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Oxidative stress biomarkers in mitochondrial myopathies, basally and after cysteine donor supplementation

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Abstract

Mitochondrial diseases are due to impairment of the mitochondrial respiratory chain. A plausible pathogenic mechanism leading to cellular dysfunction and phenotypic expression is oxidative stress, but there are surprisingly few clinical studies on this subject. Glutathione (GSH) deficiency has been reported in mitochondrial diseases, and the biosynthesis of glutathione depends on cysteine availability. We have examined oxidative stress biomarkers [advanced oxidation protein products (AOPP) and ferric reducing antioxidant power (FRAP)] in blood samples from 27 patients and 42 controls. AOPP levels were greater in patients than in controls (P value <0.00001). Therefore, we performed a double-blind cross-over study to evaluate if 30-day supplementation with a whey-based cysteine donor could modify these markers, reduce lactate concentration during aerobic exercise, or enhance muscular strength and quality of life. Treatment did not modify lactate concentration, clinical scale (MRC) or quality of life (SF-36), but significantly reduced oxidative stress levels. Our findings reinforce the notions that in mitochondrial diseases oxidative stress is important and can be reduced by administration of a cysteine donor. Oxidative stress biomarkers may be useful to detect redox imbalance in mitochondrial diseases and to provide non-invasive tools to monitor disease status.

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References

  1. Apolone G, Mosconi P (1998) The Italian SF-36 Health Survey: translation, validation and norming. J Clin Epidemiol 51:1025–1036

    Article  CAS  PubMed  Google Scholar 

  2. Atkuri K, Cowan TM, Kwan T, Ng A, Herzenberg LA, Herzenberg LA, Enns GM (2009) Inherited disorders affecting mitochondrial function are associated with glutathione deficiency and hypocitrullinemia. Proc Natl Acad Sci USA 106:3941–3945

    Article  CAS  PubMed  Google Scholar 

  3. Baker MA, Cerniglia GJ, Zaman A (1990) Microtiter plate for the measurement of glutathione and glutathione disulfide in large numbers of biological samples. Anal Biochem 190:360–365

    Article  CAS  PubMed  Google Scholar 

  4. Benzie IF, Strain JJ (1996) The ferric reducing ability of plasma (FRAP) as a measure of antioxidant power: the FRAP assay. Anal Biochem 239:70–76

    Article  CAS  PubMed  Google Scholar 

  5. Bernier FP, Boneh A, Dennett X, Chow CW, Cleary MA, Thorburn DR (2002) Diagnostic criteria for respiratory chain disorders in adults and children. Neurology 59:1406–1411

    Article  CAS  PubMed  Google Scholar 

  6. Chan DC (2006) Mitochondria: dynamic organelles in disease, aging, and development. Cell 125:1241–1252

    Article  CAS  PubMed  Google Scholar 

  7. DiMauro S, Schon EA (2003) Mitochondrial respiratory-chain diseases. N Engl J Med 348:2656–2668

    Article  CAS  PubMed  Google Scholar 

  8. DiMauro S, Servidei S, Zeviani M, DiRocco M, DeVivo DC, DiDonato S, Uziel G, Berry K, Hoganson G, Johnsen SD (1987) Cytochrome c oxidase deficiency in Leigh syndrome. Ann Neurol 22:498–506

    Article  CAS  PubMed  Google Scholar 

  9. DiMauro S, Tay S, Mancuso M (2004) Mitochondrial encephalomyopathies: diagnostic approach. Ann NY Acad Sci 1011:217–231

    Article  CAS  PubMed  Google Scholar 

  10. Guohua C, Prior RL (1998) Comparison of different analytical methods for assessing total antioxidant capacity of human serum. Clin Chem 44:1309–1315

    Google Scholar 

  11. Gutteridge JM (1995) Lipid peroxidation and antioxidants as biomarkers of tissue damage. Clin Chem 41:181–1828

    Google Scholar 

  12. Halliwell B, Gutteridge JM (1995) The definition and measurement of antioxidants in biological systems. Free Radic Biol Med 18:125–126

    Article  CAS  PubMed  Google Scholar 

  13. Hargreaves IP, Sheena Y, Land JM, Heales SJ (2005) Glutathione deficiency in patients with mitochondrial disease: implications for pathogenesis and treatment. J Inherit Metab Dis 28:81–88

    Article  CAS  PubMed  Google Scholar 

  14. Heinecke JW, Li W, Daehnke HD, Goldstein JA (1993) Dityrosine, a specific marker of oxidation, in synthesized by the myeloperoxidasehydrogen peroxide system of human neutrophils and macrophages. J Biol Chem 268:4069–4077

    CAS  PubMed  Google Scholar 

  15. Lands LC, Grey VL, Smountas AA (1999) Effect of supplementation with a cysteine donor on muscular performance. J Appl Physiol 87:1381–1385

    CAS  PubMed  Google Scholar 

  16. Medical Research Council (1943) Aids to the investigation of peripheral nerve injury. War memorandum, 2nd edn. HMSO, London, pp 11–46

    Google Scholar 

  17. Medved I, Brown MJ, Bjorksten AR, Murphy KT, Petersen AC, Sostaric S, Gong X, McKenna MJ (2004) N-acetylcysteine enhances muscle cysteine and glutathione availability and attenuates fatigue during prolonged exercise in endurance-trained individuals. J Appl Physiol 97:1477–1485

    Article  CAS  PubMed  Google Scholar 

  18. Navarro A, Boveris A (2007) The mitochondrial energy transduction system and the aging process. Am J Physiol Cell Physiol 292:C670–C686

    Article  CAS  PubMed  Google Scholar 

  19. Quinzii CM, Lopez LC, Von-Moltke J, Naini A, Krishna S, Schuelke M, Salviati L, Navas P, DiMauro S, Hirano M (2008) Respiratory chain dysfunction and oxidative stress correlate with severity of primary CoQ10 deficiency. FASEB J 22:1874–1885

    Article  CAS  PubMed  Google Scholar 

  20. Reid MB, Stokic DS, Koch SM, Khawli FA, Leis AA (1994) N-acetylcysteine inhibits muscle fatigue in humans. J Clin Investig 94:2468–2474

    Article  CAS  PubMed  Google Scholar 

  21. Ronald L, Guohua C (1999) In vivo total antioxidant capacity: comparison of different analytical methods. Free Radic Biol Med 27:1173–1181

    Article  Google Scholar 

  22. Schaefer AM, McFarland R, Blakely EL, He L, Whittaker RG, Taylor RW, Chinnery PF, Turnbull DM (2008) Prevalence of mitochondrial DNA disease in adults. Ann Neurol 63:35–39

    Article  CAS  PubMed  Google Scholar 

  23. Schaefer AM, Phoenix C, Elson JL, McFarland R, Chinnery PF, Turnbull DM (2006) Mitochondrial disease in adults: a scale to monitor progression and treatment. Neurology 66:1932–1934

    Article  CAS  PubMed  Google Scholar 

  24. Siciliano G, Piazza S, Carlesi C, Del Corona A, Franzini M, Pompella A, Malvaldi G, Mancuso M, Paolicchi A, Murri L (2007) Antioxidant capacity and protein oxidation in cerebrospinal fluid of amyotrophic lateral sclerosis. J Neurol 254:575–580

    Article  CAS  PubMed  Google Scholar 

  25. Siciliano G, Renna M, Manca ML, Prontera C, Zucchelli G, Ferrannini E, Murri L (1999) The relationship of plasma catecholamine and lactate during anaerobic threshold exercise in mitochondrial myopathies. Neuromuscul Disord 9:411–416

    Article  CAS  PubMed  Google Scholar 

  26. Siciliano G, Tessa A, Petrini S, Mancuso M, Bruno C, Grieco GS, Malandrini A, DeFlorio L, Martini B, Federico A, Nappi G, Santorelli FM, Murri L (2003) Autosomal dominant external ophthalmoplegia and bipolar affective disorder associated with a mutation in the ANT1 gene. Neuromuscul Disord 13:162–165

    Article  CAS  PubMed  Google Scholar 

  27. Tietze F (1969) Enzymic method for quantitative determination of nanogram amounts of total and oxidized glutathione: applications to mammalian blood and other tissue. Anal Biochem 27:502–522

    Article  CAS  PubMed  Google Scholar 

  28. Turrens JF (2003) Mitochondrial formation of reactive oxygen species. J Physiol 552:335–344

    Article  CAS  PubMed  Google Scholar 

  29. Verkaart S, Koopman WJ, van Emst-de Vries SE, Nijtmans LG, van den Heuvel LW, Smeitink JA, Willems PH (2007) Superoxide production is inversely related to complex I activity in inherited complex I deficiency. Biochim Biophys Acta 1772:373–381

    CAS  PubMed  Google Scholar 

  30. Vives-Bauza C, Gonzalo R, Manfredi G, Garcia-Arumi E, Andreu AL (2006) Enhanced ROS production and antioxidant defenses in cybrids harbouring mutations in mtDNA. Neurosci Lett 391:136–141

    Article  CAS  PubMed  Google Scholar 

  31. Witko-Sarsat V, Friedlander M, Capeillere-Blandin C, Nguyen-Khoa T, Nguyen AT, Zingraff J, Jungers P, Descamps-Latsch B (1996) Advanced oxidation protein products as a novel marker of oxidative stress in uremia. Kidney Int 49:1304–1313

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors are grateful to Professors Salvatore DiMauro and Michio Hirano (Columbia University, New York) for their critical reading of the manuscript. This work was performed in the frame of AMBISEN Center, High Technology Center for the study of the Environmental Damage of Endocrine and Nervous System, University of Pisa.

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Authors and Affiliations

  1. Department of Neuroscience, Neurological Clinic, University of Pisa, Via Roma 67, 56126, Pisa, Italy

    Michelangelo Mancuso, Daniele Orsucci, Annalisa LoGerfo, Anna Rocchi, Lucia Petrozzi, Claudia Nesti, Luigi Murri & Gabriele Siciliano

  2. Department of Internal Medicine, University of Pisa, Via Roma 67, 56126, Pisa, Italy

    Fabio Galetta & Gino Santoro

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  1. Michelangelo Mancuso
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  2. Daniele Orsucci
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  10. Gabriele Siciliano
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Correspondence to Michelangelo Mancuso.

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Mancuso, M., Orsucci, D., LoGerfo, A. et al. Oxidative stress biomarkers in mitochondrial myopathies, basally and after cysteine donor supplementation. J Neurol 257, 774–781 (2010). https://doi.org/10.1007/s00415-009-5409-7

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  • DOI: https://doi.org/10.1007/s00415-009-5409-7

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