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Minocycline chelates Ca2+, binds to membranes, and depolarizes mitochondria by formation of Ca2+-dependent ion channels

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Abstract

Minocycline (an anti-inflammatory drug approved by the FDA) has been reported to be effective in mouse models of amyotrophic lateral sclerosis and Huntington disease. It has been suggested that the beneficial effects of minocycline are related to its ability to influence mitochondrial functioning. We tested the hypothesis that minocycline directly inhibits the Ca2+-induced permeability transition in rat liver mitochondria. Our data show that minocycline does not directly inhibit the mitochondrial permeability transition. However, minocycline has multiple effects on mitochondrial functioning. First, this drug chelates Ca2+ ions. Secondly, minocycline, in a Ca2+-dependent manner, binds to mitochondrial membranes. Thirdly, minocycline decreases the proton-motive force by forming ion channels in the inner mitochondrial membrane. Channel formation was confirmed with two bilayer lipid membrane models. We show that minocycline, in the presence of Ca2+, induces selective permeability for small ions. We suggest that the beneficial action of minocycline is related to the Ca2+-dependent partial uncoupling of mitochondria, which indirectly prevents induction of the mitochondrial permeability transition.

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References

  • Castanares M, Vera Y, Erkkila K, Kyttanen S, Lue Y, Dunkel L, Wang C, Swerdloff RS, Hikim AP (2005) Biochem Biophys Res Commun 337:663–669

    Article  CAS  Google Scholar 

  • Chen Y, Schindler M, Simon SM (1999) J Biol Chem 274:18364–18373

    Article  CAS  Google Scholar 

  • Chu HC, Lin YL, Sytwu HK, Lin SH, Liao CL, Chao YC (2005) Br J Pharmacol 144:275–282

    Article  CAS  Google Scholar 

  • Cornet S, Spinnewyn B, Delaflotte S, Charnet C, Roubert V, Favre C, Hider H, Chabrier PE, Auguet M (2004) Eur J Pharmacol 505:111–119

    Article  CAS  Google Scholar 

  • Feigin AM, Aronov EV, Teeter JH, Brand JG (1995) Biochim Biophys Acta 1234:43–51

    Article  Google Scholar 

  • Fernandez-Gomez FJ, Gomez-Lazaro M, Pastor D, Calvo S, Aguirre N, Galindo MF, Jordán J (2005a) Neurobiol Dis 20:384–391

    Article  CAS  Google Scholar 

  • Fernandez-Gomez FJ, Galindo MF, Gomez-Lazaro M, González-García C, Ceña V, Aguirre N, Jordán J (2005b) Neuroscience 133:959–967

    Article  CAS  Google Scholar 

  • Gunter TE, Pfeiffer DR (1990) Am J Physiol 258:C755–786

    CAS  Google Scholar 

  • Halestrap AP, Woodfield KY, Connern CP (1997) J Biol Chem 272:3346–3354

    Article  CAS  Google Scholar 

  • Krasnikov BF, Zorov DB, Antonenko YN, Zaspa AA, Kulikov IV, Kristal BS, Cooper AJL, Brown AM (2005) Biochim Biophys Acta 1708:375–392

    Article  CAS  Google Scholar 

  • Kupsch K, Hertel S, Kreutzmann P, Wolf G, Wallesch CW, Siemen D, Schönfeld P (2009) FEBS J 276:1729–1738

    Article  CAS  Google Scholar 

  • Lin Q, Katakura K, Suzuki M (2002) FEBS Lett 515:71–74

    Article  CAS  Google Scholar 

  • Mansson R, Hansson MJ, Morota S, Uchino H, Ekdahl CT, Elmer E (2007) Neurobiol Dis 25:198–205

    Article  CAS  Google Scholar 

  • Matlib MA, Zhou Z, Knight S, Ahmed S, Choi KM, Krause-Bauer J, Phillips R, Altschuld R, Katsube Y, Sperelakis N, Bers DM (1998) J Biol Chem 273:10223–10231

    Article  CAS  Google Scholar 

  • Matsuki S, Iuchi Y, Ikeda Y, Sasagawa I, Tomita Y, Fujii J (2003) Biochem Biophys Res Commun 312:843–849

    Article  CAS  Google Scholar 

  • Mueller P, Rudin DO, Tien HT, Wescott WC (1963) J Phys Chem 67:534–535

    CAS  Google Scholar 

  • O’Brodovich H, Wang X, Li C, Rafii B, Correa J, Bear C (1993) Am J Physiol 264:C1532–1537

    Google Scholar 

  • Petronilli V, Cola C, Bernardi P (1993) J Biol Chem 268:1011–1016

    CAS  Google Scholar 

  • Sapadin AN, Fleischmajer R (2006) J Am Acad Dermatol 54:258–265

    Article  Google Scholar 

  • Scarabelli TM, Stephanou A, Pasini E, Gitti G, Townsend P, Lawrence K, Chen-Scarabelli C, Saravolatz L, Latchman D, Knight R, Gardin J (2004) J Am Coll Cardiol 43:865–874

    Article  CAS  Google Scholar 

  • Scott ID, Akerman KE, Nicholls DG (1980) Biochem J 192:873–880

    CAS  Google Scholar 

  • Sipos EP, Tamargo RJ, Weingart JD, Brem H (1994) Ann NY Acad Sci 732:263–272

    Article  CAS  Google Scholar 

  • Smith DL, Woodman B, Mahal A, Sathasivam K, Ghazi-Noori S, Lowden PA, Bates GP, Hockly E (2003) Ann Neurol 54:186–196

    Article  CAS  Google Scholar 

  • Teng YD, Choi H, Onario RC, Zhu S, Desilets FC, Lan S, Woodard EJ, Snyder EY, Eichler ME, Friedlander RM (2004) Proc Natl Acad Sci USA 101:3071–3076

    Article  CAS  Google Scholar 

  • Wang X, Zhu S, Drozda M, Zhang W, Stavrovskaya IG, Cattaneo E, Ferrante RJ, Kristal BS, Friedlander RM (2003) Proc Natl Acad Sci USA 100:10483–10487

    Article  CAS  Google Scholar 

  • Wang J, Wei Q, Wang CY, Hill WD, Hess DC, Dong Z (2004) J Biol Chem 279:19948–19954

    Article  CAS  Google Scholar 

  • White JR, Pearce FL (1982) Biochemistry 21:6309–6312

    Article  CAS  Google Scholar 

  • Yang L, Harroun TA, Weiss TM, Ding L, Huang HW (2001) Biophys J 81:1475–1485

    Article  Google Scholar 

  • Zhu S, Stavrovskaya IG, Drozda M, Kim BY, Ona V, Li M, Sarang S, Liu AS, Hartley DM, Wu DC, Gullans S, Ferrante RJ, Przedborski S, Kristal BS, Friedlander RM (2002) Nature 417:74–78

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. A.N. Belozersky Institute of Physico-Chemical Biology, Moscow State University, Moscow, 119992, Russia

    Yuri N. Antonenko & Tatyana I. Rokitskaya

  2. Department of Biochemistry and Molecular Biology, New York Medical College, 15 Dana Road, BSB, NYMC, Valhalla, NY, 10595, USA

    Arthur J. L. Cooper & Boris F. Krasnikov

Authors
  1. Yuri N. Antonenko
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  2. Tatyana I. Rokitskaya
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  3. Arthur J. L. Cooper
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  4. Boris F. Krasnikov
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Correspondence to Boris F. Krasnikov.

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Antonenko, Y.N., Rokitskaya, T.I., Cooper, A.J.L. et al. Minocycline chelates Ca2+, binds to membranes, and depolarizes mitochondria by formation of Ca2+-dependent ion channels. J Bioenerg Biomembr 42, 151–163 (2010). https://doi.org/10.1007/s10863-010-9271-1

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  • DOI: https://doi.org/10.1007/s10863-010-9271-1

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