Advertisement

Mitochondria Are the Main Cellular Source of O2, H2O2 and Oxidative Stress

  • Alberto BoverisEmail author
  • Marisa G. Repetto
Chapter
Part of the Advances in Biochemistry in Health and Disease book series (ABHD, volume 16)

Abstract

Mitochondria reduce about 1–2 % of the O2 consumed in the tissues to O2 that is dismutated in the mitochondrial matrix by the Mn-SOD reaction to O2 and H2O2. O2 as a charged and non permeable species is confined into the mitochondrial matrix where is kept at a steady state level of 10−10 M. After dismutation, non charged H2O2 freely diffuses to the cytosol, where it is kept at about 10−7 M by catalase and glutathione peroxidase. In the cytosol H2O2 encounters Fe2+ (and Cu+), suffers homolysis by the Fenton/Haber-Weiss reaction, and produces the highly reactive HO. This radical immediately abstracts one hydrogen atom from unsaturated fatty acids and starts the process of lipoperoxidation, in an open and non-equilibrium situation as long there are unsaturated fatty acids and O2. The free-radical mediated oxidations of phospholipids, proteins and nucleic acids are a consequence of aerobic life. Increased oxidations define the oxidative stress situation. Then, mitochondria are the main cellular source of O2, of H2O2 and of oxidative stress in the cell. The cellular metabolisms of O2, H2O2, NO and ONOO are integrated and faster rates of free-radical mediated reactions are considered the molecular mechanisms of pathological processes and of aging.

Keywords

Superoxide radical Hydrogen peroxide Hydroxyl radical Oxidative stress Haber-Weiss reaction Steady states Pathology molecular mechanisms Aging 

Notes

Acknowledgements

The authors acknowledge to Mg. Rosario Mussaco Sebio and to Mg. Christian Saporito Magriña for their successful experimental work that produced four publications on the toxicity of Fe and Cu overloads.

References

  1. 1.
    Gerschman R, Gilbert D, Nye SW et al (1954) Oxygen poisoning and x-irradiation: a mechanism in common. Science 119:623–626CrossRefPubMedGoogle Scholar
  2. 2.
    Michaelis L (1946) Fundamentals of oxidation and respiration. Am Sci 34:573–596PubMedGoogle Scholar
  3. 3.
    Mann PJG, Quastel JH (1946) Toxic effects of oxygen and of hydrogen peroxide on brain metabolism. Biochem J 40:139–144CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    McCord JM, Fridovich I (1969) Superoxide dismutase. An enzymic function for erythrocuprein (hemocuprein). J Biol Chem 244:6049–6055PubMedGoogle Scholar
  5. 5.
    McCord JM, Keele BB Jr, Fridovich I (1971) An enzyme-based theory of obligate anaerobiosis: the physiological function of superoxide dismutase. Proc Natl Acad Sci U S A 68:1024–1027CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Seim S (1982) Production of reactive oxygen species and chemiluminescence by human monocytes during differentiation and lymphokine activation in vitro. Acta Pathol Microbiol Immunol Scand C 90:179–185PubMedGoogle Scholar
  7. 7.
    Boveris A, Oshino N, Chance B (1972) The cellular production of hydrogen peroxide. Biochem J 128:617–630CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Boveris A, Costa LE, Cadenas E (1999) The mitochondrial production of oxygen radicals and cellular aging. In: Packer L, Cadenas E (eds) Understanding the process of aging. Marcel Dekker Inc, New York, pp 1–16Google Scholar
  9. 9.
    Loschen G, Flohé L, Chance B (1971) Respiratory chain linked H2O2 production in pigeon heart mitochondria. FEBS Lett 18:261–264CrossRefPubMedGoogle Scholar
  10. 10.
    Cadenas E, Boveris A (1980) Enhancement of hydrogen peroxide formation by protophores and ionophores in antimycin-supplemented mitochondria. Biochem J 188:31–37CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Gajavelli S, Kentaro S, Diaz J et al (2015) Glucose and oxygen metabolism after penetrating ballistic-like brain injury. J Cereb Blood Flow Metab 35:773–780CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Adamo AM, Llesuy SF, Pasquini JM, Boveris A (1989) Brain chemiluminescence and oxidative stress in hyperthyroid rats. Biochem J 263:273–277CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Loschen G, Azzi A, Richter C, Flohé L (1974) Superoxide radicals as precursors of mitochondrial hydrogen peroxide. FEBS Lett 42:68–72CrossRefPubMedGoogle Scholar
  14. 14.
    Boveris A, Cadenas E (1975) Mitochondrial production of superoxide anions and its relationship to the antimycin insensitive respiration. FEBS Lett 54:311–314CrossRefPubMedGoogle Scholar
  15. 15.
    Boveris A, Cadenas E, Stoppani AO (1976) Role of ubiquinone in the mitochondrial generation of hydrogen peroxide. Biochem J 156:435–444CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Dionisi O, Galeotti T, Terranova T, Azzi A (1975) Superoxide radicals and hydrogen peroxide formation in mitochondria from normal and neoplastic tissues. Biochim Biophys Acta 403:292–300CrossRefPubMedGoogle Scholar
  17. 17.
    Margulis L (1996) Archaeal-eubacterial mergers in the origin of eukarya: phylogenetic classification of life. Proc Natl Acad Sci U S A 93:1071–1076CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Boveris A, Chance B (1973) The mitochondrial generation of hydrogen peroxide. General properties and the effect of hyperbaric oxygen. Biochem J 134:707–716CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Turrens JF, Boveris A (1980) Generation of superoxide anion by the NADH dehydrogenase of bovine heart mitochondria. Biochem J 191:421–427CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Muller FL, Liu Y, Van Remmen H (2004) Complex III releases superoxide to both sides of the inner mitochondrial membrane. J Biol Chem 279:49064–49073CrossRefPubMedGoogle Scholar
  21. 21.
    Okado-Matsumoto A, Fridovich I (2001) Subcellular distribution of superoxide dismutases (SOD) in rat liver: Cu, Zn-SOD in mitochondria. J Biol Chem 276:38388–38393CrossRefPubMedGoogle Scholar
  22. 22.
    Chance B, Sies H, Boveris A (1979) Hydroperoxide metabolism in mammalian organs. Physiol Rev 59:527–605PubMedGoogle Scholar
  23. 23.
    Boveris A, Cadenas E, Reiter R et al (1980) Organ chemiluminescence: noninvasive assay for oxidative radical reactions. Proc Natl Acad Sci U S A 77:347–351CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Nelson DL, Cox MM (2000) Lehninger principles of biochemistry, 3rd edn. Worth Publishers, New YorkGoogle Scholar
  25. 25.
    Dawson AG (1979) Oxidation of cytosolic NADH formed during aerobic metabolism in mammalian cells. Trends Biochem Sci 4:171–176CrossRefGoogle Scholar
  26. 26.
    Jequier E, Acheson K, Schutz Y (1987) Assessment of energy expenditure and fuel utilization in man. Ann Rev Nutr 7:187–208CrossRefGoogle Scholar
  27. 27.
    Boveris A, Repetto M, Bustamante J et al (2008) The concept of oxidative stress in pathology. In: Alvarez S, Evelson P, Boveris A (eds) Free radical pathophysiology. Research Signpost, Kerala, pp 1–17Google Scholar
  28. 28.
    Cadenas E, Giulivi C, Ursini F et al (1994) Electronically-excited state formation during lipid peroxidation. Methods Toxicol 1B:384–399Google Scholar
  29. 29.
    Repetto M, Boveris A (2012) Transition metals: bioinorganic and redox reactions in biological systems. In: Mishra A (ed) Transition metals: characteristics, properties and uses. Nova Science Publihers, Hauppauge, pp 349–370Google Scholar
  30. 30.
    Sies H (1985) Introductory remarks. In: Sies H (ed) Oxidative stress. Academic, LondonGoogle Scholar
  31. 31.
    Sies H (1991) Oxidative stress: from basic research to clinical application. Am J Med 91:31–38CrossRefGoogle Scholar
  32. 32.
    Gonzalez Flecha B, Cutrin JC, Boveris A (1993) Time course and mechanism of oxidative stress and tissue damage in rat liver subjected to in vivo ischemia-reperfusion. J Clin Invest 91:456–464CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Sies H, Jones DP (2007) Oxidative Stress. In: Fink G (ed) Encyclopedia of stress, vol 3, 2nd edn. Elsevier, Amsterdam, pp 45–48CrossRefGoogle Scholar
  34. 34.
    Kemp M, Go Y, Jones DP (2008) Non equilibrium thermodynamics of thiol/disulfide redox systems: a perspective on redox system biology. Free Radic Biol Med 44:921–937CrossRefPubMedGoogle Scholar
  35. 35.
    Jaeschke H, Gores GJ, Cederbaum AI et al (2002) Mechanisms of hepatotoxicity. Toxicol Sci 65:166–176CrossRefPubMedGoogle Scholar
  36. 36.
    Yuan L, Kaplowitz N (2009) Glutathione in liver diseases and hepatotoxicity. Mol Aspects Med 30:29–41CrossRefPubMedGoogle Scholar
  37. 37.
    Orrenius S, Nicotera P, Zhivotovsky B (2011) Cell death mechanisms and their implications in toxicology. Toxicol Sci 119:3–19CrossRefPubMedGoogle Scholar
  38. 38.
    Arnér ES, Holmgren A (2000) Physiological functions of thioredoxin and thioredoxin reductase. Eur J Biochem 267:6102–6109CrossRefPubMedGoogle Scholar
  39. 39.
    Halliwell B, Gutteridge J (1989) Lipid peroxidation: a radical chain reaction. In: Free Radical Biology and Medicine, 2nd edn. Clarendon, Oxford, pp 188–276Google Scholar
  40. 40.
    Musacco-Sebio R, Ferrarotti N, Saporito-Magriñá C et al (2014) Rat brain oxidative damage in iron and copper overloads. Metallomics 6:1410–1416CrossRefPubMedGoogle Scholar
  41. 41.
    Semprine J, Ferrarotti N, Musacco-Sebio R et al (2014) Brain antioxidant response to iron and copper acute intoxications in rats. Metallomics 6:2083–2089CrossRefPubMedGoogle Scholar
  42. 42.
    Gorlach A, Dimova E, Petry A et al (2015) Reactive oxygen species, nutrition, hipoxia and diseases: problems solved? Redox Biol 6:372–385CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Giulivi C, Poderoso JJ, Boveris A (1998) Production of nitric oxide by mitochondria. J Biol Chem 273:11038–11043CrossRefPubMedGoogle Scholar
  44. 44.
    Niki E (2000) Oxidative stress and aging. Intern Med 39:324–326CrossRefPubMedGoogle Scholar
  45. 45.
    Yoshida Y, Saito Y, Hayakawa M et al (2007) Levels of lipid peroxidation in human plasma and erythrocytes: comparison between fatty acids and cholesterol. Lipids 42:439–449CrossRefPubMedGoogle Scholar
  46. 46.
    Harman D (1956) Aging: a theory based on free radical and radiation chemistry. J Gerontol 11:298–300CrossRefPubMedGoogle Scholar
  47. 47.
    Harman D (1981) The aging process. Proc Natl Acad Sci U S A 78:7124–7128CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Navarro A, Sanchez-Pino MJ, Gomez C et al (2007) Dietary thioproline decreases spontaneous food intake and increases survival and neurological function in mice. Antiox Redox Signal 9:131–141CrossRefGoogle Scholar
  49. 49.
    Boveris A, Navarro A (2008) Brain mitochondrial dysfunction in aging. IUBMB Life 60:308–314CrossRefPubMedGoogle Scholar
  50. 50.
    Jin K (2010) Modern biological theories of aging. Aging Dis 1:72–74PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Department of General Chemistry, Faculty of Pharmacy and BiochemistryUniversity of Buenos AiresBuenos AiresArgentina
  2. 2.Institute of Biochemistry and Molecular Medicine (UBA-CONICET), School of Pharmacy and BiochemistryUniversity of Buenos AiresBuenos AiresArgentina

Personalised recommendations