Skip to main content
SpringerLink
Log in

Mitochondrial ROS metabolism: 10 Years later

  • Review
  • Published:
Biochemistry (Moscow) Aims and scope Submit manuscript

Abstract

The role of mitochondria in oxidative stress is well recognized, but many questions are still to be answered. This article is intended to update our comprehensive review in 2005 by highlighting the progress in understanding of mitochondrial reactive oxygen species (ROS) metabolism over the past 10 years. We review the recently identified or re-appraised sources of ROS generation in mitochondria, such as p66shc protein, succinate dehydrogenase, and recently discovered properties of the mitochondrial antioxidant system. We also reflect upon some controversies, disputes, and misconceptions that confound the field.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

DCF:

dichlorofluorescin

DCF-DA:

dichlorofluorescin diacetate

DHO:

dihydroorotate

DHO DH:

dihydroorotate dehydrogenase

DLD:

dihydrolipoamide dehydrogenase

ETF:

electron-transferring flavoprotein

F.e.T.:

forward electron transport

GPx1:

glutathione peroxidase 1

GR:

glutathione reductase

HRP:

horseradish peroxidase

IDH:

isocitrate dehydrogenase, NADP-dependent

IM:

inner mitochondrial membrane

ME:

NADP-dependent malic enzyme

MnSOD:

manganese-containing superoxide dismutase (SOD2)

Prx3:

peroxiredoxins 3

Prx5:

peroxiredoxins 5

R.e.T.:

reverse electron transport

ROS:

reactive oxygen species

SOD:

superoxide dismutase

TH:

transhydrogenase

Trx2-ox:

thioredoxin 2 oxidized

Trx2-red:

thioredoxin 2 reduced

TrxR2:

thioredoxin reductase 2

TTFA:

thenoyltrifluoroacetone

Δψ:

membrane potential

References

  1. Zimorski, V., Ku, C., Martin, W. F., and Gould, S. B. (2014) Endosymbiotic theory for organelle origins, Curr. Opin. Microbiol., 22C, 38–48.

    Google Scholar 

  2. Galluzzi, L., Bravo-San Pedro, J. M., and Kroemer, G. (2014) Organelle-specific initiation of cell death, Nat. Cell Biol., 16, 728–736.

    CAS  PubMed  Google Scholar 

  3. Skulachev, V. P. (2000) Mitochondria in the programmed death phenomena; a principle of biology: “it is better to die than to be wrong”, IUBMB Life, 49, 365–373.

    CAS  PubMed  Google Scholar 

  4. Kushnareva, Y., and Newmeyer, D. D. (2010) Bioenergetics and cell death, Ann. NY Acad. Sci., 1201, 50–57.

    PubMed Central  CAS  PubMed  Google Scholar 

  5. Tait, S. W., and Green, D. R. (2012) Mitochondria and cell signaling, J. Cell Sci., 125, 807–815.

    PubMed Central  CAS  PubMed  Google Scholar 

  6. Andreyev, A. Y., Kushnareva, Y. E., and Starkov, A. A. (2005) Mitochondrial metabolism of reactive oxygen species, Biochemistry (Moscow), 70, 200–214.

    CAS  Google Scholar 

  7. Drose, S., Brandt, U., and Wittig, I. (2014) Mitochondrial respiratory chain complexes as sources and targets of thiol-based redox-regulation, Biochim. Biophys. Acta, 1844, 1344–1354.

    PubMed  Google Scholar 

  8. Grivennikova, V. G., and Vinogradov, A. D. (2013) Mitochondrial production of reactive oxygen species, Biochemistry (Moscow), 78, 1490–1511.

    CAS  Google Scholar 

  9. Kaludercic, N., Deshwal, S., and Di Lisa, F. (2014) Reactive oxygen species and redox compartmentalization, Front. Physiol., 5, 285.

    PubMed Central  PubMed  Google Scholar 

  10. Lambert, A. J., and Brand, M. D. (2009) Reactive oxygen species production by mitochondria, Methods Mol. Biol., 554, 165–181.

    CAS  PubMed  Google Scholar 

  11. Murphy, M. P. (2009) How mitochondria produce reactive oxygen species, Biochem. J., 417, 1–13.

    PubMed Central  CAS  PubMed  Google Scholar 

  12. Murphy, M. P. (2014) Antioxidants as therapies: can we improve on nature? Free Radic. Biol. Med., 66, 20–23.

    CAS  PubMed  Google Scholar 

  13. Skulachev, V. P. (2013) Cationic antioxidants as a powerful tool against mitochondrial oxidative stress, Biochem. Biophys. Res. Commun., 44, 275–279.

    Google Scholar 

  14. Zorov, D. B., Juhaszova, M., and Sollott, S. J. (2014) Mitochondrial reactive oxygen species (ROS) and ROS-induced ROS release, Physiol. Rev., 94, 909–950.

    CAS  PubMed  Google Scholar 

  15. Starkov, A. A. (2008) The role of mitochondria in reactive oxygen species metabolism and signaling, Ann. NY Acad. Sci., 1147, 37–52.

    PubMed Central  CAS  PubMed  Google Scholar 

  16. Boveris, A., and Chance, B. (1973) The mitochondrial generation of hydrogen peroxide. General properties and effect of hyperbaric oxygen, Biochem. J., 134, 707–716.

    PubMed Central  CAS  PubMed  Google Scholar 

  17. Kareyeva, A. V., Grivennikova, V. G., and Vinogradov, A. D. (2012) Mitochondrial hydrogen peroxide production as determined by the pyridine nucleotide pool and its redox state, Biochim. Biophys. Acta, 1817, 1879–1885.

    CAS  PubMed  Google Scholar 

  18. Kussmaul, L., and Hirst, J. (2006) The mechanism of superoxide production by NADH:ubiquinone oxidoreductase (complex I) from bovine heart mitochondria, Proc. Natl. Acad. Sci. USA, 103, 7607–7612.

    PubMed Central  CAS  PubMed  Google Scholar 

  19. Vinogradov, A. D., and Grivennikova, V. G. (2005) Generation of superoxide-radical by the NADH:ubiquinone oxidoreductase of heart mitochondria, Biochemistry (Moscow), 70, 120–127.

    CAS  Google Scholar 

  20. Hoffman, D. L., and Brookes, P. S. (2009) Oxygen sensitivity of mitochondrial reactive oxygen species generation depends on metabolic conditions, J. Biol. Chem., 284, 16236–16245.

    PubMed Central  CAS  PubMed  Google Scholar 

  21. Hoffman, D. L., Salter, J. D., and Brookes, P. S. (2007) Response of mitochondrial reactive oxygen species generation to steady-state oxygen tension: implications for hypoxic cell signaling, Am. J. Physiol. Heart Circ. Physiol., 292, H101–108.

    CAS  PubMed  Google Scholar 

  22. Grivennikova, V. G., and Vinogradov, A. D. (2013) Partitioning of superoxide and hydrogen peroxide production by mitochondrial respiratory complex I, Biochim. Biophys. Acta, 1827, 446–454.

    CAS  PubMed  Google Scholar 

  23. Brown, G. C., and Borutaite, V. (2012) There is no evidence that mitochondria are the main source of reactive oxygen species in mammalian cells, Mitochondrion, 12, 1–4.

    CAS  PubMed  Google Scholar 

  24. Starkov, A. A., Andreyev, A. Y., Zhang, S. F., Starkova, N. N., Korneeva, M., Syromyatnikov, M., and Popov, V. N. (2014) Scavenging of H2O2 by mouse brain mitochondria, J. Bioenerg. Biomembr., 46, 471–477.

    CAS  PubMed  Google Scholar 

  25. Chouchani, E. T., Pell, V. R., Gaude, E., Aksentijevic, D., Sundier, S. Y., Robb, E. L., Logan, A., Nadtochiy, S. M., Ord, E. N., Smith, A. C., Eyassu, F., Shirley, R., Hu, C. H., Dare, A. J., James, A. M., Rogatti, S., Hartley, R. C., Eaton, S., Costa, A. S., Brookes, P. S., Davidson, S. M., Duchen, M. R., Saeb-Parsy, K., Shattock, M. J., Robinson, A. J., Work, L. M., Frezza, C., Krieg, T., and Murphy, M. P. (2014) Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS, Nature, 515, 431–435.

    CAS  PubMed  Google Scholar 

  26. Kushnareva, Y., Murphy, A. N., and Andreyev, A. (2002) Complex I-mediated reactive oxygen species generation: modulation by cytochrome c and NAD(P)+ oxidation-reduction state, Biochem. J., 368 (Pt. 2), 545–553.

    PubMed Central  CAS  PubMed  Google Scholar 

  27. Ambrus, A., and Adam-Vizi, V. (2013) Molecular dynamics study of the structural basis of dysfunction and the modulation of reactive oxygen species generation by pathogenic mutants of human dihydrolipoamide dehydrogenase, Arch. Biochem. Biophys., 538, 145–155.

    CAS  PubMed  Google Scholar 

  28. Ambrus, A., Tretter, L., and Adam-Vizi, V. (2009) Inhibition of the alpha-ketoglutarate dehydrogenase-mediated reactive oxygen species generation by lipoic acid, J. Neurochem., 109 (Suppl. 1), 222–229.

    CAS  PubMed  Google Scholar 

  29. Kareyeva, A. V., Grivennikova, V. G., Cecchini, G., and Vinogradov, A. D. (2011) Molecular identification of the enzyme responsible for the mitochondrial NADH-supported ammonium-dependent hydrogen peroxide production, FEBS Lett., 585, 385–389.

    PubMed Central  CAS  PubMed  Google Scholar 

  30. Quinlan, C. L., Goncalves, R. L., Hey-Mogensen, M., Yadava, N., Bunik, V. I., and Brand, M. D. (2014) The 2-oxoacid dehydrogenase complexes in mitochondria can produce superoxide/hydrogen peroxide at much higher rates than complex I, J. Biol. Chem., 289, 8312–8325.

    PubMed Central  CAS  PubMed  Google Scholar 

  31. Starkov, A. A., Fiskum, G., Chinopoulos, C., Lorenzo, B. J., Browne, S. E., Patel, M. S., and Beal, M. F. (2004) Mitochondrial alpha-ketoglutarate dehydrogenase complex generates reactive oxygen species, J. Neurosci., 24, 7779–7788.

    CAS  PubMed  Google Scholar 

  32. Tahara, E. B., Barros, M. H., Oliveira, G. A., Netto, L. E., and Kowaltowski, A. J. (2007) Dihydrolipoyl dehydrogenase as a source of reactive oxygen species inhibited by caloric restriction and involved in Saccharomyces cerevisiae aging, FASEB J., 21, 274–283.

    CAS  PubMed  Google Scholar 

  33. Tretter, L., and Adam-Vizi, V. (2004) Generation of reactive oxygen species in the reaction catalyzed by alphaketoglutarate dehydrogenase, J. Neurosci., 24, 7771–7778.

    CAS  PubMed  Google Scholar 

  34. Zundorf, G., Kahlert, S., Bunik, V. I., and Reiser, G. (2009) α-Ketoglutarate dehydrogenase contributes to production of reactive oxygen species in glutamate-stimulated hippocampal neurons in situ, Neuroscience, 158, 610–616.

    CAS  PubMed  Google Scholar 

  35. Pryde, K. R., and Hirst, J. (2011) Superoxide is produced by the reduced flavin in mitochondrial complex I: a single, unified mechanism that applies during both forward and reverse electron transfer, J. Biol. Chem., 286, 18056–18065.

    PubMed Central  CAS  PubMed  Google Scholar 

  36. Treberg, J. R., Quinlan, C. L., and Brand, M. D. (2011) Evidence for two sites of superoxide production by mitochondrial NADH-ubiquinone oxidoreductase (complex I), J. Biol. Chem., 286, 27103–27110.

    PubMed Central  CAS  PubMed  Google Scholar 

  37. Ohnishi, S. T., Shinzawa-Itoh, K., Ohta, K., Yoshikawa, S., and Ohnishi, T. (2010) New insights into the superoxide generation sites in bovine heart NADH-ubiquinone oxidoreductase (complex I): the significance of protein-associated ubiquinone and the dynamic shifting of generation sites between semiflavin and semiquinone radicals, Biochim. Biophys. Acta, 1797, 1901–1909.

    CAS  PubMed  Google Scholar 

  38. Sled, V. D., Rudnitzky, N. I., Hatefi, Y., and Ohnishi, T. (1994) Thermodynamic analysis of flavin in mitochondrial NADH:ubiquinone oxidoreductase (complex I), Biochemistry, 33, 10069–10075.

    CAS  PubMed  Google Scholar 

  39. Ohnishi, T. (1975) Thermodynamic and EPR characterization of iron-sulfur centers in the NADH-ubiquinone segment of the mitochondrial respiratory chain in pigeon heart, Biochim. Biophys. Acta, 387, 475–490.

    CAS  PubMed  Google Scholar 

  40. Ohnishi, T. (1998) Iron-sulfur clusters/semiquinones in complex I, Biochim. Biophys. Acta, 1364, 186–206.

    CAS  PubMed  Google Scholar 

  41. Ksenzenko, M., Konstantinov, A. A., Khomutov, G. B., Tikhonov, A. N., and Ruuge, E. K. (1983) Effect of electron transfer inhibitors on superoxide generation in the cytochrome bc1 site of the mitochondrial respiratory chain, FEBS Lett., 155, 19–24.

    CAS  PubMed  Google Scholar 

  42. McLennan, H. R., and Degli Esposti, M. (2000) The contribution of mitochondrial respiratory complexes to the production of reactive oxygen species, J. Bioenerg. Biomembr., 32, 153–162.

    CAS  PubMed  Google Scholar 

  43. Ohnishi, T., and Trumpower, B. L. (1980) Differential effects of antimycin on ubisemiquinone bound in different environments in isolated succinate:cytochrome c reductase complex, J. Biol. Chem., 255, 3278–3284.

    CAS  PubMed  Google Scholar 

  44. Quinlan, C. L., Orr, A. L., Perevoshchikova, I. V., Treberg, J. R., Ackrell, B. A., and Brand, M. D. (2012) Mitochondrial complex II can generate reactive oxygen species at high rates in both the forward and reverse reactions, J. Biol. Chem., 287, 27255–27264.

    PubMed Central  CAS  PubMed  Google Scholar 

  45. Siebels, I., and Drose, S. (2013) Q-site inhibitor induced ROS production of mitochondrial complex II is attenuated by TCA cycle dicarboxylates, Biochim. Biophys. Acta, 1827, 1156–1164.

    CAS  PubMed  Google Scholar 

  46. Miyadera, H., Shiomi, K., Ui, H., Yamaguchi, Y., Masuma, R., Tomoda, H., Miyoshi, H., Osanai, A., Kita, K., and Omura, S. (2003) Atpenins, potent and specific inhibitors of mitochondrial complex II (succinateubiquinone oxidoreductase), Proc. Natl. Acad. Sci. USA, 100, 473–477.

    PubMed Central  CAS  PubMed  Google Scholar 

  47. St-Pierre, J., Buckingham, J. A., Roebuck, S. J., and Brand, M. D. (2002) Topology of superoxide production from different sites in the mitochondrial electron transport chain, J. Biol. Chem., 277, 44784–44790.

    CAS  PubMed  Google Scholar 

  48. Mills, E., and O’Neill, L. A. (2014) Succinate: a metabolic signal in inflammation, Trends Cell Biol., 24, 313–320.

    CAS  PubMed  Google Scholar 

  49. Forman, H. J., and Kennedy, J. A. (1974) Role of superoxide radical in mitochondrial dehydrogenase reactions, Biochem. Biophys. Res. Commun., 60, 1044–1050.

    CAS  PubMed  Google Scholar 

  50. Forman, H. J., and Kennedy, J. (1975) Superoxide production and electron transport in mitochondrial oxidation of dihydroorotic acid, J. Biol. Chem., 250, 4322–4326.

    CAS  PubMed  Google Scholar 

  51. Dileepan, K. N., and Kennedy, J. (1985) Complete inhibition of dihydro-orotate oxidation and superoxide production by 1,1,1-trifluoro-3-thenoylacetone in rat liver mitochondria, Biochem. J., 225, 189–194.

    PubMed Central  CAS  PubMed  Google Scholar 

  52. Lakaschus, G., and Loffler, M. (1992) Differential susceptibility of dihydroorotate dehydrogenase/oxidase to brequinar sodium (NSC 368 390) in vitro, Biochem. Pharmacol., 43, 1025–1030.

    CAS  PubMed  Google Scholar 

  53. Loffler, M., Becker, C., Wegerle, E., and Schuster, G. (1996) Catalytic enzyme histochemistry and biochemical analysis of dihydroorotate dehydrogenase/oxidase and succinate dehydrogenase in mammalian tissues, cells and mitochondria, Histochem. Cell Biol., 105, 119–128.

    CAS  PubMed  Google Scholar 

  54. Hey-Mogensen, M., Goncalves, R. L., Orr, A. L., and Brand, M. D. (2014) Production of superoxide/H2O2 by dihydroorotate dehydrogenase in rat skeletal muscle mitochondria, Free Radic. Biol. Med., 72, 149–155.

    CAS  PubMed  Google Scholar 

  55. Hail, N., Jr., Chen, P., Kepa, J. J., Bushman, L. R., and Shearn, C. (2010) Dihydroorotate dehydrogenase is required for N-(4-hydroxyphenyl)retinamide-induced reactive oxygen species production and apoptosis, Free Radic. Biol. Med., 49, 109–116.

    PubMed Central  CAS  PubMed  Google Scholar 

  56. Pinton, P., Rimessi, A., Marchi, S., Orsini, F., Migliaccio, E., Giorgio, M., Contursi, C., Minucci, S., Mantovani, F., Wieckowski, M. R., Del Sal, G., Pelicci, P. G., and Rizzuto, R. (2007) Protein kinase Cβ and prolyl isomerase 1 regulate mitochondrial effects of the life-span determinant p66Shc, Science, 315, 659–663.

    CAS  PubMed  Google Scholar 

  57. 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., and Pelicci, P. G. (2005) Electron transfer between cytochrome c and p66Shc generates reactive oxygen species that trigger mitochondrial apoptosis, Cell, 122, 221–233.

    CAS  PubMed  Google Scholar 

  58. Gertz, M., Fischer, F., Leipelt, M., Wolters, D., and Steegborn, C. (2009) Identification of peroxiredoxin 1 as a novel interaction partner for the lifespan regulator protein p66Shc, Aging (Albany NY), 1, 254–265.

    CAS  Google Scholar 

  59. Banus, M. G. (1941) A design for a saturated calomel electrode, Science, 93, 601–602.

    CAS  PubMed  Google Scholar 

  60. Zhen, Y., Hoganson, C. W., Babcock, G. T., and Ferguson-Miller, S. (1999) Definition of the interaction domain for cytochrome c on cytochrome c oxidase. I. Biochemical, spectral, and kinetic characterization of surface mutants in subunit ii of Rhodobacter sphaeroides cytochrome aa 3, J. Biol. Chem., 274, 38032–38041.

    CAS  PubMed  Google Scholar 

  61. Gertz, M., and Steegborn, C. (2010) The lifespan-regulator p66Shc in mitochondria: redox enzyme or redox sensor? Antioxid. Redox Signal., 13, 1417–1428.

    CAS  PubMed  Google Scholar 

  62. Galimov, E. R. (2010) The role of p66shc in oxidative stress and apoptosis, Acta Naturae, 2, 44–51.

    PubMed Central  CAS  PubMed  Google Scholar 

  63. Galimov, E. R., Chernyak, B. V., Sidorenko, A. S., Tereshkova, A. V., and Chumakov, P. M. (2014) Prooxidant properties of p66shc are mediated by mitochondria in human cells, PLoS One, 9, e86521.

    PubMed Central  PubMed  Google Scholar 

  64. Vogel, R., Wiesinger, H., Hamprecht, B., and Dringen, R. (1999) The regeneration of reduced glutathione in rat forebrain mitochondria identifies metabolic pathways providing the NADPH required, Neurosci. Lett., 275, 97–100.

    CAS  PubMed  Google Scholar 

  65. Lopert, P., and Patel, M. (2014) Nicotinamide nucleotide transhydrogenase (Nnt) links the substrate requirement in brain mitochondria for hydrogen peroxide removal to the thioredoxin/peroxiredoxin (Trx/Prx) system, J. Biol. Chem., 289, 15611–15620.

    CAS  PubMed  Google Scholar 

  66. Freeman, H. C., Hugill, A., Dear, N. T., Ashcroft, F. M., and Cox, R. D. (2006) Deletion of nicotinamide nucleotide transhydrogenase: a new quantitative trait locus accounting for glucose intolerance in C57BL/6J mice, Diabetes, 55, 2153–2156.

    CAS  PubMed  Google Scholar 

  67. Huang, T. T., Naeemuddin, M., Elchuri, S., Yamaguchi, M., Kozy, H. M., Carlson, E. J., and Epstein, C. J. (2006) Genetic modifiers of the phenotype of mice deficient in mitochondrial superoxide dismutase, Hum. Mol. Genet., 15, 1187–1194.

    CAS  PubMed  Google Scholar 

  68. Chen, Y., Zhang, J., Lin, Y., Lei, Q., Guan, K. L., Zhao, S., and Xiong, Y. (2011) Tumor suppressor SIRT3 deacetylates and activates manganese superoxide dismutase to scavenge ROS, EMBO Rep., 12, 534–541.

    PubMed Central  CAS  PubMed  Google Scholar 

  69. Tao, R., Coleman, M. C., Pennington, J. D., Ozden, O., Park, S. H., Jiang, H., Kim, H. S., Flynn, C. R., Hill, S., Hayes McDonald, W., Olivier, A. K., Spitz, D. R., and Gius, D. (2010) Sirt3-mediated deacetylation of evolutionarily conserved lysine 122 regulates MnSOD activity in response to stress, Mol. Cell, 40, 893–904.

    PubMed Central  CAS  PubMed  Google Scholar 

  70. Tao, R., Vassilopoulos, A., Parisiadou, L., Yan, Y., and Gius, D. (2014) Regulation of MnSOD enzymatic activity by Sirt3 connects the mitochondrial acetylome signaling networks to aging and carcinogenesis, Antioxid. Redox Signal., 20, 1646–1654.

    PubMed Central  CAS  PubMed  Google Scholar 

  71. Radi, R., Turrens, J. F., Chang, L. Y., Bush, K. M., Crapo, J. D., and Freeman, B. A. (1991) Detection of catalase in rat heart mitochondria, J. Biol. Chem., 266, 22028–22034.

    CAS  PubMed  Google Scholar 

  72. Salvi, M., Battaglia, V., Brunati, A. M., La Rocca, N., Tibaldi, E., Pietrangeli, P., Marcocci, L., Mondovi, B., Rossi, C. A., and Toninello, A. (2007) Catalase takes part in rat liver mitochondria oxidative stress defense, J. Biol. Chem., 282, 24407–24415.

    CAS  PubMed  Google Scholar 

  73. Cadenas, E. (2004) Mitochondrial free radical production and cell signaling, Mol. Aspects Med., 25, 17–26.

    CAS  PubMed  Google Scholar 

  74. Cox, A. G., Winterbourn, C. C., and Hampton, M. B. (2010) Mitochondrial peroxiredoxin involvement in antioxidant defense and redox signaling, Biochem. J., 425, 313–325.

    CAS  Google Scholar 

  75. Drechsel, D. A., and Patel, M. (2010) Respiration-dependent H2O2 removal in brain mitochondria via the thioredoxin/peroxiredoxin system, J. Biol. Chem., 285, 27850–27858.

    PubMed Central  CAS  PubMed  Google Scholar 

  76. Ho, Y. S., Magnenat, J. L., Bronson, R. T., Cao, J., Gargano, M., Sugawara, M., and Funk, C. D. (1997) Mice deficient in cellular glutathione peroxidase develop normally and show no increased sensitivity to hyperoxia, J. Biol. Chem., 272, 16644–16651.

    CAS  PubMed  Google Scholar 

  77. Cao, Z., Bhella, D., and Lindsay, J. G. (2007) Reconstitution of the mitochondrial PrxIII antioxidant defense pathway: general properties and factors affecting PrxIII activity and oligomeric state, J. Mol. Biol., 372, 1022–1033.

    CAS  PubMed  Google Scholar 

  78. Trujillo, M., Clippe, A., Manta, B., Ferrer-Sueta, G., Smeets, A., Declercq, J. P., Knoops, B., and Radi, R. (2007) Pre-steady state kinetic characterization of human peroxiredoxin 5: taking advantage of Trp84 fluorescence increase upon oxidation, Arch. Biochem. Biophys., 467, 95–106.

    CAS  PubMed  Google Scholar 

  79. Starkov, A. A. (2014) Measuring mitochondrial reactive oxygen species (ROS) production, in Systems Biology of Free Radicals and Antioxidants (Laher, I., ed.) Springer, Berlin-Heidelberg, pp. 265–278.

    Google Scholar 

  80. Starkov, A. A. (2010) Measurement of mitochondrial ROS production, Methods Mol. Biol., 648, 245–255.

    PubMed Central  CAS  PubMed  Google Scholar 

  81. Zhou, M., Diwu, Z., Panchuk-Voloshina, N., and Haugland, R. P. (1997) A stable nonfluorescent derivative of resorufin for the fluorometric determination of trace hydrogen peroxide: applications in detecting the activity of phagocyte NADPH oxidase and other oxidases, Anal. Biochem., 253, 162–168.

    CAS  PubMed  Google Scholar 

  82. Cathcart, R., Schwiers, E., and Ames, B. N. (1983) Detection of picomole levels of hydroperoxides using a fluorescent dichlorofluorescein assay, Anal. Biochem., 134, 111–116.

    CAS  PubMed  Google Scholar 

  83. LeBel, C. P., Ischiropoulos, H., and Bondy, S. C. (1992) Evaluation of the probe 2′,7′-dichlorofluorescin as an indicator of reactive oxygen species formation and oxidative stress, Chem. Res. Toxicol., 5, 227–231

    CAS  PubMed  Google Scholar 

  84. Brandt, R., and Keston, A. S. (1965) Synthesis of diacetyldichlorofluorescin: a stable reagent for fluorometric analysis, Anal. Biochem., 11, 6–9.

    CAS  PubMed  Google Scholar 

  85. Keston, A. S., and Brandt, R. (1965) The fluorometric analysis of ultramicro quantities of hydrogen peroxide, Anal. Biochem., 11, 1–5.

    CAS  PubMed  Google Scholar 

  86. Black, M. J., and Brandt, R. B. (1974) Spectrofluorometric analysis of hydrogen peroxide, Anal. Biochem., 58, 246–254.

    CAS  PubMed  Google Scholar 

  87. Zheng, M., Aslund, F., and Storz, G. (1998) Activation of the OxyR transcription factor by reversible disulfide bond formation, Science, 279, 1718–1721.

    CAS  PubMed  Google Scholar 

  88. Choi, H., Kim, S., Mukhopadhyay, P., Cho, S., Woo, J., Storz, G., and Ryu, S. E. (2001) Structural basis of the redox switch in the OxyR transcription factor, Cell, 105, 103–113.

    CAS  PubMed  Google Scholar 

  89. Aslund, F., Zheng, M., Beckwith, J., and Storz, G. (1999) Regulation of the OxyR transcription factor by hydrogen peroxide and the cellular thiol-disulfide status, Proc. Natl. Acad. Sci. USA, 96, 6161–6165.

    PubMed Central  CAS  PubMed  Google Scholar 

  90. Lee, C., Lee, S. M., Mukhopadhyay, P., Kim, S. J., Lee, S. C., Ahn, W. S., Yu, M. H., Storz, G., and Ryu, S. E. (2004) Redox regulation of OxyR requires specific disulfide bond formation involving a rapid kinetic reaction path, Nat. Struct. Mol. Biol., 11, 1179–1185.

    CAS  PubMed  Google Scholar 

  91. Belousov, V. V., Fradkov, A. F., Lukyanov, K. A., Staroverov, D. B., Shakhbazov, K. S., Terskikh, A. V., and Lukyanov, S. (2006) Genetically encoded fluorescent indicator for intracellular hydrogen peroxide, Nat. Methods, 3, 281–286.

    CAS  PubMed  Google Scholar 

  92. Bilan, D. S., Pase, L., Joosen, L., Gorokhovatsky, A. Y., Ermakova, Y. G., Gadella, T. W., Grabher, C., Schultz, C., Lukyanov, S., and Belousov, V. V. (2013) HyPer-3: a genetically encoded H2O2 probe with improved performance for ratiometric and fluorescence lifetime imaging, ACS Chem. Biol., 8, 535–542.

    CAS  PubMed  Google Scholar 

  93. Malinouski, M., Zhou, Y., Belousov, V. V., Hatfield, D. L., and Gladyshev, V. N. (2011) Hydrogen peroxide probes directed to different cellular compartments, PLoS One, 6, e14564.

    PubMed Central  CAS  PubMed  Google Scholar 

  94. Mishina, N. M., Tyurin-Kuzmin, P. A., Markvicheva, K. N., Vorotnikov, A. V., Tkachuk, V. A., Laketa, V., Schultz, C., Lukyanov, S., and Belousov, V. V. (2011) Does cellular hydrogen peroxide diffuse or act locally? Antioxid. Redox Signal., 14, 1–7.

    CAS  PubMed  Google Scholar 

  95. Markvicheva, K. N., Bilan, D. S., Mishina, N. M., Gorokhovatsky, A. Y., Vinokurov, L. M., Lukyanov, S., and Belousov, V. V. (2011) A genetically encoded sensor for H2O2 with expanded dynamic range, Bioorg. Med. Chem., 19, 1079–1084.

    CAS  PubMed  Google Scholar 

  96. Ermakova, Y. G., Bilan, D. S., Matlashov, M. E., Mishina, N. M., Markvicheva, K. N., Subach, O. M., Subach, F. V., Bogeski, I., Hoth, M., Enikolopov, G., and Belousov, V. V. (2014) Red fluorescent genetically encoded indicator for intracellular hydrogen peroxide, Nat. Commun., 5, 5222.

    CAS  PubMed  Google Scholar 

  97. Costa, A., Drago, I., Behera, S., Zottini, M., Pizzo, P., Schroeder, J. I., Pozzan, T., and Lo Schiavo, F. (2010) H2O2 in plant peroxisomes: an in vivo analysis uncovers a Ca2+-dependent scavenging system, Plant J., 62, 760–772.

    PubMed Central  CAS  PubMed  Google Scholar 

  98. Elsner, M., Gehrmann, W., and Lenzen, S. (2011) Peroxisome-generated hydrogen peroxide as important mediator of lipotoxicity in insulin-producing cells, Diabetes, 60, 200–208.

    PubMed Central  CAS  PubMed  Google Scholar 

  99. Brejc, K., Sixma, T. K., Kitts, P. A., Kain, S. R., Tsien, R. Y., Ormo, M., and Remington, S. J. (1997) Structural basis for dual excitation and photoisomerization of the Aequorea victoria green fluorescent protein, Proc. Natl. Acad. Sci. USA, 94, 2306–2311.

    PubMed Central  CAS  PubMed  Google Scholar 

  100. Elsliger, M. A., Wachter, R. M., Hanson, G. T., Kallio, K., and Remington, S. J. (1999) Structural and spectral response of green fluorescent protein variants to changes in pH, Biochemistry, 38, 5296–5301.

    CAS  PubMed  Google Scholar 

  101. Hanson, G. T., McAnaney, T. B., Park, E. S., Rendell, M. E., Yarbrough, D. K., Chu, S., Xi, L., Boxer, S. G., Montrose, M. H., and Remington, S. J. (2002) Green fluorescent protein variants as ratiometric dual emission pH sensors. 1. Structural characterization and preliminary application, Biochemistry, 41, 15477–15488.

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacology, University of California, San Diego, 9500 Gilman Drive, MC 0601, La Jolla, CA, 92093-0601, USA

    A. Y. Andreyev & A. N. Murphy

  2. La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA, 92037, USA

    Y. E. Kushnareva

  3. Brain and Mind Research Institute, Weill Medical College of Cornell University, 407 East 61st Street, 5th floor, New York, NY, 10065, USA

    A. A. Starkov

Authors
  1. A. Y. Andreyev
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Y. E. Kushnareva
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A. N. Murphy
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A. A. Starkov
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to A. Y. Andreyev or A. A. Starkov.

Additional information

Published in Russian in Biokhimiya, 2015, Vol. 80, No. 5, pp. 612–630.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Andreyev, A.Y., Kushnareva, Y.E., Murphy, A.N. et al. Mitochondrial ROS metabolism: 10 Years later. Biochemistry Moscow 80, 517–531 (2015). https://doi.org/10.1134/S0006297915050028

Download citation

  • Received:

  • Revised:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1134/S0006297915050028

Key words

Search

Navigation