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Interactions of melatonin with mammalian mitochondria. Reducer of energy capacity and amplifier of permeability transition

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Abstract

Melatonin, a metabolic product of the amino acid tryptophan, induces a dose-dependent energy drop correlated with a decrease in the oxidative phosphorylation process in isolated rat liver mitochondria. This effect involves a gradual decrease in the respiratory control index and significant alterations in the state 4/state 3 transition of membrane potential (ΔΨ). Melatonin, alone, does not affect the insulating properties of the inner membrane but, in the presence of supraphysiological Ca2+, induces a ΔΨ drop and colloid-osmotic mitochondrial swelling. These events are sensitive to cyclosporin A and the inhibitors of Ca2+ transport, indicative of the induction or amplification of the mitochondrial permeability transition. This phenomenon is triggered by oxidative stress induced by melatonin and Ca2+, with the generation of hydrogen peroxide and the consequent oxidation of sulfydryl groups, glutathione and pyridine nucleotides. In addition, melatonin, again in the presence of Ca2+, can also induce substantial release of cytochrome C and AIF (apoptosis-inducing factor), thus revealing its potential as a pro-apoptotic agent.

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Abbreviations

AdNT:

Adenine nucleotide translocator

AIF:

Apoptosis-inducing factor

BKA:

Bongkrekic acid

CsA:

Cyclosporin A

DTE:

Dithioerythritol

ΔE :

Electrical transmembrane potential

ΔμH+ :

Transmembrane electrochemical gradient

ΔΨ:

Electric membrane potential

EGTA:

Ethylene glycol tetraacetic acid

MLT:

Melatonin

MPT:

Mitochondrial permeability transition

NEM:

N-Ethylmaleimide

RCI:

Respiratory control index

RHM:

Rat heart mitochondria

RLM:

Rat liver mitochondria

ROS:

Reactive oxygen species

RR:

Ruthenium red

tBOOH:

Tert-butylhydroperoxide

TPP+ :

Tetraphenylphosphonium

References

  • Agostinelli E, Marques MPM, Calheiros R, Gil FPSC, Tempera G, Viceconte N, Battaglia V, Grancara S, Toninello A (2009) Polyamines: fundamental characters in chemistry and biology. Amino Acids 38:393–403

    Article  PubMed  Google Scholar 

  • Andrabi SA, Sayeed I, Siemen D, Wolf G, Horn TF (2004) Direct inhibition of the mitochondrial permeability transition pore: a possible mechanism responsible for anti-apoptotic effects of melatonin. FASEB J 18:869–871

    PubMed  CAS  Google Scholar 

  • Arendt J (1996) Melatonin. BMJ 312:1242–1243

    Article  PubMed  CAS  Google Scholar 

  • Battaglia V, Brunati AM, Fiore C, Rossi CA, Salvi M, Tibaldi E, Palermo M, Armanini D, Toninello A (2008) Glycyrrhetinic acid as inhibitor or amplifier of permeability transition in rat heart mitochondria. Biochim Biophys Acta 1778:313–323

    Article  PubMed  CAS  Google Scholar 

  • Battaglia V, Grancara S, Satriano J, Saccoccio S, Agostinelli E, Toninello A (2010) Agmatine prevents the Ca(2+)-dependent induction of permeability transition in rat brain mitochondria. Amino Acids 38:431–437

    Article  PubMed  CAS  Google Scholar 

  • Bejarano I, Redondo PC, Espino J, Rosado JA, Paredes SD, Barriga C, Reiter RJ, Pariente JA, Rodríguez AB (2009) Melatonin induces mitochondrial-mediated apoptosis in human myeloid HL-60 cells. J Pineal Res 46:392–400

    Article  PubMed  CAS  Google Scholar 

  • Bergstrom WH, Hakanson DO (1998) Melatonin: the dark force. Adv Pediatr 45:91–106

    PubMed  CAS  Google Scholar 

  • Buscemi N, Vandermeer B, Hooton N, Pandya R, Tjosvold L, Hartling L, Vohra S, Klassen TP, Baker G (2006) Efficacy and safety of exogenous melatonin for secondary sleep disorders and sleep disorders accompanying sleep restriction: meta-analysis. BMJ 332:385–393

    Article  PubMed  CAS  Google Scholar 

  • Büyükavcı M, Özdemir Ö, Buck S, Stout M, Ravindranath Y, Savaşan S (2006) Melatonin cytotoxicity in human leukemia cells: relation with its pro-oxidant effect. Fundam Clin Pharmacol 20:73–79

    Article  PubMed  Google Scholar 

  • Cardillo S, De Iuliis A, Battaglia V, Toninello A, Stevanato R, Vianello F (2009) Novel copper amine oxidase activity from rat liver mitochondria matrix. Arch Biochem Biophys 485:97–101

    Article  PubMed  CAS  Google Scholar 

  • Cassone VM (1990) Effects of melatonin on vertebrate circadian systems. Trends Neurosci 13:457–464

    Article  PubMed  CAS  Google Scholar 

  • Chan T-Y, Tang P-L (1996) Characterization of the antioxidant effects of melatonin and related indoleamines in vitro. J Pineal Res 20:187–191

    Article  PubMed  CAS  Google Scholar 

  • De Marchi U, Biasutto L, Garbisa S, Toninello A, Zoratti M (2009) Quercetin can act either as an inhibitor or an inducer of the mitochondrial permeability transition pore: a demonstration of the ambivalent redox character of polyphenols. Biochim Biophys Acta 1787:1425–1432

    Article  PubMed  Google Scholar 

  • Espino J, Bejarano I, Redondo PC, Rosado JA, Barriga C, Reiter RJ, Pariente JA, Rodríguez AB (2010) Melatonin reduces apoptosis induced by calcium signaling in human leukocytes: evidence for the involvement of mitochondria and Bax activation. J Membr Biol 233:105–118

    Article  PubMed  CAS  Google Scholar 

  • Gornall AG, Bardawill CJ, David MM (1949) Determination of serum proteins by means of the biuret reaction. J Biol Chem 177:751–766

    PubMed  CAS  Google Scholar 

  • Grijalba MT, Vercesi AE, Schreier S (1999) Ca2+-induced increased lipid packing and domain formation in submitochondrial particles. A possible early step in the mechanism of Ca2 + stimulated generation of reactive oxygen species by the respiratory chain. Biochemistry 38:13279–13287

    Article  PubMed  CAS  Google Scholar 

  • Gutiérrez CI, Urbina M, Obregion F, Glykys J, Lima L (2006) Characterization of tryptophan high affinity transport system in pinealocytes of the rat. Day–night modulation. Amino Acids 25:95–105

    Google Scholar 

  • Hansson MJ, Morota S, Teilum M, Mattiasson G, Uchino H, Elmér E (2010) Increased potassium conductance of brain mitochondria induces resistance to permeability transition by enhancing matrix volume. J Biol Chem 285:741–750

    Article  PubMed  CAS  Google Scholar 

  • Herxheimer A (2006) Does melatonin help people to sleep? BMJ 332:373–374

    Article  PubMed  Google Scholar 

  • Jensen BD, Gunter KK, Gunter TE (1986) The efficiencies of the component steps of oxidative phosphorylation. II. Experimental determination of the efficiencies in mitochondria and examination of the equivalence of membrane potential and pH gradient in phosphorylation. Arch Biochem Biophys 248:305–323

    Article  PubMed  CAS  Google Scholar 

  • Kamo N, Muratsugu M, Hongoh R, Kobatake Y (1979) Membrane potential of mitochondria measured with an electrode sensitive to tetraphenylphosphonium and relationship between proton electrochemical potential and phosphorylation potential in steady state. J Membr Biol 49:105–121

    Article  PubMed  CAS  Google Scholar 

  • Lemasters JJ, Hackenbrock CR (1976) Continuous measurement and rapid kinetics of ATP synthesis in rat liver mitochondria, mitoplasts and inner membrane vesicles determined by firefly-luciferase luminescence. Eur J Biochem 67:1–10

    Article  PubMed  CAS  Google Scholar 

  • Lerner AB, Case JD, Takahashi Y, Lee TH, Mori W (1958) Isolation of melatonin, the pineal gland factor that lightens melanocytes. J Am Chem Soc 80:2587

    Article  CAS  Google Scholar 

  • Leung AW, Halestrap AP (2008) Recent progress in elucidating the molecular mechanism of the mitochondrial permeability transition pore. Biochim Biophys Acta 1777:946–952

    Article  PubMed  CAS  Google Scholar 

  • Leung AW, Varanyuwatana P, Halestrap AP (2008) The mitochondrial phosphate carrier interacts with cyclophilin-D and may play a key role in the permeability transition. J Biol Chem 283:26312–26323

    Article  PubMed  CAS  Google Scholar 

  • Loschen G, Azzi A, Flohè L (1973) Mitochondrial H2O2 formation: relationship with energy conservation. FEBS Lett 33:84–87

    Article  PubMed  CAS  Google Scholar 

  • Lötscher HR, Winterhalter KH, Carafoli E, Richter C (1980) The energy-state of mitochondria during the transport of Ca2+. Eur J Biochem 110:211–216

    Article  PubMed  Google Scholar 

  • Martín M, Macías M, León J, Escames G, Khaldy H, Acuña-Castroviejo D (2002) Melatonin increases the activity of the oxidative phosphorylation enzymes and the production of ATP in rat brain and liver mitochondria. Int J Biochem Cell Biol 34:348–357

    Article  PubMed  Google Scholar 

  • Matuszak Z, Reszka K, Chignell CF (1997) Reaction of melatonin and related indoles with hydroxyl radicals: EPR and spin trapping investigations. Free Radic Biol Med 23:367–372

    Article  PubMed  CAS  Google Scholar 

  • McStay GP, Clarke SJ, Halestrap AP (2002) Role of critical thiol groups on the matrix surface of the adenine nucleotide translocase in the mechanism of the mitochondrial permeability transition pore. Biochem J 367:541–548

    Article  PubMed  CAS  Google Scholar 

  • Osseni RA, Rat P, Bogdan A, Warnet JM, Touitou Y (2000) Evidence of prooxidant and antioxidant action of melatonin on human liver cell line HepG2. Life Sci 68:387–399

    Article  PubMed  CAS  Google Scholar 

  • Pandi-Perumal SR, Trakht I, Srinivasan V, Spence DW, Maestroni GJ, Zisapel N, Cardinali DP (2008) Physiological effects of melatonin: role of melatonin receptors and signal transduction pathways. Prog Neurobiol 85:335–353

    Article  PubMed  CAS  Google Scholar 

  • Petrosillo G, Moro N, Ruggiero FM, Paradies G (2009) Melatonin inhibits cardiolipin peroxidation in mitochondria and prevents the mitochondrial permeability transition and cytochrome c release. Free Radic Biol Med 47:969–974

    Article  PubMed  CAS  Google Scholar 

  • Pieri C, Marra M, Moroni F, Recchioni R, Marcheselli F (1994) Melatonin: a peroxyl radical scavenger more effective than vitamin E. Life Sci 55:271–276

    Article  Google Scholar 

  • Reiter RJ, Tan DX (2002) What constitutes a physiological concentration of melatonin? J Pineal Res 34:79–80

    Article  Google Scholar 

  • Sainz RM, Mayo JC, Rodriguez C, Tan DX, Lopez-Burillo S, Reiter RJ (2003) Melatonin and cell death: differential actions on apoptosis in normal and cancer cells. Cell Mol Life Sci 60:1407–1426

    Article  PubMed  CAS  Google Scholar 

  • Salvi M, Brunati AM, Clari G, Toninello A (2002) Interaction of genistein with the mitochondrial electron transport chain results in opening of the membrane transition pore. Biochim Biophys Acta 1556:187–196

    Article  PubMed  CAS  Google Scholar 

  • Santos AC, Uyemura SA, Lopes JL, Bazon JN, Mingatto FE, Curti C (1998) Effect of naturally occurring flavonoids on lipid peroxidation and membrane permeability transition in mitochondria. Free Radic Biol Med 24:1455–1461

    Article  PubMed  CAS  Google Scholar 

  • Schneider WC, Hogeboom GH (1950) Intracellular distribution of enzymes V. Further studies on the distribution of cytochrome c in rat liver homogenates. J Biol Chem 183:123–128

    CAS  Google Scholar 

  • Slominski A, Tobin DJ, Zmijewski MA, Wortsman J, Paus R (2008) Melatonin in the skin: synthesis, metabolism and functions. Trends in endocrinology and metabolism 19:17–24

    Article  PubMed  CAS  Google Scholar 

  • Srinivasan V, Spence W, Pandi-Perumal SR, Trakht I, Cardinali DP (2008) Therapeutic actions of melatonin in cancer: possible mechanisms. Integr Cancer Ther 7:189–203

    Article  PubMed  CAS  Google Scholar 

  • Tietze F (1969) Enzymatic method for quantitative determination of nanogram amounts of total and oxidized glutathione. Anal Biochem 27:502–522

    Article  PubMed  CAS  Google Scholar 

  • Wölfler A, Caluba HC, Abuja PM, Dohr G, Schauenstein K, Liebmann PM (2001) Prooxidant activity of melatonin promotes fas-induced cell death in human leukemic Jurkat cells. FEBS Lett 502:127–131

    Article  PubMed  Google Scholar 

  • Yankovskaya V, Horsefield R, Tornroth S, Luna-Chavez C, Miyoshi H, Leger C, Byrne B, Cecchini G, Iwata S (2003) Architecture of succinate dehydrogenase and reactive oxygen species generation. Science 299:700–704

    Article  PubMed  CAS  Google Scholar 

  • Zhang HM, Zhang Y, Zhang BX (2011) The role of mitochondrial complex III in melatonin-induced ROS production in cultured mesangial cells. J Pineal Res 50:78–82

    Article  PubMed  CAS  Google Scholar 

Download references

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Authors and Affiliations

  1. Department of Biological Chemistry, University of Padua, Viale G. Colombo 3, 35121, Padua, Italy

    P. Martinis, L. Zago, M. Maritati, V. Battaglia, S. Grancara, V. Rizzoli & A. Toninello

  2. Department of Biochemical Sciences, Institutes of Biology and Molecular Pathology, University of Rome, CNR, Piazzale Aldo Moro 5, 00185, Rome, Italy

    E. Agostinelli

  3. Department of Molecular Sciences and Nanosystems, Ca’ Foscari University of Venice, Dorsoduro 2137, 30123, Venice, Italy

    M. Bragadin

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  1. P. Martinis
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  2. L. Zago
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Correspondence to A. Toninello.

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Martinis, P., Zago, L., Maritati, M. et al. Interactions of melatonin with mammalian mitochondria. Reducer of energy capacity and amplifier of permeability transition. Amino Acids 42, 1827–1837 (2012). https://doi.org/10.1007/s00726-011-0903-5

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  • DOI: https://doi.org/10.1007/s00726-011-0903-5

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