Fedor F Severin

Lomonosov Moscow State University, Moskva, Moscow, Russia

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Publications (67)397.69 Total impact

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    ABSTRACT: Here we present a concept that considers organism aging as an additional facultative function promoting evolution, but counterproductive for an individual. We hypothesize that aging can be inhibited or even arrested when full mobilization of all resources is needed for the survival of an individual. We believe that the organism makes such a decision based on the analysis of signals of special receptors that monitor a number of parameters of the internal and external environment. The amount of available food is one of these parameters. Food restriction is perceived by the organism as a signal of coming starvation; in response to it, the organism inhibits its counterproductive programs, in particular, aging. We hypothesize that the level of protein obtained with food is estimated based on blood concentration of one of the essential amino acids (methionine), of carbohydrates - via glucose level, and fats - based on the level of one of the free fatty acids. When the amount of available food is sufficient, these receptors transmit the signal allowing aging. In case of lack of food, this signal is cancelled, and as a result aging is inhibited, i.e. age-related weakening of physiological functions is inhibited, and lifespan increases (the well-known geroprotective effect of partial food restriction). In Caenorhabditis elegans, lowering of the ambient temperature has a similar effect. This geroprotective effect is removed by the knockout of one of the cold receptors, and replacement of the C. elegans receptor by a similar human receptor restores the ability of low temperature to increase the lifespan of the nematode. A chain of events linking the receptor with the aging mechanism has been discovered in mice - for one of the pain receptors in neurons, the nerve endings of which entwine pancreas β-cells. Age-related activation of these receptors inhibits the work of insulin genes in β-cells. Problems with insulin secretion lead to oxidative stress, chronic inflammation, and type II diabetes, which can be regarded as one of the forms of senile phenoptosis. In conclusion, we consider the role of some psychological factors in the regulation of the aging program.
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    ABSTRACT: Multiple drug resistance pumps are potential drug targets. Here we asked whether the lipophilic cation dodecyltriphenylphosphonium (C12TPP) can interfere with their functioning. First, we found that suppression of ABC transporter gene PDR5 increases the toxicity of C12TPP in yeast. Second, C12TPP appeared to prevent the efflux of rhodamine 6G - a fluorescent substrate of Pdr5p. Moreover, C12TPP increased the cytostatic effects of some other known Pdr5p substrates. The chemical nature of C12TPP suggests that after Pdr5p-driven extrusion the molecules return to the plasma membrane and then into the cytosol, thus effectively competing with other substrates of the pump.
    Biochemical and Biophysical Research Communications 07/2014; 450(4). DOI:10.1016/j.bbrc.2014.07.017 · 2.28 Impact Factor
  • Biochimica et Biophysica Acta (BBA) - Bioenergetics 07/2014; 1837:e28. DOI:10.1016/j.bbabio.2014.05.298 · 4.83 Impact Factor
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    ABSTRACT: In search of fluorescent uncouplers of oxidative phosphorylation, three esters of fluorescein, n-butyl-, n-octyl-, and n-dodecyl-oxycarbonyl-fluorescein (C4-FL, C8-FL, C12-FL) were synthesized and characterized. With increasing liposomal lipid content, the long-chain alkyl derivatives of fluorescein (C8-FL, C12-FL and commercially available C18-FL), but not C4-FL and unsubstituted fluorescein, exhibited an increase in fluorescence polarization reflecting the dye binding to liposomes. C12-FL induced proton permeability in lipid membranes, while C4-FL was inactive. In contrast to C4-FL and C18-FL, C12-FL and C8-FL increased the respiration rate and decreased the membrane potential of isolated rat liver mitochondria with half-maximal effective concentrations of 700 nM and 300 nM, respectively. The effect of Cn-FL on the respiration correlated with that on proton permeability of the inner mitochondrial membrane, as measured by induction of mitochondria swelling in the potassium acetate medium. Binding of C8-FL to mitochondria depended on their energization, which was apparently associated with pH gradient generation across the inner mitochondrial membrane in the presence of a respiratory substrate. In wild-type yeast cells, C12-FL localized predominantly in plasma membrane, whereas in AD1-8 mutants lacking MDR pumps, it stained cytoplasmic organelles with some preference for mitochondria. Fluorescent uncouplers can be useful as a tool for determining its localization in a cell or distribution between different tissues in a living animal by fluorescent microscopy.
    Biochimica et Biophysica Acta 09/2013; 1837(1). DOI:10.1016/j.bbabio.2013.09.011 · 4.66 Impact Factor
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    F F Severin, B A Feniouk, V P Skulachev
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    ABSTRACT: During the last decade, evidence has been accumulating supporting the hypothesis that aging is genetically programmed and, therefore, precisely timed. This hypothesis poses a question: what is the mechanism of the biological clock that controls aging? Measuring the level of the advanced glycation end products (AGE) is one of the possible principles underlying the functioning of the biological clock. Protein glycation is an irreversible, non-enzymatic, and relatively slow process. Moreover, many types of cells have receptors that can measure AGE level. We propose the existence of a protein that has a lifespan comparable to that of the whole organism. Interaction of the advanced glycation end product generated from this protein with a specific AGE receptor might initiate apoptosis in a vitally important non-regenerating tissue that produces a primary juvenile hormone. This could result in the age-dependent decrease in the level of this hormone leading to aging of the organism.
    Biochemistry (Moscow) 09/2013; 78(9):1043-1047. DOI:10.1134/S0006297913090101 · 1.35 Impact Factor
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    ABSTRACT: Glycolysis lies at the basis of metabolism and cell energy supply. The disregulation of glycolysis is involved in such pathological processes as cancer proliferation, neurodegenerative diseases, and amplification of ischemic damage. Phosphofructokinase-2 (PFK-2), a bifunctional enzyme and regulator of glycolytic flux, has recently emerged as a promising anticancer target. Herein, the computer-aided design of a new class of aminofurazan-triazole regulators of PFK-2 is described along with the results of their in vitro evaluation. The aminofurazan-triazoles differ from other recently described inhibitors of PFK-2 and demonstrate the ability to modulate glycolytic flux in rat muscle lysate, producing a twofold decrease by inhibitors and fourfold increase by activators. The most potent compounds in the series were shown to inhibit the kinase activity of the hypoxia-inducible form of PFK-2, PFKFB3, as well as proliferation of HeLa, lung adenocarcinoma, colon adenocarcinoma, and breast cancer cells at concentrations in the low micromolar range.
    ChemMedChem 08/2013; 8(8). DOI:10.1002/cmdc.201300154 · 3.05 Impact Factor
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    ABSTRACT: they fuse and divide. Here we summarize data on the protein machinery driving mitochondrial dynamics in yeast and also discuss the factors that affect the fusion-fission balance. Fission is a general stress response of cells, and in the case of yeast this response appears to be prosurvival. At the same time, even under normal conditions yeast mitochondria undergo continuous cycles of fusion and fission. This seems to be a futile cycle and also expensive from the energy point of view. Why does it exist? Benefits might be the same as in the case of sexual reproduction. Indeed, mixing and separating of mitochondrial content allows mitochondrial DNA to segregate and recombine randomly, leading to high variation in the numbers of mutations per individual mitochondrion. This opens a possibility for effective purifying selection-elimination of mitochondria highly contaminated by deleterious mutations. The beneficial action presumes a mechanism for removal of defective mitochondria. We argue that selective mitochondrial autophagy or asymmetrical distribution of mitochondria during cell division could be at the core of such mechanism.
    Oxidative Medicine and Cellular Longevity 07/2013; 2013:139491. DOI:10.1155/2013/139491 · 3.36 Impact Factor
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    ABSTRACT: Vectors for the expression of MFS transporter CefT of Acremonium chrysogenum—a producer of beta-lactam antibiotic cephalosporin C—and in Saccharomyces cerevisiae as a fusion with the cyan fluorescent protein (CFP) have been generated. The subcellular localization of the CefT-CFP hybrid protein in yeast cells has been investigated. It was shown that the CefT-CFP hybrid protein is capable of complementation of the qdr3, tpo1, and tpo3 genes encoding for orthologous MFS transporters of Saccharomycetes, making the corresponding strains resistant to spermidine, ethidium bromide, and hygromycin B. High-producing strain A. chrysogenum VKM F 4081D, expressing the cefT-cfp fusion construct, was obtained by an agrobacteria mediated transformation. It was also shown that the constitutive expression of cefT in A. chrysogenum VKM F-4081D led to a change in the biosynthetic profiles of cephalosporin C and its precursors. This resulted in a 25–35% decrease in the amount of the final product accumulated in the cultural liquid with a simultaneous increase in the concentration of its intermediates.
    Applied Biochemistry and Microbiology 07/2013; 49(4). DOI:10.1134/S0003683813040042 · 0.66 Impact Factor
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    ABSTRACT: Since the times of the Bible, an extract of black cumin seeds was used as a medicine to treatmany human pathologies. Thymoquinone (2-demethylplastoquinone derivative) was identified as an active antioxidant component of this extract. Recently, it was shown that conjugates of plastoquinone and penetrating cations are potent mitochondria-targeted antioxidants effective in treating a large number of age-related pathologies. This review summarizes new data on the antioxidant and some other properties of membrane-penetrating cationic compounds where 2-demethylplastoquinone substitutes for plastoquinone. It was found that such a substitution significantly increases a window between anti- and prooxidant concentrations of the conjugates. Like the original plastoquinone derivatives, the novel compounds are easily reduced by the respiratory chain, penetrate through model and natural membranes, specifically accumulate in mitochondria in an electrophoretic fashion, and strongly inhibit H2O2-induced apoptosis at pico- and nanomolar concentrations in cell cultures. At present, cationic demethylplastoquinone derivatives appear to be the most promising mitochondria-targeted drugs of the quinone series.
    FEBS letters 05/2013; 587(13). DOI:10.1016/j.febslet.2013.04.043 · 3.34 Impact Factor
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    ABSTRACT: Protonophorous uncouplers causing a partial decrease in mitochondrial membrane potential are promising candidates for therapeutic applications. Here we showed that hydrophobic penetrating cations specifically targeted to mitochondria in a membrane potential-driven fashion increased proton-translocating activity of the anionic uncouplers 2,4-dinitrophenol (DNP) and carbonylcyanide-p-trifluorophenylhydrazone (FCCP). In planar bilayer lipid membranes (BLM) separating two compartments with different pH values, DNP-mediated diffusion potential of H(+) ions was enhanced in the presence of dodecyltriphenylphosphonium cation (C12TPP). The mitochondria-targeted penetrating cations strongly increased DNP- and carbonylcyanide m-chlorophenylhydrazone (CCCP)-mediated steady-state current through BLM when a transmembrane electrical potential difference was applied. Carboxyfluorescein efflux from liposomes initiated by the plastoquinone-containing penetrating cation SkQ1 was inhibited by both DNP and FCCP. Formation of complexes between the cation and CCCP was observed spectophotometrically. In contrast to the less hydrophobic tetraphenylphosphonium cation (TPP), SkQ1 and C12TPP promoted the uncoupling action of DNP and FCCP on isolated mitochondria. C12TPP and FCCP exhibited a synergistic effect decreasing the membrane potential of mitochondria in yeast cells. The stimulating action of penetrating cations on the protonophore-mediated uncoupling is assumed to be useful for medical applications of low (non-toxic) concentrations of protonophores.
    PLoS ONE 04/2013; 8(4):e61902. DOI:10.1371/journal.pone.0061902 · 3.53 Impact Factor
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    ABSTRACT: Stressed Saccharomyces cerevisiae cells easily lose respiratory function due to deletions in mitochondrial DNA, and this increases their general stress resistance. Is the loss active? We found that erythromycin (an inhibitor of mitochondrial translation) prevents the loss in control cells but not in the ones expressing mitochondrially-encoded protein Var1 in the nucleus. Var1 is a component of mitochondrial ribosomes; it is hydrophilic, positively charged, and prone to aggregation. Addition of DNase altered Var1 content in a preparation of mitochondrial nucleoids. Our data indicate that Var1 physically interacts with mitochondrial DNA and under stress negatively regulates its maintenance.
    European journal of cell biology 03/2013; DOI:10.1016/j.ejcb.2013.02.001 · 3.70 Impact Factor
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    ABSTRACT: Yeasts growing limited for nitrogen source or treated with fusel alcohols form elongated cells - pseudohyphae. Absence of mitochondrial DNA or anaerobic conditions inhibits this process, but the precise role of mitochondria is not clear. We found that a significant percentage of pseudohyphal cells contained mitochondria with different levels of membrane potential within one cell. An uncoupler FCCP, but not the ATP-synthase inhibitor oligomycin D, prevented pseudohyphal growth. Interestingly, repression of the MIH1 gene encoding phosphatase activator of the G2/M transition partially restores the ability of yeast to form pseudohyphal cells in the presence of FCCP or in the absence of mitochondrial DNA. At the same time, retrograde signaling (the one triggered by dysfunctional mitochondria) appeared to be a positive regulator of butanol-induced pseudohyphae formation: the deletion of any of the retrograde signaling genes (RTG1, RTG2, or RTG3) partially suppressed pseudohyphal growth. Together, our data suggests that two subpopulations of mitochondria are required for filamentous growth: one with high and another with low transmembrane potential. These mitochondria activated signaling pathways appear to converge at Mih1p level. © 2013 Federation of European Microbiological Societies. Published by Blackwell Publishing Ltd. All rights reserved.
    FEMS Yeast Research 02/2013; 13(4). DOI:10.1111/1567-1364.12039 · 2.44 Impact Factor
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    ABSTRACT: One of the arguments against aging being programmed is the assumption that variation in the timing of aging-related outcomes is much higher compared to variation in timing of the events programmed by ontogenesis. The main objective of this study was to test the validity of this argument. To this aim, we compared absolute variability (standard deviation) and relative variability (coefficient of variation) for parameters that are known to be determined by the developmental program (age at sexual maturity) with variability of characteristics related to aging (ages at menopause and death). We used information on the ages at sexual maturation (menarche) and menopause from the nationally representative survey of the adult population of the United States (MIDUS) as well as published data for 14 countries. We found that coefficients of variation are in the range of 8-13% for age at menarche, 7-11% for age at menopause, and 16-21% for age at death. Thus, the relative variability for the age at death is only twice higher than for the age at menarche, while the relative variability for the age at menopause is almost the same as for the age at menarche.
    Biochemistry (Moscow) 07/2012; 77(7):754-60. DOI:10.1134/S0006297912070085 · 1.35 Impact Factor
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    ABSTRACT: The current view on phenoptosis and apoptosis as genetic programs aimed at eliminating potentially dangerous organisms and cells, respectively, is given. Special emphasis is placed on apoptosis (phenoptosis) in yeasts: intracellular defects and a plethora of external stimuli inducing apoptosis in yeasts; distinctive morphological and biochemical hallmarks accompanying apoptosis in yeasts; pro- and antiapoptotic factors involved in yeast apoptosis signaling; consecutive stages of apoptosis from external stimulus to the cell death; a prominent role of mitochondria and other organelles in yeast apoptosis; possible pathways for release of apoptotic factors from the intermembrane mitochondrial space into the cytosol are described. Using some concrete examples, the obvious physiological importance and expediency of altruistic death of yeast cells is shown. Poorly known aspects of yeast apoptosis and prospects for yeast apoptosis study are defined.
    Biochemistry (Moscow) 07/2012; 77(7):761-75. DOI:10.1134/S0006297912070097 · 1.35 Impact Factor
  • D A Knorre, F F Severin
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    ABSTRACT: In Saccharomyces cerevisiae yeast cells a decrease in the mitochondrial membrane potential caused by protonophores or by a loss of mitochondrial DNA leads to an increase in longevity (replicative life span). The loss of mitochondrial DNA also activates retrograde signaling that results in certain changes in transcription. Recently, Miceli and coauthors ((2011) Front. Genet., 2, 102) showed that retrograde response is triggered by a drop in the membrane potential. Independently, it has been shown that retrograde response activates autophagic mitochondrial degradation (mitophagy). Together, it suggests that activation of selective mitophagy increases lifespan by protecting cells from accumulation of damaged mitochondria in cells. Low concentrations of protonophores can be beneficial by increasing the accuracy of the mitophagosomal degradation of mitochondria with deleterious mutations in their DNA.
    Biochemistry (Moscow) 07/2012; 77(7):793-4. DOI:10.1134/S0006297912070127 · 1.35 Impact Factor
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    ABSTRACT: Plastoquinone, a very effective electron carrier and antioxidant of chloroplasts, was conjugated with decyltriphenylphosphonium to obtain a cation easily penetrating through membranes. This cation, called SkQ1, is specifically targeted to mitochondria by electrophoresis in the electric field formed by the mitochondrial respiratory chain. The respiratory chain also regenerates reduced SkQ1H2 from its oxidized form that appears as a result of the antioxidant activity of SkQ1H2. SkQ1H2 prevents oxidation of cardiolipin, a mitochondrial phospholipid that is especially sensitive to attack by reactive oxygen species (ROS). In cell cultures, SkQ1 and its analog plastoquinonyl decylrhodamine 19 (SkQR1) arrest H2O2-induced apoptosis. When tested in vivo, SkQs (i) prolong the lifespan of fungi, crustaceans, insects, fish, and mice, (ii) suppress appearance of a large number of traits typical for age-related senescence (cataract, retinopathies, achromotrichia, osteoporosis, lordokyphosis, decline of the immune system, myeloid shift of blood cells, activation of apoptosis, induction of β-galactosidase, phosphorylation of H2AX histones, etc.) and (iii) lower tissue damage and save the lives of young animals after treatments resulting in kidney ischemia, rhabdomyolysis, heart attack, arrhythmia, and stroke. We suggest that the SkQs reduce mitochondrial ROS and, as a consequence, inhibit mitochondriamediated apoptosis, an obligatory step of execution of programs responsible for both senescence and fast “biochemical suicide” of an organism after a severe metabolic crisis.
    Current Drug Targets 05/2011; 12(6):800-826. DOI:10.2174/138945011795528859 · 3.60 Impact Factor
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    ABSTRACT: Hydrophobic cations with delocalized charge are used to deliver drugs to mitochondria. However, micromolar concentrations of such compounds could be toxic due to their excessive accumulation in mitochondria. We studied possible pathophysiological effects of one such cation, i.e. dodecyltriphenylphosphonium (C(12)-TPP), in the yeast Saccharomyces cerevisiae. First, we found that C(12)-TPP induces high-amplitude mitochondrial swelling. The swelling can be prevented by addition of protonophorous uncoupler FCCP or antioxidant alpha-tocopherol, but not other tested antioxidants (N-acetylcysteine and Trolox). Second, FCCP prevents ROS-sensitive fluorescent dye (dichlorofluorescein diacetate) staining of yeast treated with C(12)-TPP. We also showed that all tested antioxidants partially restore the growth inhibited by C(12)-TPP. The latter points that ROS rather than the mitochondria swelling limit the growth rate.
    Journal of Bioenergetics 03/2011; 43(2):175-80. DOI:10.1007/s10863-011-9345-8 · 2.71 Impact Factor
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    ABSTRACT: 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.
    Journal of Biological Chemistry 03/2011; 286(20):17831-40. DOI:10.1074/jbc.M110.212837 · 4.60 Impact Factor
  • Biophysical Journal 02/2011; 100(3). DOI:10.1016/j.bpj.2010.12.2694 · 3.83 Impact Factor
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    ABSTRACT: Recently it was convincingly shown that the yeast Saccharomyces cerevisiae does possess the basic modules of programmed cell death machinery. As programmed cell death is suicide for a unicellular organism, it is reasonable to assume that they trigger the program when the death is beneficial for the rest of the population. Not surprisingly, most of the scenarios of physiological death of S. cerevisiae, i.e. cell death in stationary culture, during meiosis, during mating, and driven by viruses are dependent on quorum sensing, meaning that they depend on the cell density. Here we also discuss possible mechanisms that govern fitness decline during replicative aging of S. cerevisiae cells. We argue that loss of mitochondrial DNA function that occurs during replicative aging is programmed and adaptive. Indeed, yeast cells with nonfunctional mitochondrial DNA are known to be extremely stress-resistant, and also the presence of a subpopulation of such cells might protect the culture from degeneration by preventing the fixation of opportunistic mutations.
    Biochemistry (Moscow) 02/2011; 76(2):167-71. DOI:10.1134/S0006297911020015 · 1.35 Impact Factor

Publication Stats

3k Citations
397.69 Total Impact Points


  • 2008–2014
    • Lomonosov Moscow State University
      • Faculty of Bioengineering and Bioinformatics
      Moskva, Moscow, Russia
  • 2008–2013
    • Moscow State Forest University
      Mytishi, Moskovskaya, Russia
  • 2003–2007
    • Technische Universität Dresden
      • • Chair of Cellular Machines
      • • Biotechnology Center
      Dresden, Saxony, Germany
  • 2000–2007
    • Max Planck Institute of Molecular Cell Biology and Genetics
      Dresden, Saxony, Germany
  • 1997–2002
    • European Molecular Biology Laboratory
      • Cell Biology and Biophysics Unit (Heidelberg)
      Heidelburg, Baden-Württemberg, Germany
    • Johns Hopkins University
      Baltimore, Maryland, United States
  • 1999
    • Albert Einstein College of Medicine
      • Department of Molecular Pharmacology
      New York, New York, United States
  • 1994
    • Marine Biological Laboratory
      Falmouth, Massachusetts, United States
    • Massachusetts Institute of Technology
      • Department of Biology
      Cambridge, MA, United States