Cellular and Molecular Life Sciences

, Volume 69, Issue 11, pp 1787–1797 | Cite as

Cytochrome c: the Achilles’ heel in apoptosis

  • A. V. Kulikov
  • E. S. Shilov
  • I. A. Mufazalov
  • V. Gogvadze
  • S. A. Nedospasov
  • B. Zhivotovsky
Review

Abstract

Cytochrome c is a well-known mitochondrial protein that fulfills life-supporting functions by transferring electrons to the respiratory chain to maintain ATP production. However, during the activation of apoptotic machinery, it is released from mitochondria and, being in the cytosol, it either triggers the activation of the caspase cascade in intrinsic apoptotic pathway, or it is involved in the amplification of extrinsic apoptotic signaling. Accumulating evidence suggests that only unmodified holocytochrome c is efficient in the stimulation of apoptosis. Considering the importance of cytochrome c in both life and death, it was of significant interest to investigate the complete or partial cytochrome c deficiency in vivo. Here, we discuss the importance of distinct amino acid residues for various functions of cytochrome c in cells and mice with targeted cytochrome c mutations.

Keywords

Cytochrome c Mutagenesis Knockout Respiration Apoptosis 

References

  1. 1.
    Keilin D (1925) On cytochrome, a respiratory pigment, common to animals, yeast, and higher plants. Proc R Soc Lond, Ser B 98:312–339CrossRefGoogle Scholar
  2. 2.
    Dickerson RE, Takano T, Eisenberg D, Kallai OB, Samson L, Cooper A, Margoliash E (1971) Ferricytochrome c. I. General features of the horse and bonito proteins at 2.8 A resolution. J Biol Chem 246:1511–1535PubMedGoogle Scholar
  3. 3.
    Ashwell G, Hickman J (1952) Effect of x-irradiation upon the enzyme systems of the mouse spleen. Proc Soc Exp Biol Med 80:407–410PubMedGoogle Scholar
  4. 4.
    Hanson KP, Mytareva LV (1967) Mechanisms of effects of ionizing radiation on oxidative phosphorylation in animals. Proc Acad Sci (Estonia) 16:80–87Google Scholar
  5. 5.
    Van Bekkum DW (1957) The effect of x-rays on phosphorylations in vivo. Biochim Biophys Acta 25:487–492CrossRefGoogle Scholar
  6. 6.
    van Bekkum DW, de Vries MJ, Klouwen HM (1965) Biochemical and morphological changes in lymphatic tissues after partial-body irradiation. Int J Radiat Biol Relat Stud Phys Chem Med 9:449–459PubMedCrossRefGoogle Scholar
  7. 7.
    Scaife JF (1964) The nature of the radiation-induced lesion of the electron transport chain of thymus mitochondria. Can J Biochem Physiol 42:431–434PubMedCrossRefGoogle Scholar
  8. 8.
    Manoilov SE, Hanson KP (1964) Effect of exogenous cytochrome c on oxidative phosphorylation in mitochondria from tissues isolated from irradiated animals. Vopr Medic Chem (Russia) 10:410–416Google Scholar
  9. 9.
    Scaife JF, Hill B (1963) Uncoupling of oxidative phosphorylation by ionizing radiation. II. The stability of mitochondrial lipids and cytochrome c. Can J Biochem Physiol 41:1223–1233PubMedCrossRefGoogle Scholar
  10. 10.
    Scaife JF (1966) The effect of lethal doses of x-irradiation on the enzymatic activity of mitochondrial cytochrome c. Can J Biochem 44:433–448PubMedCrossRefGoogle Scholar
  11. 11.
    Kharbanda S, Pandey P, Schofield L, Israels S, Roncinske R, Yoshida K, Bharti A, Yuan ZM, Saxena S, Weichselbaum R, Nalin C, Kufe D (1997) Role for Bcl-xL as an inhibitor of cytosolic cytochrome c accumulation in DNA damage-induced apoptosis. Proc Natl Acad Sci USA 94:6939–6942PubMedCrossRefGoogle Scholar
  12. 12.
    Chauhan D, Pandey P, Ogata A, Teoh G, Krett N, Halgren R, Rosen S, Kufe D, Kharbanda S, Anderson K (1997) Cytochrome c-dependent and -independent induction of apoptosis in multiple myeloma cells. J Biol Chem 272:29995–29997PubMedCrossRefGoogle Scholar
  13. 13.
    Krippner A, Matsuno-Yagi A, Gottlieb RA, Babior BM (1996) Loss of function of cytochrome c in Jurkat cells undergoing fas-mediated apoptosis. J Biol Chem 271:21629–21636PubMedCrossRefGoogle Scholar
  14. 14.
    Liu X, Kim CN, Yang J, Jemmerson R, Wang X (1996) Induction of apoptotic program in cell-free extracts: requirement for dATP and cytochrome c. Cell 86:147–157. doi:S0092-8674(00)80085-9 PubMedCrossRefGoogle Scholar
  15. 15.
    Kroemer G, Dallaporta B, Resche-Rigon M (1998) The mitochondrial death/life regulator in apoptosis and necrosis. Annu Rev Physiol 60:619–642. doi:10.1146/annurev.physiol.60.1.619 PubMedCrossRefGoogle Scholar
  16. 16.
    Skulachev VP (1998) Cytochrome c in the apoptotic and antioxidant cascades. FEBS Lett 423:275–280. doi:S0014-5793(98)00061-1 PubMedCrossRefGoogle Scholar
  17. 17.
    Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES, Wang X (1997) Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell 91:479–489. doi:S0092-8674(00)80434-1 PubMedCrossRefGoogle Scholar
  18. 18.
    Zou H, Henzel WJ, Liu X, Lutschg A, Wang X (1997) Apaf-1, a human protein homologous to C elegans CED-4, participates in cytochrome c-dependent activation of caspase-3. Cell 90:405–413. doi:S0092-8674(00)80501-2 PubMedCrossRefGoogle Scholar
  19. 19.
    Zhivotovsky B, Orrenius S, Brustugun OT, Doskeland SO (1998) Injected cytochrome c induces apoptosis. Nature 391:449–450. doi:10.1038/35058 PubMedCrossRefGoogle Scholar
  20. 20.
    Kluck RM, Martin SJ, Hoffman BM, Zhou JS, Green DR, Newmeyer DD (1997) Cytochrome c activation of CPP32-like proteolysis plays a critical role in a Xenopus cell-free apoptosis system. EMBO J 16:4639–4649. doi:10.1093/emboj/16.15.4639 PubMedCrossRefGoogle Scholar
  21. 21.
    Yang J, Liu X, Bhalla K, Kim CN, Ibrado AM, Cai J, Peng TI, Jones DP, Wang X (1997) Prevention of apoptosis by Bcl-2: release of cytochrome c from mitochondria blocked. Science 275:1129–1132PubMedCrossRefGoogle Scholar
  22. 22.
    Hampton MB, Zhivotovsky B, Slater AF, Burgess DH, Orrenius S (1998) Importance of the redox state of cytochrome c during caspase activation in cytosolic extracts. Biochem J 329:95–99PubMedGoogle Scholar
  23. 23.
    Hunter DR, Haworth RA (1979) The Ca2+-induced membrane transition in mitochondria. I. The protective mechanisms. Arch Biochem Biophys 195:453–459PubMedCrossRefGoogle Scholar
  24. 24.
    Crompton M (1999) The mitochondrial permeability transition pore and its role in cell death. Biochem J 341:233–249PubMedCrossRefGoogle Scholar
  25. 25.
    Baines CP, Kaiser RA, Sheiko T, Craigen WJ, Molkentin JD (2007) Voltage-dependent anion channels are dispensable for mitochondrial-dependent cell death. Nat Cell Biol 9:550–555PubMedCrossRefGoogle Scholar
  26. 26.
    Kokoszka JE, Waymire KG, Levy SE, Sligh JE, Cai J, Jones DP, MacGregor GR, Wallace DC (2004) The ADP/ATP translocator is not essential for the mitochondrial permeability transition pore. Nature 427:461–465PubMedCrossRefGoogle Scholar
  27. 27.
    Baines CP, Kaiser RA, Purcell NH, Blair NS, Osinska H, Hambleton MA, Brunskill EW, Sayen MR, Gottlieb RA, Dorn GW, Robbins J, Molkentin JD (2005) Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death. Nature 434:658–662PubMedCrossRefGoogle Scholar
  28. 28.
    Youle RJ, Strasser A (2008) The BCL-2 protein family: opposing activities that mediate cell death. Natl Rev Mol Cell Biol 9:47–59. doi:10.1038/nrm2308 CrossRefGoogle Scholar
  29. 29.
    Wei MC, Zong WX, Cheng EH, Lindsten T, Panoutsakopoulou V, Ross AJ, Roth KA, MacGregor GR, Thompson CB, Korsmeyer SJ (2001) Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death. Science 292:727–730. doi:10.1126/science.1059108 PubMedCrossRefGoogle Scholar
  30. 30.
    D’Alessio M, De Nicola M, Coppola S, Gualandi G, Pugliese L, Cerella C, Cristofanon S, Civitareale P, Ciriolo MR, Bergamaschi A, Magrini A, Ghibelli L (2005) Oxidative Bax dimerization promotes its translocation to mitochondria independently of apoptosis. Faseb J 19:1504–1506PubMedGoogle Scholar
  31. 31.
    Nie C, Tian C, Zhao L, Petit PX, Mehrpour M, Chen Q (2008) Cysteine 62 of Bax is critical for its conformational activation and its proapoptotic activity in response to H2O2-induced apoptosis. J Biol Chem 283:15359–15369PubMedCrossRefGoogle Scholar
  32. 32.
    Froud RJ, Ragan CI (1984) Cytochrome c mediates electron transfer between ubiquinol-cytochrome c reductase and cytochrome c oxidase by free diffusion along the surface of the membrane. Biochem J 217:561–571PubMedGoogle Scholar
  33. 33.
    Tuominen EK, Wallace CJ, Kinnunen PK (2002) Phospholipid-cytochrome c interaction: evidence for the extended lipid anchorage. J Biol Chem 277:8822–8826. doi:10.1074/jbc.M200056200 PubMedCrossRefGoogle Scholar
  34. 34.
    Sinibaldi F, Howes BD, Piro MC, Polticelli F, Bombelli C, Ferri T, Coletta M, Smulevich G, Santucci R (2010) Extended cardiolipin anchorage to cytochrome c: a model for protein-mitochondrial membrane binding. J Biol Inorg Chem 15:689–700. doi:10.1007/s00775-010-0636-z PubMedCrossRefGoogle Scholar
  35. 35.
    Rytomaa M, Kinnunen PK (1994) Evidence for two distinct acidic phospholipid-binding sites in cytochrome c. J Biol Chem 269:1770–1774PubMedGoogle Scholar
  36. 36.
    Ascenzi P, Ciaccio C, Sinibaldi F, Santucci R, Coletta M (2011) Cardiolipin modulates allosterically peroxynitrite detoxification by horse heart cytochrome c. Biochem Biophys Res Commun 404:190–194. doi:10.1016/j.bbrc.2010.11.091 PubMedCrossRefGoogle Scholar
  37. 37.
    Cortese JD, Voglino AL, Hackenbrock CR (1998) Multiple conformations of physiological membrane-bound cytochrome c. Biochemistry 37:6402–6409. doi:10.1021/bi9730543 PubMedCrossRefGoogle Scholar
  38. 38.
    MacLennan DH, Lenaz G, Szarkowska L (1966) Studies on the mechanisms of oxidative phosphorylation. IX. Effect of cytochrome c on energy-linked processes. J Biol Chem 241:5251–5259PubMedGoogle Scholar
  39. 39.
    Cortese JD, Voglino AL, Hackenbrock CR (1995) Persistence of cytochrome c binding to membranes at physiological mitochondrial intermembrane space ionic strength. Biochim Biophys Acta 1228:216–228PubMedCrossRefGoogle Scholar
  40. 40.
    Ott M, Robertson JD, Gogvadze V, Zhivotovsky B, Orrenius S (2002) Cytochrome c release from mitochondria proceeds by a two-step process. Proc Natl Acad Sci USA 99:1259–1263. doi:10.1073/pnas.241655498 PubMedCrossRefGoogle Scholar
  41. 41.
    Ott M, Gogvadze V, Orrenius S, Zhivotovsky B (2007) Mitochondria, oxidative stress and cell death. Apoptosis 12:913–922. doi:10.1007/s10495-007-0756-2 PubMedCrossRefGoogle Scholar
  42. 42.
    Cai J, Jones DP (1998) Superoxide in apoptosis. Mitochondrial generation triggered by cytochrome c loss. J Biol Chem 273:11401–11404PubMedCrossRefGoogle Scholar
  43. 43.
    Kagan VE, Tyurin VA, Jiang J, Tyurina YY, Ritov VB, Amoscato AA, Osipov AN, Belikova NA, Kapralov AA, Kini V, Vlasova II, Zhao Q, Zou M, Di P, Svistunenko DA, Kurnikov IV, Borisenko GG (2005) Cytochrome c acts as a cardiolipin oxygenase required for release of proapoptotic factors. Nat Chem Biol 1:223–232. doi:10.1038/nchembio727 PubMedCrossRefGoogle Scholar
  44. 44.
    Giorgio M, Migliaccio E, Orsini F, Paolucci D, Moroni M, Contursi C, Pelliccia G, Luzi L, Minucci S, Marcaccio M, Pinton P, Rizzuto R, Bernardi P, Paolucci F, Pelicci PG (2005) Electron transfer between cytochrome c and p66Shc generates reactive oxygen species that trigger mitochondrial apoptosis. Cell 122:221–233PubMedCrossRefGoogle Scholar
  45. 45.
    Sun L, Xiao L, Nie J, Liu FY, Ling GH, Zhu XJ, Tang WB, Chen WC, Xia YC, Zhan M, Ma MM, Peng YM, Liu H, Liu YH, Kanwar YS (2010) p66Shc mediates high-glucose and angiotensin II-induced oxidative stress renal tubular injury via mitochondrial-dependent apoptotic pathway. Am J Physiol Renal Physiol 299:F1014–F1025PubMedCrossRefGoogle Scholar
  46. 46.
    Lee I, Salomon AR, Yu K, Doan JW, Grossman LI, Huttemann M (2006) New prospects for an old enzyme: mammalian cytochrome c is tyrosine-phosphorylated in vivo. Biochemistry 45:9121–9128PubMedCrossRefGoogle Scholar
  47. 47.
    Yu H, Lee I, Salomon AR, Yu K, Huttemann M (2008) Mammalian liver cytochrome c is tyrosine-48 phosphorylated in vivo, inhibiting mitochondrial respiration. Biochim Biophys Acta 1777:1066–1071PubMedCrossRefGoogle Scholar
  48. 48.
    Yu T, Wang X, Purring-Koch C, Wei Y, McLendon GL (2001) A mutational epitope for cytochrome c binding to the apoptosis protease activation factor-1. J Biol Chem 276:13034–13038. doi:10.1074/jbc.M009773200 PubMedCrossRefGoogle Scholar
  49. 49.
    Brown GC, Borutaite V (2008) Regulation of apoptosis by the redox state of cytochrome c. Biochim Biophys Acta 1777:877–881. doi:10.1016/j.bbabio.2008.03.024 PubMedCrossRefGoogle Scholar
  50. 50.
    Ripple MO, Abajian M, Springett R (2010) Cytochrome c is rapidly reduced in the cytosol after mitochondrial outer membrane permeabilization. Apoptosis 15:563–573. doi:10.1007/s10495-010-0455-2 PubMedCrossRefGoogle Scholar
  51. 51.
    Li K, Li Y, Shelton JM, Richardson JA, Spencer E, Chen ZJ, Wang X, Williams RS (2000) Cytochrome c deficiency causes embryonic lethality and attenuates stress-induced apoptosis. Cell 101:389–399. doi:S0092-8674(00)80849-1 PubMedCrossRefGoogle Scholar
  52. 52.
    Kim IC (1980) Isolation and properties of somatic and testicular cytochromes c from rat tissues. Arch Biochem Biophys 203:519–528PubMedCrossRefGoogle Scholar
  53. 53.
    Hennig B (1975) Change of cytochrome c structure during development of the mouse. Eur J Biochem 55:167–183PubMedCrossRefGoogle Scholar
  54. 54.
    Vempati UD, Diaz F, Barrientos A, Narisawa S, Mian AM, Millan JL, Boise LH, Moraes CT (2007) Role of cytochrome c in apoptosis: increased sensitivity to tumor necrosis factor alpha is associated with respiratory defects but not with lack of cytochrome c release. Mol Cell Biol 27:1771–1783. doi:10.1128/MCB.00287-06 PubMedCrossRefGoogle Scholar
  55. 55.
    Narisawa S, Hecht NB, Goldberg E, Boatright KM, Reed JC, Millan JL (2002) Testis-specific cytochrome c-null mice produce functional sperm but undergo early testicular atrophy. Mol Cell Biol 22:5554–5562PubMedCrossRefGoogle Scholar
  56. 56.
    Goldberg E, Sberna D, Wheat TE, Urbanski GJ, Margoliash E (1977) Cytochrome c: immunofluorescent localization of the testis-specific form. Science 196:1010–1012PubMedCrossRefGoogle Scholar
  57. 57.
    Liu Z, Lin H, Ye S, Liu QY, Meng Z, Zhang CM, Xia Y, Margoliash E, Rao Z, Liu XJ (2006) Remarkably high activities of testicular cytochrome c in destroying reactive oxygen species and in triggering apoptosis. Proc Natl Acad Sci USA 103:8965–8970. doi:10.1073/pnas.0603327103 PubMedCrossRefGoogle Scholar
  58. 58.
    Morison IM, Cramer Borde EM, Cheesman EJ, Cheong PL, Holyoake AJ, Fichelson S, Weeks RJ, Lo A, Davies SM, Wilbanks SM, Fagerlund RD, Ludgate MW, da Silva Tatley FM, Coker MS, Bockett NA, Hughes G, Pippig DA, Smith MP, Capron C, Ledgerwood EC (2008) A mutation of human cytochrome c enhances the intrinsic apoptotic pathway but causes only thrombocytopenia. Nat Genet 40:387–389. doi:10.1038/ng.103 PubMedCrossRefGoogle Scholar
  59. 59.
    Bushnell GW, Louie GV, Brayer GD (1990) High-resolution three-dimensional structure of horse heart cytochrome c. J Mol Biol 214:585–595. doi:10.1016/0022-2836(90)90200-6 PubMedCrossRefGoogle Scholar
  60. 60.
    Olteanu A, Patel CN, Dedmon MM, Kennedy S, Linhoff MW, Minder CM, Potts PR, Deshmukh M, Pielak GJ (2003) Stability and apoptotic activity of recombinant human cytochrome c. Biochem Biophys Res Commun 312:733–740. doi:10.1016/j.bbrc.2003.10.182 PubMedCrossRefGoogle Scholar
  61. 61.
    Solary E, Giordanetto F, Kroemer G (2008) Re-examining the role of cytochrome c in cell death. Nat Genet 40:379–380. doi:10.1038/ng0408-379 PubMedCrossRefGoogle Scholar
  62. 62.
    Liptak MD, Fagerlund RD, Ledgerwood EC, Wilbanks SM, Bren KL (2011) The proapoptotic G41S mutation to human cytochrome c alters the heme electronic structure and increases the electron self-exchange rate. J Am Chem Soc 133:1153–1155. doi:10.1021/ja106328k PubMedCrossRefGoogle Scholar
  63. 63.
    Banci L, Bertini I, Rosato A, Varani G (1999) Mitochondrial cytochromes c: a comparative analysis. J Biol Inorg Chem 4:824–837PubMedCrossRefGoogle Scholar
  64. 64.
    Kluck RM, Ellerby LM, Ellerby HM, Naiem S, Yaffe MP, Margoliash E, Bredesen D, Mauk AG, Sherman F, Newmeyer DD (2000) Determinants of cytochrome c pro-apoptotic activity. The role of lysine 72 trimethylation. J Biol Chem 275:16127–16133. pii:275/21/16127PubMedCrossRefGoogle Scholar
  65. 65.
    DeLange RJ, Glazer AN, Smith EL (1970) Identification and location of episilon-N-trimethyllysine in yeast cytochromes c. J Biol Chem 245:3325–3327PubMedGoogle Scholar
  66. 66.
    Takakura H, Yamamoto T, Sherman F (1997) Sequence requirement for trimethylation of yeast cytochrome c. Biochemistry 36:2642–2648. doi:10.1021/bi962245n PubMedCrossRefGoogle Scholar
  67. 67.
    Hao Z, Duncan GS, Chang CC, Elia A, Fang M, Wakeham A, Okada H, Calzascia T, Jang Y, You-Ten A, Yeh WC, Ohashi P, Wang X, Mak TW (2005) Specific ablation of the apoptotic functions of cytochrome c reveals a differential requirement for cytochrome c and Apaf-1 in apoptosis. Cell 121:579–591. doi:10.1016/j.cell.2005.03.016 PubMedCrossRefGoogle Scholar
  68. 68.
    Santucci R, Sinibaldi F, Patriarca A, Santucci D, Fiorucci L (2010) Misfolded proteins and neurodegeneration: role of non-native cytochrome c in cell death. Expert Rev Proteomics 7:507–517. doi:10.1586/epr.10.50 PubMedCrossRefGoogle Scholar
  69. 69.
    Selak MA, Armour SM, MacKenzie ED, Boulahbel H, Watson DG, Mansfield KD, Pan Y, Simon MC, Thompson CB, Gottlieb E (2005) Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase. Cancer Cell 7:77–85. doi:10.1016/j.ccr.2004.11.022 PubMedCrossRefGoogle Scholar
  70. 70.
    Abdullaev Z, Bodrova ME, Chernyak BV, Dolgikh DA, Kluck RM, Pereverzev MO, Arseniev AS, Efremov RG, Kirpichnikov MP, Mokhova EN, Newmeyer DD, Roder H, Skulachev VP (2002) A cytochrome c mutant with high electron transfer and antioxidant activities but devoid of apoptogenic effect. Biochem J 362:749–754PubMedCrossRefGoogle Scholar
  71. 71.
    Sharonov GV, Feofanov AV, Bocharova OV, Astapova MV, Dedukhova VI, Chernyak BV, Dolgikh DA, Arseniev AS, Skulachev VP, Kirpichnikov MP (2005) Comparative analysis of proapoptotic activity of cytochrome c mutants in living cells. Apoptosis 10:797–808. doi:10.1007/s10495-005-0366-9 PubMedCrossRefGoogle Scholar
  72. 72.
    Chertkova RV, Sharonov GV, Feofanov AV, Bocharova OV, Latypov RF, Chernyak BV, Arseniev AS, Dolgikh DA, Kirpichnikov MP (2008) Proapoptotic activity of cytochrome c in living cells: effect of K72 substitutions and species differences. Mol Cell Biochem 314:85–93. doi:10.1007/s11010-008-9768-7 PubMedCrossRefGoogle Scholar
  73. 73.
    Mufazalov IA, Pen’kov DN, Cherniak BV, Pletiushkina O, Vysokikh M, Kirpichnikov MP, Dolgikh DA, Kruglov AA, Kuprash DV, Skulachev VP, Nedospasov SA (2009) Preparation and characterization of mouse embryonic fibroblasts with K72 W mutation in somatic cytochrome c gene. Mol Biol (Mosk) 43:648–656CrossRefGoogle Scholar
  74. 74.
    Godoy LC, Munõz-Pinedo C, Castro L, Cardacia S, Schonhoffa CM, Kinga M, Tórtora V, Marín M, Miao Q, Jiang JF, Kapralov A, Jemmerson R, Silkstone GG, Patel JN, Evans JE, Wilson MT, Green DR, Kagan VE, Radic R, Mannick JB. (2009) Disruption of the M80-Fe ligation stimulates the translocation of cytochrome c to the cytoplasm and nucleus in nonapoptotic cells. Proc Natl Acad Sci USA 106:2653–2658PubMedCrossRefGoogle Scholar

Copyright information

© Springer Basel AG 2012

Authors and Affiliations

  • A. V. Kulikov
    • 1
  • E. S. Shilov
    • 1
    • 2
  • I. A. Mufazalov
    • 3
    • 4
  • V. Gogvadze
    • 1
    • 5
  • S. A. Nedospasov
    • 2
    • 3
    • 4
  • B. Zhivotovsky
    • 1
    • 5
  1. 1.Faculty of Fundamental MedicineLomonosov Moscow State UniversityMoscowRussia
  2. 2.Faculty of BiologyLomonosov Moscow State UniversityMoscowRussia
  3. 3.Belozersky Institute of Physico-Chemical BiologyLomonosov Moscow State UniversityMoscowRussia
  4. 4.Engelhardt Institute of Molecular BiologyRussian Academy of SciencesMoscowRussia
  5. 5.Division of ToxicologyInstitute of Environmental Medicine, Karolinska InstitutetStockholmSweden

Personalised recommendations