…SkQ1 also reduced lipid peroxidation and protein carbonylation in skeletal muscle, and prolonged lifespan at early and middle stages of aging [Neroev et al, 2008]. Finally, it was demonstrated that SkQR1 selectively accumulates in mitochondria of normal and tumor cells and protects the cellular pool of reduced glutathione, a major cellular antioxidant, during oxidative stress [Fetisova et al, 2010].…”

Section: Skq Compoundsmentioning

confidence: 97%

Complex I disorders: Causes, mechanisms, and development of treatment strategies at the cellular level

Valsecchi

Koopman

Manjeri

et al. 2010

Dev Disabil Res Revs

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Mitochondrial oxidative phosphorylation (OXPHOS) represents the final step in the conversion of nutrients into cellular energy. Genetic defects in the OXPHOS system have an incidence between 1:5,000 and 1:10,000 live births. Inherited isolated deficiency of the first complex (CI) of this system, a multisubunit assembly of 45 different proteins, occurs most frequently and originates from mutations in either the nuclear DNA, encoding 38 structural subunits and several assembly factors, or the mitochondrial DNA, encoding 7 structural subunits. The deficiency is associated with devastating multisystemic disorders, often affecting the brain, with onset in early childhood. There are currently no rational treatment strategies. Here, we present an overview of the genetic origins and cellular consequences of this deficiency and discuss how these insights might aid future development of treatment strategies.

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Section: Skq Compoundsmentioning

confidence: 97%

Complex I disorders: Causes, mechanisms, and development of treatment strategies at the cellular level

Valsecchi

Koopman

Manjeri

et al. 2010

Dev Disabil Res Revs

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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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“…Moreover, its effect on cancer merits special mention, particularly SkQTR1, which is a better substrate for multidrug resistance (MDR) pumps than other SkQs. In normal cells, the amount of MDR pumps is negligible, which allows much higher concentrations of SkQTR1 in these cells than in tumor cells, an effect that may be exploited to preserve nontumor tissue during anticancer treatments (89). In light of all these promising findings, SkQ-based molecules could constitute a new generation of mitochondrial medicines.…”

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confidence: 99%

Molecular Strategies for Targeting Antioxidants to Mitochondria: Therapeutic Implications

Apostolova

Víctor

2015

Antioxidants & Redox Signaling

235

147

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Mitochondrial function and specifically its implication in cellular redox/oxidative balance is fundamental in controlling the life and death of cells, and has been implicated in a wide range of human pathologies. In this context, mitochondrial therapeutics, particularly those involving mitochondria-targeted antioxidants, have attracted increasing interest as potentially effective therapies for several human diseases. For the past 10 years, great progress has been made in the development and functional testing of molecules that specifically target mitochondria, and there has been special focus on compounds with antioxidant properties. In this review, we will discuss several such strategies, including molecules conjugated with lipophilic cations (e.g., triphenylphosphonium) or rhodamine, conjugates of plant alkaloids, amino-acid-and peptide-based compounds, and liposomes. This area has several major challenges that need to be confronted. Apart from antioxidants and other redox active molecules, current research aims at developing compounds that are capable of modulating other mitochondria-controlled processes, such as apoptosis and autophagy. Multiple chemically different molecular strategies have been developed as delivery tools that offer broad opportunities for mitochondrial manipulation. Additional studies, and particularly in vivo approaches under physiologically relevant conditions, are necessary to confirm the clinical usefulness of these molecules. Antioxid. Redox Signal. 22, 686-729.

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Mitochondria‐targeted antioxidant SkQR1 selectively protects MDR (Pgp 170)‐negative cells against oxidative stress

Cited by 43 publications

References 24 publications

Complex I disorders: Causes, mechanisms, and development of treatment strategies at the cellular level

Complex I disorders: Causes, mechanisms, and development of treatment strategies at the cellular level

Derivatives of Rhodamine 19 as Mild Mitochondria-targeted Cationic Uncouplers

Molecular Strategies for Targeting Antioxidants to Mitochondria: Therapeutic Implications

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