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Mitochondrial Complex I Inactivation After Ischemia-Reperfusion in the Stunned Heart

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Biochemistry of Oxidative Stress

Part of the book series: Advances in Biochemistry in Health and Disease ((ABHD,volume 16))

Abstract

Mitochondrial complex I (NADH-ubiquinone oxidoreductase) catalyzes the transfer of two electrons from NADH via flavin mononucleotide (FMN) and a series of iron-sulfur centers (Fe-S) to ubiquinone (UQ) in a reaction associated with proton translocation across the inner membrane, contributing to the proton-motive force. Complex I produces superoxide anion (O2 −) through the autoxidation reaction of the flavin-semiquinone (FMNH•) with molecular oxygen. Superoxide reacts with nitric oxide (NO) to yield peroxynitrite (ONOO−), a strong oxidant and nitrating compound. When the steady-state concentration of ONOO− is enhanced, tyrosine nitration, protein oxidation and damage to Fe-S centers take place, leading to a sustained complex I inhibition. Dysfunction of complex I was found in a number of clinical conditions such as Parkinson’s disease, ischemia-reperfusion, endotoxic shock, and aging. We have shown that the ventricular dysfunction observed in myocardial stunning is associated with a mitochondrial dysfunction that includes partial inactivation of complex I and mitochondrial nitric oxide synthase (mtNOS) activities, oxidative and nitrosative damages and increased H2O2 and ONOO− production rates. Moreover, adenosine proved to be effective in attenuating ventricular dysfunction and also in protecting from mitochondrial dysfunction and complex I syndrome.

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References

  1. Bolli R, Zhu W, Thornby J et al (1988) Time course and determinants of recovery of function after reversible ischemia in conscious dogs. Am J Physiol 254:H102–H114

    CAS  PubMed  Google Scholar 

  2. Bolli R (1990) Mechanism of myocardial “stunning”. Circulation 82:723–738

    Article  CAS  PubMed  Google Scholar 

  3. Olivetti G, Carpasso J, Meggs L et al (1991) Cellular basis of chronic ventricular remodeling after myocardial infarction in rats. Circulation 68:856–869

    Article  CAS  Google Scholar 

  4. Heyndrickx GG, Baig H, Nellens P et al (1978) Depression of regional blood flow and wall thickening after brief coronary occlusions. Am J Physiol 234:H653–H659

    CAS  PubMed  Google Scholar 

  5. Donato M, Gelpi RJ (2003) Adenosine and cardioprotection during reperfusion-an overview. Mol Cell Biochem 251:153–159

    Article  CAS  PubMed  Google Scholar 

  6. Vinogradov AD, Grivennikova VG (2001) The mitochondrial complex I: progress in understanding the catalytic properties. IUBMB Life 52:129–134

    Article  CAS  PubMed  Google Scholar 

  7. Hunte C, Zickermann V, Brandt U (2010) Functional modules and structural basis of conformational coupling in mitochondrial complex I. Science 329:448–451

    Article  CAS  PubMed  Google Scholar 

  8. Baradaran R, Berrisford JM, Minhas GS, Sazanov LA (2013) Crystal structure of the entire respiratory complex I. Nature 494:443–448

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Hirst J (2013) Mitochondrial complex I. Annu Rev Biochem 82:551–575

    Article  CAS  PubMed  Google Scholar 

  10. Turrens JF, Boveris A (1980) Generation of superoxide anion by the NADH dehydrogenase of bovine heart mitochondria. Biochem J 191:421–427

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Boveris A, Cadenas E (2000) Mitochondrial production of hydrogen peroxide regulation by nitric oxide and the role of ubisemiquinone. IUBMB Life 50:245–250

    Article  CAS  PubMed  Google Scholar 

  12. Boveris A, Chance B (1973) The mitochondrial generation of hydrogen peroxide. Biochem J 134:617–630

    Article  Google Scholar 

  13. Navarro A, Boveris A (2009) Brain mitochondrial dysfunction and oxidative damage in Parkinson’s disease. J Bioenerg Biomembr 41:517–521

    Article  CAS  PubMed  Google Scholar 

  14. Navarro A, Boveris A, Bández MJ et al (2009) Human brain cortex: mitochondrial oxidative damage and adaptative response in Parkinson disease and in dementia Lewy bodies. Free Rad Biol Med 46:1574–1580

    Article  CAS  PubMed  Google Scholar 

  15. Hensley K, Kotake Y, Sang H et al (2000) Dietary choline restriction causes complex I dysfunction and increased H2O2 generation in liver mitochondria. Carcinogenesis 21:983–989

    Article  CAS  PubMed  Google Scholar 

  16. Navarro A, Bandez MJ, Gomez C et al (2010) Effects of rotenone and pyridaben on complex I electron transfer and on mitochondrial nitric oxide synthase functional activity. J Bioenerg Biomembr 42:405–412

    Article  CAS  PubMed  Google Scholar 

  17. Navarro A, Bandez MJ, Lopez-Cepero JM et al (2011) High doses of vitemin E improve mitochondrial dysfunction in rat hyppocampus and frontal cortex upon aging. Am J Physiol Regul Integr Comp Physiol 300:R827–R834

    Article  CAS  PubMed  Google Scholar 

  18. Valdez LB, Zaobornyj T, Bombicino S et al (2011) Complex I syndrome in myocardial stunning and the effect of adenosine. Free Radic Biol Med 51:1203–1212

    Article  CAS  PubMed  Google Scholar 

  19. Valdez LB, Zaobornyj T, Bombicino SS et al (2011) Regulation of heart mitochondrial nitric oxide synthase (mtNOS) by oxygen. In: Cadenas S (ed) Mitochondrial pathophysiology. Transworld Research Network, Kerala, pp 29–42

    Google Scholar 

  20. Yin F, Boveris A, Cadenas E (2014) Mitochondrial energy metabolism and redox signaling in brain aging and neurodegeneration. Antioxid Redox Signal 20:353–371

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Yin F, Cadenas E (2015) Mitochondria: the cellular hub of the dynamic coordinated network. Antioxid Redox Signal 22:961–964

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Boveris A, Valdez LB, Zaobornyj T, Bustamante J (2006) Mitochondrial metabolic states regulate nitric oxide and hydrogen peroxide diffusion to the cytosol. Biochim Biophys Acta 1757:535–542

    Article  CAS  PubMed  Google Scholar 

  23. Tatoyan A, Giulivi C (1998) Purification and characterization of a nitric oxide synthase from rat liver mitochondria. J Biol Chem 273:11044–11048

    Article  CAS  PubMed  Google Scholar 

  24. Giulivi C, Poderoso JJ, Boveris A (1998) Production of nitric oxide by mitochondria. J Biol Chem 273:11038–11043

    Article  CAS  PubMed  Google Scholar 

  25. Elfering SL, Sarkela TM, Giulivi C (2002) Biochemistry of mitochondrial nitric oxide synthase. J Biol Chem 277:38079–38086

    Article  CAS  PubMed  Google Scholar 

  26. Valdez LB, Zaobornyj T, Boveris A (2006) Mitochondrial metabolic states and membrane potential modulate mtNOS activity. Biochim Biophys Acta 1757:166–172

    Article  CAS  PubMed  Google Scholar 

  27. Valdez LB, Alvarez S, Lores-Arnaiz S et al (2000) Reactions of peroxynitrite in the mitochondrial matrix. Free Radic Biol Med 29:349–356

    Article  CAS  PubMed  Google Scholar 

  28. Franco MC, Arciuch VG, Peralta JG et al (2006) Hypothyroid phenotype is contributed by mitochondrial complex I inactivation due to translocated neuronal nitric oxide synthase. J Biol Chem 281:4779–4786

    Article  CAS  PubMed  Google Scholar 

  29. Parihar MS, Nazarewicz RR, Kincaid E et al (2008) Association of mitochondrial nitric oxide synthase activity with respiratorty chain complex I. Biochem Biophys Res Commun 366:23–28

    Article  CAS  PubMed  Google Scholar 

  30. Parihar MS, Parihar A, Villamena FA et al (2008) Inactivation of mitochondrial respiratory chain complex I leads mitochondrial nitric oxide synthase to become pro-oxidative. Biochem Biophys Res Commun 367:761–767

    Article  CAS  PubMed  Google Scholar 

  31. Valdez LB, Boveris A (2007) Mitochondrial nitric oxide synthase, a voltage-dependent enzyme, is responsible for nitric oxide diffusion to cytosol. Front Biosci 12:1210–1219

    Article  CAS  PubMed  Google Scholar 

  32. Kissner R, Nauser T, Bugnon P et al (1997) Formation and properties of peroxynitrite as studied by laser flash photolysis, high-pressure stopped-flow technique and pulse radiolysis. Chem Res Toxicol 10:1285–1292

    Article  CAS  PubMed  Google Scholar 

  33. McCord JM, Fridovich I (1969) Superoxide dismutase. An enzymatic function for erythrocuprein (hemocuprein). J Biol Chem 244:6049–6055

    CAS  PubMed  Google Scholar 

  34. Poderoso JJ, Carreras MC, Schöpfer F et al (1999) The reaction of nitric oxide with ubiquinol: kinetic properties and biological significance. Free Radic Biol Med 26:925–935

    Article  CAS  PubMed  Google Scholar 

  35. Antunes F, Boveris A, Cadenas E (2004) On the mechanism and biology of cytochrome oxidase inhibition by nitric oxide. Proc Natl Acad Sci U S A 101:16774–16779

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Boveris A, Stoppani AO (1970) Inhibition of electron and energy transfer in mitochondria by 19-nor-ethynyltestosterone acetate. Arch Biochem Biophys 141:641–655

    Article  CAS  PubMed  Google Scholar 

  37. Costa LE, Boveris A, Koch OR, Taquini AC (1988) Liver and heart mitochondria in rats submitted to chronic hypobaric hypoxia. Am J Physiol 255:C123–C129

    CAS  PubMed  Google Scholar 

  38. Venardos KM, Zatta AJ, Marshall T et al (2009) Reduced L-arginine transport contributes to the pathogenesis of myocardial ischemia-reperfusion injury. J Cell Biochem 108:156–168

    Article  CAS  PubMed  Google Scholar 

  39. Marban E, Kitakaze M, Koretsune Y et al (1990) Quantification of [Ca2+] in perfused hearts: critical evaluation of 5F-BAPTA and the nuclear magnetic resonance method as applied for the study of ischemia and reperfusion. Circ Res 66:1255–1267

    Article  CAS  PubMed  Google Scholar 

  40. Ogawa T, Miura T, Kazuaki S, Limura OJ (1996) Activation of adenosine receptors before ischemia enhances tolerance against myocardial stunning in the rabbit heart. J Am Coll Cardiol 27:225–233

    Article  CAS  PubMed  Google Scholar 

  41. Boveris A, Carreras MC, Poderoso JJ (2010) The regulation of cell energetics and mitochondrial signaling by nitric oxide. In: Ignarro L (ed) Nitric oxide. Elsevier Academic Press, London, pp 441–482

    Chapter  Google Scholar 

  42. Chen Q, Moghaddas S, Hoppel CL, Lesnefsky EJ (2006) Reversible blockade of electron transport during ischemia protects mitochondria and decreases myocardial injury following reperfusion. J Pharmacol Exp Ther 319:1405–1412

    Google Scholar 

  43. Shiva S, Sack MN, Greer JJ et al (2007) Nitrite augments tolerance to ischemia/reperfusion injury via the modulation of mitochondrial electron transfer. J Exp Med 204:2089–2102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Duranski MR, Greer JJM, Dejam A et al (2005) Cytoprotective effects of nitrite during in vivo ischemia–reperfusion of heart and liver. J Clin Invest 115:232–1240

    Article  Google Scholar 

  45. Prime TA, Blaikie FH, Evans C et al (2009) A mitochondria-targeted S-nitrosothiol modulates respiration, nitrosates thiols, and protects against ischemia-reperfusion injury. Proc Natl Acad Sci U S A 106:10764–10769

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Chouchani ET, Methner C, Nadtochiy SM et al (2013) Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I. Nature Med 19:753–759

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Hurd TR, Costa NJ, Dahm CC et al (2005) Glutathionylation of mitochondrial proteins. Antioxid Redox Signal 7:999–1010

    Article  CAS  PubMed  Google Scholar 

  48. Mailloux RJ, Willmore WG (2014) S-glutathionylation reactions in mitochondrial function and disease. Front Cell Dev Biol http://dx.doi.org/10.3389/fcell.2014.00068

  49. Chang AH, Sancheti H, Garcia J et al (2014) Respiratory substrates regulate S-nitrosylation of mitochondrial proteins through a thiol-dependent pathway. Chem Res Toxicol 27:794–804

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  Google Scholar 

  51. Hurd TR, Requejo R, Filipovska A et al (2008) Complex I within oxidatively stressed bovine heart mitochondria is glutathionylated on Cys-531 and Cys-704 of the 75-kDa subunit: potential role of CYS residues in decreasing oxidative damage. J Biol Chem 283:24801–24815

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Chen J, Chen CL, Rawale S et al (2010) Peptide-based antibodies against glutathione-binding domain suppress superoxide production mediated by mitochondrial complex I. J Biol Chem 285:3168–3180

    Article  CAS  PubMed  Google Scholar 

  53. Kumar V, Kleffmann T, Hampton MB et al (2013) Redox proteomics of thiol proteins in mouse heart during ischemia/reperfusion using ICAT reagents and mass spectrometry. Free Radic Biol Med 58:109–117

    Article  CAS  PubMed  Google Scholar 

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Acknowledgment

This work was supported by grants from the University of Buenos Aires (UBACYT 20020110100140, 20020130100731 and 20020130100557), Agencia Nacional de Promoción Científica y Tecnológica (PICT 2013-0373, 2014-0964), and Consejo Nacional de Investigaciones Científicas y Técnicas (PIP 11220110100444).

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Authors and Affiliations

  1. Institute of Biochemistry and Molecular Medicine (IBIMOL; UBA-CONICET), Physical Chemistry Division, School of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina

    Laura B. Valdez, Silvina S. Bombicino, Darío E. Iglesias & Ivana A. Rukavina-Mikusic

  2. Institute of Biochemistry and Molecular Medicine (IBIMOL; UBA-CONICET), Pathology Division, School of Medicine, University of Buenos Aires, Buenos Aires, Argentina

    Verónica D’Annunzio

Authors
  1. Laura B. Valdez
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  2. Silvina S. Bombicino
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  3. Darío E. Iglesias
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  4. Ivana A. Rukavina-Mikusic
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  5. Verónica D’Annunzio
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Corresponding author

Correspondence to Laura B. Valdez .

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Editors and Affiliations

  1. School of Medicine, University of Buenos Aires, Buenos Aires, Argentina

    Ricardo Jorge Gelpi

  2. School of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina

    Alberto Boveris

  3. Instituto de Inmunología, Genética y Metabolismo (INIGEM, UBA–CONICET), Laboratorio de Metabolismo del Oxígeno, Hospital Universitario, Universidad de Buenos Aires, Buenos Aires, Argentina

    Juan José Poderoso

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Valdez, L.B., Bombicino, S.S., Iglesias, D.E., Rukavina-Mikusic, I.A., D’Annunzio, V. (2016). Mitochondrial Complex I Inactivation After Ischemia-Reperfusion in the Stunned Heart. In: Gelpi, R., Boveris, A., Poderoso, J. (eds) Biochemistry of Oxidative Stress. Advances in Biochemistry in Health and Disease, vol 16. Springer, Cham. https://doi.org/10.1007/978-3-319-45865-6_16

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