Skip to main content

Melatonin protects lung mitochondria from aging

Abstract

We assessed whether melatonin administration would prevent the hyperoxidative status that occurs in lung mitochondria with age. Mitochondria from lungs of male and female senescent prone mice at 5 and 10 months of age were studied. Age-dependent mitochondrial oxidative stress was evaluated by measuring the levels of lipid peroxidation and nitrite, glutathione/glutathione disulfide ratio, and glutathione peroxidase and reductase activities. Mitochondrial respiratory chain and oxidative phosphorylation capability were also measured. Age induces a significant oxidative/nitrosative status in lung mitochondria, which exhibited a significantly reduced activity of the respiratory chain and ATP production. These manifestations of age were more pronounced in males than in females. After 9 months of melatonin administration in the drinking water, the hyperoxidative status and functional deficiency of aged lung mitochondria were totally counteracted, and had increased ATP production. The beneficial effects of melatonin were generally similar in both mice genders. Thus, melatonin administration, as a single therapy, maintained fully functioning lung mitochondria during aging, a finding with important consequences in the pathophysiology of lung aging. In view of these data melatonin, the production of which decreases with age, should be considered a preventive therapy against the hyperoxidative status of the aged lungs, and its use may lead to the avoidance of respiratory complications in the elderly.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

References

  1. Acuña-Castroviejo D, Martín M, Macías M, Escames G, León J, Khaldy H, Reiter RJ (2001) Melatonin, mitochondria and cellular bioenergetics. J Pineal Res 30:65–74

    PubMed  Article  Google Scholar 

  2. Acuña-Castroviejo D, Escames G, Rodríguez MI, López LC (2007) Melatonin role in the mitochondrial function. Front Biosci 12:947–963

    PubMed  Article  Google Scholar 

  3. Acuña-Castroviejo D, López LC, Escames G, López A, García JA, Reiter RJ (2011) Melatonin-mitochondria interplay in health and disease. Curr Top Med Chem 11:221–240

    PubMed  Google Scholar 

  4. Antolin I, Rodríguez C, Sainz RM, Mayo JC, Uría H, Kotler ML, Rodríguez-Colunga MJ, Tolivia D, Menéndez-Peláez A (1996) Neurohormone melatonin prevents cell damage: effect on gene expression for antioxidant enzymes. FASEB J 10:882–890

    PubMed  CAS  Google Scholar 

  5. Baleeiro CE, Wilcoxen SE, Morris SB, Standiford TJ, Paine R 3rd (2003) Sublethal hyperoxia impairs pulmonary innate immunity. J Immunol 171:955–963

    PubMed  CAS  Google Scholar 

  6. Barrientos A (2002) In vivo and in organelle assessment of OXPHOS activities. Methods 26:307–316

    PubMed  CAS  Article  Google Scholar 

  7. Benard G, Faustin B, Passerieux E, Galinier A, Rocher C, Bellance N, Delage J-P, Casteilla L, Letellier T, Rossignol R (2006) Physiological diversity of mitochondrial oxidative phosphorylation. Am J Physiol Cell Physiol 291:C1172–C1182

    PubMed  CAS  Article  Google Scholar 

  8. Brown GC (2001) Regulation of mitochondrial respiration by nitric oxide inhibition of cytochrome c oxidase. Biochim Biophys Acta 1504:46–57

    PubMed  CAS  Article  Google Scholar 

  9. Brown GC, Boroutaite V (2004) Inhibition of mitochondrial respiratory complex I by nitric oxide, peroxynitrite and S-nitrosothiols. Biochim Biophys Acta 1658:44–49

    PubMed  CAS  Article  Google Scholar 

  10. Brown GC, Borutaite V (2002) Nitric oxide inhibition of mitochondrial respiration and its role in cell death. Free Radic Biol Med 33:1440–1450

    PubMed  CAS  Article  Google Scholar 

  11. Brusque AM, Rosa RB, Schuck PF, Dalcin KB, Ribeiro CAJ, Silva CG, Wannmacher CMD, Dutra-Filho CS, Wyse ATS, Briones P, Wajner M (2002) Inhibition of the mitochondrial respiratory chain complex activities in rat cerebral cortex by methylmalonic acid. Neurochem Int 40:593–601

    PubMed  CAS  Article  Google Scholar 

  12. Caballero B, Vega-Naredo I, Sierra V, Huidobro-Fernández C, Soria-Valles C, De Gonzalo-Calvo D, Tolivia D, Pallás M, Camins A, Rodríguez-Colunga MJ, Coto-Montes A (2009) Melatonin alters cell death processes in response to age-related oxidative stress in the brain of senescence-accelerated mice. J Pineal Res 46:106–114

    PubMed  CAS  Article  Google Scholar 

  13. Campbell SE, Febbraio MA (2001) Effect of ovarian hormones on mitochondrial enzyme activity in the fat oxidation pathway of skeletal muscle. Am J Physiol Endocrinol Metab 281:E803–E808

    PubMed  CAS  Google Scholar 

  14. Candore G, Balistreri CR, Colonna-Romano G, Lio D, Listì F, Vasto S, Caruso C (2010) Gender-related immune-inflammatory factors, age-related diseases, and longevity. Rejuvenation Res 13:292–297

    PubMed  CAS  Article  Google Scholar 

  15. Carretero M, Escames G, López LC, Venegas C, Dayoub JC, García LC, Acuña-Castroviejo D (2009) Long-term melatonin administration protects brain mitochondria from aging. J Pineal Res 47:192–200

    PubMed  CAS  Article  Google Scholar 

  16. Crespo E, Macías M, Pozo D, Escames G, Martín M, Vives F, Guerrero JM, Acuña-Castroviejo D (1999) Melatonin inhibits expression of the inducible NO synthase II in liver and lung and prevents endotoxemia in lipopolysaccharide-induced multiple organ dysfunction syndrome in rats. FASEB J 13:1537–1546

    PubMed  CAS  Google Scholar 

  17. De Lourdes M, Seabra V, Bignotto M, Pinto LR, Tufik S (2000) Randomised double blind clinical trial, controlled with placebo of the toxicology of chronic melatonin treatment. J Pineal Res 29:193–200

    Article  Google Scholar 

  18. Droge W (2002) Free radicals in the physiological control of cell function. Physiol Rev 82:47–95

    PubMed  CAS  Google Scholar 

  19. Elder AC, Gelein R, Finkelstein JN, Cox C, Oberdorster G (2000) Pulmonary inflammatory response to inhaled ultrafine particles is modified by age, ozone exposure, and bacterial toxin. Inhal Toxicol 12:227–246

    PubMed  CAS  Article  Google Scholar 

  20. Escames G, León J, Macías M, Khaldy H, Acuña-Castroviejo D (2003) Melatonin counteracts lipopolysaccharide-induced expression and activity of mitochondrial nitric oxide synthase in rats. FASEB J 17:932–934

    PubMed  CAS  Google Scholar 

  21. Escames G, López LC, Ortiz F, Ros E, Acuña-Castroviejo D (2006) Age-dependent lipopolysaccharide-induced iNOS expression and multiorgan failure in rats: effects of melatonin treatment. Exp Gerontol 41:1165–1173

    PubMed  CAS  Article  Google Scholar 

  22. Escames G, López LC, Ortiz F, López A, García JA, Ros E, Acuña-Castroviejo D (2007) Attenuation of cardiac mitochondrial dysfunction by melatonin in septic mice. FEBS J 274:2135–2147

    PubMed  CAS  Article  Google Scholar 

  23. Esterbauer H, Cheeseman KH (1990) Determination of aldehidic lipid peroxidation products: malonaldehide and 4-hydroxynonenal. Methods Enzymol 186:407–421

    PubMed  CAS  Article  Google Scholar 

  24. Garcia J, Han D, Sancheti H, Yap LP, Kaplowitz N, Cadenas E (2010) Regulation of mitochondrial glutathione redox status and protein glutathionylation by respiratory substrates. J Biol Chem. doi:10.1074/jbc.M110.164160

    Google Scholar 

  25. Gonzalvez F, Gottlieb E (2007) Cardiolipin: setting the beat of apoptosis. Apoptosis 12:877–885

    PubMed  CAS  Article  Google Scholar 

  26. Green LC, Ruiz de Luzuriaga K (1981) Nitrate biosynthesis in man. Proc Natl Acad Sci USA 78:7764–7768

    PubMed  CAS  Article  Google Scholar 

  27. Griffith OW (1999) Biologic and pharmacologic regulation of mammalian glutathione synthesis. Free Radic Biol Med 27:922–935

    PubMed  CAS  Article  Google Scholar 

  28. Hardeland R, Tan DX, Reiter RJ (2009) Kynuramines, metabolites of melatonin and other indoles: the resurrection of an almost forgotten class of biogenic amines. J Pineal Res 47:109–126

    PubMed  CAS  Article  Google Scholar 

  29. Hissin PJ, Hilf R (1976) A fluorimetric method for determination of oxidized and reduced glutathione in tissues. Anal Biochem 74:214–226

    PubMed  CAS  Article  Google Scholar 

  30. Hosokawa M (2002) A higher oxidative status accelerates senescence and aggravates age dependent disorders in SAMP strains of mice. Mech Aging Dev 123:1553–1561

    PubMed  CAS  Article  Google Scholar 

  31. Jones DP (2002) Redox potential of GSH/GSSG couple: assay and biological significance. Meth Enzymol 348:93–112

    PubMed  CAS  Article  Google Scholar 

  32. Jones DP (2006) Extracellular redox state: refining the definition of oxidative stress in aging. Rejuvenation Res 9:169–181

    CAS  Article  Google Scholar 

  33. Jou MJ, Peng TI, Hsu LF, Jou SB, Reiter RJ, Yang CM, Chiao CC, Lin YF, Chen CC (2010) Visualization of melatonin's multiple mitochondrial levels of protection against mitochondrial Ca(2+)-mediated permeability transition and beyond in rat brain astrocytes. J Pineal Res 48:20–38

    PubMed  CAS  Article  Google Scholar 

  34. Kirkwood TB (2005) Understanding the odd science of aging. Cell 120:437–447

    PubMed  CAS  Article  Google Scholar 

  35. Lardone PJ, Alvarez-García O, Carrillo-Vico A, Vega-Naredo I, Caballero B, Guerrero JM, Coto-Montes A (2006) Inverse correlation between endogenous melatonin levels and oxidative damage in some tissues of SAM P8 mice. J Pineal Res 40:153–157

    PubMed  CAS  Article  Google Scholar 

  36. Liu W, Porter NA, Schneider C, Brash AR, Yin H (2010) Formation of 4-hydroxynonenal from cardiolipin oxidation: intramolecular peroxyl radical addition and decomposition. Free Radic Biol Med. doi:10.1016/j.freeradbiomed.2010.10.709

    Google Scholar 

  37. López LC, Escames G, Tapias V, Utrilla MP, León J, Acuña-Castroviejo D (2006) Identification of an inducible nitric oxide synthase in diaphragm mitochondria from septic mice. Its relation with mitochondrial dysfunction and prevention by melatonin. Int J Biochem Cell Biol 38:267–278

    PubMed  Article  Google Scholar 

  38. López A, García JA, Escames G, Venegas C, Ortiz F, López LC, Acuña-Castroviejo D (2009) Melatonin protects the mitochondria from oxidative damage reducing oxygen consumption, membrane potential, and superoxide anion production. J Pineal Res 46:188–198

    PubMed  Article  Google Scholar 

  39. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with Folin phenol reagent. J Biol Chem 193:265–275

    PubMed  CAS  Google Scholar 

  40. Martín M, Macías M, Escames G, León J, Acuña-Castroviejo D (2000) Melatonin but not vitamins C and E maintains glutathione homeostasis in t-butyl hydroperoxide-induced mitochondrial oxidative stress. FASEB J 14:1677–1679

    PubMed  Google Scholar 

  41. Martín M, Macías M, León J, Escames G, Khaldy H, Acuña-Castroviejo D (2002) Melatonin increases the activity of the complexes I and IV of the electron transport chain and the ATP production in rat brain and liver mitochondria. Int J Biochem Cell Biol 34:348–357

    PubMed  Article  Google Scholar 

  42. Matsugo S, Kitagawa T, Minami S, Esashi Y, Oomura Y, Tokumaru S, Kojo S, Matsushima K, Sasaki K (2000) Age-dependent changes in lipid peroxide levels in peripheral organs, but not in brain, in senescence-accelerated mice. Neurosci Lett 278:105–108

    PubMed  CAS  Article  Google Scholar 

  43. Meister A (1988) Glutathione metabolism and its selective modification. J Biol Chem 263:17205–17208

    PubMed  CAS  Google Scholar 

  44. Meyer KC (2005) Aging. Proc Am Thorac Soc 2:433–439

    PubMed  CAS  Article  Google Scholar 

  45. Mikerov AN, Gan X, Umstead TM, Miller L, Chinchilli VM, Phelps DS, Floros J (2008) Sex differences in the impact of ozone on survival and alveolar macrophage function of mice after Klebsiella pneumoniae infection. Respir Res 9:24

    PubMed  Article  Google Scholar 

  46. Miquel J (1998) An update on the oxygen stress-mitochondrial mutation theory of aging: genetic and evolutionary implications. Exp Gerontol 33:113–126

    PubMed  CAS  Article  Google Scholar 

  47. Mora AL, Rojas M (2008) Aging and lung injury repair: a role for bone marrow derived mesenchymal stem cells. J Cell Biochem 105:641–647

    PubMed  CAS  Article  Google Scholar 

  48. Nathan C, Xie QW (1994) Nitric oxide synthases: roles, trolls and controls. Cell 78:915–918

    PubMed  CAS  Article  Google Scholar 

  49. Paradies G, Petrosillo G, Paradies V, Reiter RJ, Ruggiero FM (2010) Melatonin, cardiolipin and mitochondrial bioenergetics in health and disease. J Pineal Res 48:297–310

    PubMed  CAS  Article  Google Scholar 

  50. Pendyala S, Natarajan V (2010) Redox regulation of NOx proteins. Respir Physiol Neurobiol. doi:10.1016/j.resp.2010.09.016

    PubMed  Google Scholar 

  51. Pissarek M, Reinhhardt R, Reichelt C, Manaenko A, Krauss GJ, Illes P (1999) Rapid assay for one-run determination of purine and pyrimidine mucleotide contents in neocortical slices and cell cultures. Brain Res Protoc 4:314–321

    CAS  Article  Google Scholar 

  52. Rebrin I, Kamzalov S, Sohal RS (2003) Effects of age and caloric restriction on glutathione redox state in mice. Free Radic Biol Med 35:626–635

    PubMed  CAS  Article  Google Scholar 

  53. Reiter RJ, Paredes SD, Manchester LC, Tan DX (2009) Reducing oxidative/nitrosative stress: a newly-discovered genre for melatonin. Crit Rev Biochem Mol Biol 44:175–200

    PubMed  CAS  Article  Google Scholar 

  54. Riahi Y, Cohen G, Shamni O, Sasson S (2010) Signaling and cytotoxic functions of 4-Hydroxyalkenals. Am J Physiol Endocrinol Metab. doi:10.1152/ajpendo.00508.201

    PubMed  Google Scholar 

  55. Rodríguez MI, Escames G, López LC, García JA, Ortiz F, López A, Acuña-Castroviejo D (2007a) Melatonin administration prevents cardiac and diaphragmatic mitochondrial oxidative damage in senescence-accelerated mice. J Endocrinol 194:637–643

    Article  Google Scholar 

  56. Rodríguez I, Escames G, Lopez LC, Lopez A, Garcia JA, Ortiz F, Sanchez V, Romeu M, Acuña-Castroviejo D (2008) Improved mitocondrial function and increased life span after chronic melatonin treatment in senescent prone mice. Exp Gerontol 43:479–756

    Article  Google Scholar 

  57. Rodríguez MI, Escames G, López LC, López A, García JA, Ortiz F, Acuña-Castroviejo D (2007b) Chronic melatonin treatment reduces the age-dependent inflammatory process in senescence-accelerated mice. J Pineal Res 42:272–279

    Article  Google Scholar 

  58. Sharma G, Goodwin J (2006) Effect of aging on respiratory system physiology and immunology. Clin Interv Aging 1:253–260

    PubMed  CAS  Article  Google Scholar 

  59. Shoal RS, Mockett RJ, Orr WC (2002) Mechanisms of aging: an appraisal of the oxidative stress hypothesis. Free Radic Biol Med 33:575–586

    Article  Google Scholar 

  60. Sprung J, Gajic O, Warner DO (2006) Review article: age related alterations in respiratory function - anesthetic considerations. Can J Anaesth 53:1244–1257

    PubMed  Article  Google Scholar 

  61. Squadrito GL, Pryor WA (1998) Oxidative chemistry of nitric oxide: the roles of superoxide, peroxynitrite and carbon dioxide. Free Radic Biol Med 25:392–403

    PubMed  CAS  Article  Google Scholar 

  62. Takeda T (1999) Senescence-accelerated mouse (SAM): a biogerontological resource in aging research. Neurobiol Aging 20:105–110

    PubMed  CAS  Article  Google Scholar 

  63. Tan DX, Chen LD, Poeggeler B, Manchester LC, Reiter RJ (1993) Melatonin: a potent, endogenous hydroxyl radical scavenger. Endocr J 1:57–60

    Google Scholar 

  64. Tan DX, Manchester LC, Reiter RJ, Plummer BF, Hardies LJ, Vijayalaxmi WST, Shepherd AM (1998) A novel melatonin metabolite, cyclic 3-hydroxymelatonin: a biomarker of in vivo hydroxyl radical generation. Biochem Biophys Res Commun 253:614–620

    PubMed  CAS  Article  Google Scholar 

  65. Tan DX, Manchester LC, Burkhardt S, Sainz RM, Mayo JC, Kohen R, Shohami E, Huo YS, Hardeland R, Reiter RJ (2001) N 1-acetyl-N 2-formyl-5-methoxykynuramine, a biogenic amine and melatonin metabolite, functions as a potent antioxidant. FASEB J 15:2294–2296

    PubMed  CAS  Google Scholar 

  66. Tan DX, Manchester LC, Terron MP, Flores LJ, Reiter RJ (2007) One molecule, many derivates: a never-ending interacting of melatonin with reactive and oxygen and nitrogen species? J Pineal Res 42:28–42

    PubMed  CAS  Article  Google Scholar 

  67. Teramoto S, Fukuchi Y, Uejima Y, Teramoto K, Oka T, Orimo H (1994) A novel model of senile lung: senescence-accelerated mouse (SAM). Am J Respir Crit Care Med 150:238–244

    PubMed  CAS  Google Scholar 

  68. Uejima Y, Fukuchi Y, Nagase T, Matsuse T, Yamaoka M, Tabata R, Orimo H (1990) Influence of inhaled tobacco smoke on the senescence accelerated mouse (SAM). Eur Respir J 3:1029–1036

    PubMed  CAS  Google Scholar 

  69. Umstead TM, Freeman WM, Chinchilli VM, Phelps DS (2009) Age-related changes in the expression and oxidation of bronchoalveolar lavage proteins in the rat. Am J Physiol Lung Cell Mol Physiol 296:L14–L29

    PubMed  CAS  Article  Google Scholar 

  70. Viña J, Borrás C (2010) Women live longer than men: understanding molecular mechanisms offers opportunities to intervene by using estrogenic compounds. Antioxid Redox Signal 13:269–278

    PubMed  Article  Google Scholar 

  71. Waldhauser F, Kovács J, Reiter E (1998) Age-related changes in melatonin levels in humans and its potential consequences for sleep disorders. Exp Gerontol 33:759–772

    PubMed  CAS  Article  Google Scholar 

  72. Wang J, Green PS, Simpkins JW (2001) Estradiol protects against ATP depletion, mitochondrial membrane potential decline and the generation of reactive oxygen species induced by 3-nitroproprionic acid in SK-N-SH human neuroblastoma cells. J Neurochem 77:804–811

    PubMed  CAS  Article  Google Scholar 

Download references

Acknowledgements

The authors thank A. Puertas for technical assistance. This study was partially supported by grants from the Instituto de Salud Carlos III (RD06/0013/0008, PI08-1664), and from the Consejería de Innovación, Ciencia y Empresa, Junta de Andalucía (P07-CTS-03135 and CTS-101).

Author information

Affiliations

Authors

Corresponding author

Correspondence to Germaine Escames.

About this article

Cite this article

Acuña-Castroviejo, D., Carretero, M., Doerrier, C. et al. Melatonin protects lung mitochondria from aging. AGE 34, 681–692 (2012). https://doi.org/10.1007/s11357-011-9267-8

Download citation

Keywords

  • Lung
  • Aging
  • Mitochondria
  • Respiratory chain
  • Oxidative phosphorylation
  • Oxidative stress