Skip to main content

Advertisement

SpringerLink
Log in

Mitochondrial permeability transition pore: a promising target for the treatment of Parkinson’s disease

  • Review Article
  • Published:
Protoplasma Aims and scope Submit manuscript

Abstract

Among the neurodegenerative diseases (ND), Parkinson’s disease affects 6.3 million people worldwide characterized by the progressive loss of dopaminergic neurons in substantia nigra. The mitochondrial permeability transition pore (mtPTP) is a non-selective voltage-dependent mitochondrial channel whose opening modifies the permeability properties of the mitochondrial inner membrane. It is recognized as a potent pharmacological target for diseases associated with mitochondrial dysfunction and excessive cell death including ND such as Parkinson’s disease (PD). Imbalance in Ca2+ concentration, change in mitochondrial membrane potential, overproduction of reactive oxygen species (ROS), or mutation in mitochondrial genome has been implicated in the pathophysiology of the opening of the mtPTP. Different proteins are released by permeability transition including cytochrome c which is responsible for apoptosis. This review aims to discuss the importance of PTP in the pathophysiology of PD and puts together different positive as well as negative aspects of drugs such as pramipexole, ropinirole, minocyclin, rasagilin, and safinamide which act as a blocker or modifier for mtPTP. Some of them may be detrimental in their neuroprotective nature.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  • Anglade P, Vyas S, Javoy-Agid F, Herrero MT, Michel PP, Marquez J, Mouatt-Prigent A, Ruberg M, Hirsch EC, Agid Y (1997) Apoptosis and autophagy in nigral neurons of patients with Parkinson’s disease. Histol Histopathol 12:25–31

    CAS  PubMed  Google Scholar 

  • Baines CP, Kaiser RA, Sheiko T, Craigen WJ, Molkentin JD (2007) Voltage-dependent anion channels are dispensable for mitochondrial-dependent cell death. Nat Cell Biol 9:550–555

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Banerjee R, Starkov AA, Beal MF, Thomas B (2009) Mitochondrial dysfunction in limelight of Parkinson’s disease pathogenesis. Biochim Biophys Acta 1792:651–663

    Article  CAS  PubMed  Google Scholar 

  • Barber-Singh J, Seo BB, Matsuno-Yagi A, Yagi T (2010) Protective role of rAAV-NDI1, serotype 5, in an acute MPTP mouse Parkinson’s model. Parkinsons Dis 2011:438370

    PubMed  PubMed Central  Google Scholar 

  • Beal MF (2000) Energetics in the pathogenesis of neurodegenerative diseases. Trends Neurosci 23(7):298–304

    Article  CAS  PubMed  Google Scholar 

  • Bennett JP, Jr MF, Piercey MF (1999) Pramipexole—a new dopamine agonist for the treatment of Parkinson’s disease. J Neurosci 163(1):25–31

    CAS  Google Scholar 

  • Berman SB, Hastings TG (1999) Dopamine oxidation alters mitochondrial respiration and induces permeability transition in brain mitochondria: implications for Parkinson’s disease. J Neurochem 73(3):1127–1137

    Article  CAS  PubMed  Google Scholar 

  • Bernardi P (2013) The mitochondrial permeability transition pore: a mystery solved? Front Physiol 4:95

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bernardi P, Krauskopf A, Basso E, Petronilli V, Blachly-Dyson E, Di Lisa F, Forte MA (2006) The mitochondrial permeability transition from in vitro artifact to disease target. FEBS J 273(10):2077–2099

    Article  CAS  PubMed  Google Scholar 

  • Betarbet R, Sherer TB, Greenamyre JT (2002) Animal models of Parkinson’s disease. Bioessays 24(4):308–318

    Article  CAS  PubMed  Google Scholar 

  • Brenner C, Moulin M (2012) Physiological roles of the permeability transition pore. Circ Res 111(9):1237–1247

    Article  CAS  PubMed  Google Scholar 

  • Burkhard P, Dominici P, Borri-Voltattorni C, Jansonius JN, Malashkevich VN (2001) Structural insight into Parkinson’s disease treatment from drug-inhibited DOPA decarboxylase. Nat Struct Biol 8(11):963–967

    Article  CAS  PubMed  Google Scholar 

  • Cannon JR, Greenamyre JT (2013) Gene-environment interactions in Parkinson’s disease: specific evidence in humans and mammalian models. Neurobiol Dis 57:38–46

    Article  CAS  PubMed  Google Scholar 

  • Cassarino DS, Fall CP, Smith TS, Bennett JP Jr (1998) Pramipexole reduces reactive oxygen species production in vivo and in vitro and inhibits the mitochondrial permeability transition produced by the parkinsonian neurotoxin methylpyridinium ion. J Neurochem 71(1):295–301

    Article  CAS  PubMed  Google Scholar 

  • Celsi F, Pizzo P, Brini M, Leo S, Fotino C, Pinton P, Rizzuto R (2009) Mitochondria, calcium and cell death: a deadly triad in neurodegeneration. Biochim Biophys Acta 1787(5):335–344

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cheng Y, Gulbins E, Siemen D (2009) Activation of the permeability transition pores by Bax via inhibition of the mitochondrial BK channel. Cell Physiol Biochem 27(3–4):191–200

    Google Scholar 

  • Cheng Y, Debska-Vielhaber YZ, Siemen D (2010) Interaction of mitochondrial potassium channels with the permeability transition pores. FEBS Lett 584(10):2005–2012

    Article  CAS  PubMed  Google Scholar 

  • Cohen JJ (1991) Programmed cell death in the immune system. Adv Immunol 50:55–85

    Article  CAS  PubMed  Google Scholar 

  • de Castro IP, Martins LM, Loh SH (2011) Mitochondrial quality control and Parkinson’s disease: a pathway unfolds. Mol Neurobiol 43(2):80–86

    Article  CAS  PubMed  Google Scholar 

  • Dexter DT, Jenner P (2013) Parkinson disease: from pathology to molecular disease mechanisms. Free Radic Biol Med 62:132–144

    Article  CAS  PubMed  Google Scholar 

  • Dixit A, Srivastava G, Verma D, Mishra M, Singh PJK, Prakash O, Singh MP (2013) Minocycline, levodopa and MnTMPyP induced changes in the mitochondrial proteome profile of MPTP and maneb and paraquat mice models of Parkinson’s disease. Biochim Biophys Acta 1832(8):1227–1240

    Article  CAS  PubMed  Google Scholar 

  • Du Y, Ma Z, Lin S, Dodel RC, Gao F, Bales KR, Triarhou LC, Chernet E, Perry KW, Nelson DL, Luecke S, Phebus LA, Bymaster FP, Paul SM (2001) Minocycline prevents nigrostriatal dopaminergic neurodegeneration in the MPTP model of Parkinson’s disease. Proc Natl Acad Sci U S A 98(25):14669–14674

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Feissner RF, Skalska J, Gaum WE, Sheu SS (2009) Crosstalk signaling between mitochondrial Ca2+ and ROS. Front Biosci (Landmark Ed) 14:1197–1218

    Article  CAS  Google Scholar 

  • Geller LN, Potter H (1999) Chromosome missegregation and trisomy 21 mosaicism in Alzheimer’s disease. Neurobiol Dis 6(3):167–179

    Article  CAS  PubMed  Google Scholar 

  • Ghavami S, Shojaei S, Yeganeh B, Jangamreddy JR, Mehrpour M, Christoffersson J, Chaabane W, Moghadam AR, Kashani HH, Hashemi M, Owji AA (2014) Autophagy and apoptosis dysfunction in neurodegenerative disorders. Prog Neurobiol 112:24–49

    Article  CAS  PubMed  Google Scholar 

  • Gordon PH, Moore DH, Miller RG, Florence JM, Verheijde JL, Doorish C, Hilton JF, Spitalny GM, MacArthur RB, Mitsumoto H, Neville HE, Boylan K, Mozaffar T, Belsh JM, Ravits J, Bedlack RS, Graves MC, McCluskey LF, Barohn RJ, Tandan R, Western ALS Study Group (2007) Efficacy of minocycline in patients with amyotrophic lateral sclerosis: a phase III randomised trial. Lancet Neurol 6(12):1045–1053

    Article  CAS  PubMed  Google Scholar 

  • Green DR (1998) Apoptotic pathways: the roads to ruin. Cell 94(6):695–698

    Article  CAS  PubMed  Google Scholar 

  • Hauser DN, Hastings TG (2013) Mitochondrial dysfunction and oxidative stress in Parkinson’s disease and monogenic parkinsonism. Neurobiol Dis 51:35–42

    Article  CAS  PubMed  Google Scholar 

  • Hwang O (2013) Role of oxidative stress in Parkinson’s disease. Exp Neurobiol 22(1):11–17

    Article  PubMed  PubMed Central  Google Scholar 

  • Imai Y, Lu B (2011) Mitochondrial dynamics and mitophagy in Parkinson’s disease: disordered cellular power plant becomes a big deal in a major movement disorder. Curr Opin Neurobiol 21(6):935–941

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Johri A, Beal MF (2012) Mitochondrial dysfunction in neurodegenerative diseases. J Pharmacol Exp Ther 342:619–630

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kamel F (2013) Paths from pesticides to Parkinson's. Science 341:722–723

  • Kandadai RM, Jabeen SA, Kanikannan MA, Borgohain R (2014) Safinamide for the treatment of Parkinson’s disease. Expert Rev Clin Pharmacol 7(6):747–759

    Article  CAS  PubMed  Google Scholar 

  • Keane PC, Kurzawa M, Blain PG, Morris CM (2011) Mitochondrial dysfunction in Parkinson’s disease. Parkinsons Dis 2011:716871

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kinnally KW, Antonsson B (2007) A tale of two mitochondrial channels, MAC and PTP, in apoptosis. Apoptosis 12(5):857–868

    Article  CAS  PubMed  Google Scholar 

  • Kokoszka JE, Waymire KG, Levy SE, Sligh JE, Cai J, Jones DP et al (2004) The ADP/ATP translocator is not essential for the mitochondrial permeability transition pore. Nature 427:461–465

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Krauskopf A, Eriksson O, Craigen WJ, Forte MA, Bernardi P (2006) Properties of the permeability transition in VDAC1(−/−) mitochondria. Biochim Biophys Acta 1757(5–6):590–595

    Article  CAS  PubMed  Google Scholar 

  • Krumschnabel G, Sohm B, Bock F, Manzl C, Villunger A (2009) The enigma of caspase-2: the laymen’s view. Cell Death Differ 16:195–207

    Article  CAS  PubMed  Google Scholar 

  • Kuwana T, Smith JJ, Muzio M, Dixit V, Newmeyer DD (1998) Apoptosis induction by caspase 8 is amplified through the mitochondrial release of cytochrome c. J Biol Chem 273:16589–16594

    Article  CAS  PubMed  Google Scholar 

  • Langston JW, Ballard P, Tetrud JW, Irwin I (1983) Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis. Science 219:979–980

  • Lee SM, Yune TY, Kim SJ, Kim YC, Oh YJ, Markelonis GJ, Oh TH (2004) Minocycline inhibits apoptotic cell death via attenuation of TNF-alpha expression following iNOS/NO induction by lipopolysaccharide in neuron/glia co-cultures. J Neurochem 91(3):568–578

    Article  CAS  PubMed  Google Scholar 

  • Leung AW, Halestrap AP (2008) Recent progress in elucidating the molecular mechanism of the mitochondrial permeability transition pore. Biochim Biophys Acta 1777(7–8):946–952

    Article  CAS  PubMed  Google Scholar 

  • Lezi E, Swerdlow RH (2012) Mitochondria in neurodegeneration. Adv Exp Med Biol 942:269–286

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lim KL, Ng XH, Grace G, Yao TP (2012) Mitochondrial dynamics and Parkinson’s disease: focus on parkin. Antioxid Redox Signal 16(9):935–949

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Martin LJ (2012) Biology of mitochondria in neurodegenerative diseases. Prog Mol Biol Transl Sci 107:355–415

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McCoy MK, Cookson MR (2012) Mitochondrial quality control and dynamics in Parkinson’s disease. Antioxid Redox Signal 16(9):869–882

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Moon HE, Paek SH (2015) Mitochondrial dysfunction in Parkinson’s disease. Exp Neurobiol 24(2):103–116

    Article  PubMed  PubMed Central  Google Scholar 

  • Müller T (2013) Current status of safinamide for the drug portfolio of Parkinson’s disease therapy. Expert Rev Neurother 13(9):969–977

    Article  PubMed  Google Scholar 

  • Norenberg MD, Rao KV (2007) The mitochondrial permeability transition in neurologic disease. Neurochem Int 50(7–8):983–997

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nuytemans K, Theuns J, Cruts M, Van Broeckhoven C (2010) Genetic etiology of Parkinson disease associated with mutations in the SNCA, PARK2, PINK1, PARK7, and LRRK2 genes: a mutation update. Hum Mutat 31(7):763–780

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Obeso JA, Rodriguez-Oroz MC, Goetz CG, Marin C, Kordower JH, Rodriguez M, Hirsch EC, Farrer M, Schapira AH, Halliday G (2010) Missing pieces in the Parkinson’s disease puzzle. Nat Med 16(6):653–661

    Article  CAS  PubMed  Google Scholar 

  • Oliveira JM (2010) Nature and cause of mitochondrial dysfunction in Huntington’s disease: focusing on huntingtin and the striatum. J Neurochem 114(1):1–12

    CAS  PubMed  Google Scholar 

  • Parvez S, Winkler-Stuck K, Hertel S, Schönfeld P, Siemen D (2010) The dopamine-D2-receptor agonist ropinirole dose-dependently blocks the Ca2+-triggered permeability transition of mitochondria. Biochim Biophys Acta 1797(6–7):1245–1250

    Article  CAS  PubMed  Google Scholar 

  • Pezzolin G, Cereda E (2013) Exposure to pesticides or solvents and risk of Parkinson disease. Neurology 80(22):2035–2041

    Article  Google Scholar 

  • Rasola A, Bernardi P (2011) Mitochondrial permeability transition in Ca(2+)-dependent apoptosis and necrosis. Cell Calcium 50(3):222–233

    Article  CAS  PubMed  Google Scholar 

  • Reddy PH, Reddy TP (2011) Mitochondria as a therapeutic target for aging and neurodegenerative diseases. Curr Alzheimer Res 8(4):393–409

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rodrigues CM, Solá S, Brito MA, Brondino CD, Brites D, Moura JJ (2001) Amyloid beta-peptide disrupts mitochondrial membrane lipid and protein structure: protective role of tauroursodeoxycholate. Biochem Biophys Res Commun 281(2):468–474

    Article  CAS  PubMed  Google Scholar 

  • Ross CA, Pantelyat A, Kogan J, Brandt J (2014) Determinants of functional disability in Huntington’s disease: role of cognitive and motor dysfunction. Mov Disord 29(11):1351–1358

    Article  PubMed  PubMed Central  Google Scholar 

  • Sadeghian M, Mullali G, Pocock JM, Piers T, Roach A, Smith KJ (2015). Neuroprotection by safinamide in the 6-hydroxydopamine model of Parkinson’s disease. Neuropathol Appl Neurobiol.

  • Sanders LH, Greenamyre JT (2013) Oxidative damage to macromolecules in human Parkinson disease and the rotenone model. Free Radic Biol Med 62:111–120

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sayeed I, Parvez S, Winkler-Stuck K, Seitz G, Trieu I, Wallesch CW, Schönfeld P, Siemen D (2006) Patch clamp reveals powerful blockade of the mitochondrial permeability transition pore by the D2-receptor agonist pramipexole. FASEB J 20(3):556–558

  • Schapira AH, Jenner P (2011) Etiology and pathogenesis of Parkinson’s disease. Mov Disord 26(6):1049–1055

    Article  PubMed  Google Scholar 

  • Schönfeld P, Siemen D, Kreutzmann P, Franz C, Wojtczak L (2013) Interaction of the antibiotic minocycline with liver mitochondria—role of membrane permeabilization in the impairment of respiration. FEBS J 280(24):6589–6599

    Article  PubMed  Google Scholar 

  • Silindir M, Ozer AY (2014) The benefits of pramipexole selection in the treatment of Parkinson’s disease. Neurol Sci 35(10):1505–1511

    Article  PubMed  Google Scholar 

  • Slee EA, Adrain C, Martin SJ (2001) Executioner caspase-3, -6, and -7 perform distinct, non-redundant roles during the demolition phase of apoptosis. J Biol Chem 276(10):7320–7326

    Article  CAS  PubMed  Google Scholar 

  • Stelzer AC, Frazee RW, Van HC, Cleary J, Opipari AW Jr, Glick GD et al (2010) NMR studies of an immunomodulatory benzodiazepine binding to its molecular target on the mitochondrial F1F0-ATPase. Biopolymers 93:85–92

    Article  CAS  PubMed  Google Scholar 

  • Stennicke HR, Salvesen GS (2000) Caspases —controlling intracellular signals by protease zymogen activation. Biochim Biophys Acta 1477:299–306

    Article  CAS  PubMed  Google Scholar 

  • Taetzsch T, Block ML (2013) Pesticides, microglial NOX2, and Parkinson’s disease. J Biochem Mol Toxicol 27(2):137–149

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tan LCS (2013) Epidemiology of Parkinson’s disease. Neurology Asia 18(3):231–238

    Google Scholar 

  • Thomas M, Le WD (2004) Minocycline: neuroprotective mechanisms in Parkinson's disease. Curr Pharm 10(6):679–686

  • Vianello A, Casolo V, Petrussa E, Peresson C, Patui S, Bertolini A, Passamonti S, Braidot E, Zancani M (2012) The mitochondrial permeability transition pore (PTP)—an example of multiple molecular exaptation? Biochim Biophys Acta 1817(11):2072–2086

    Article  CAS  PubMed  Google Scholar 

  • Vila M, Ramonet D, Perier C (2008) Mitochondrial alterations in Parkinson’s disease: new clues. J Neurochem 107(2):317–328

    Article  CAS  PubMed  Google Scholar 

  • Weinreb O, Amit T, Bar-Am O, Youdim MB (2010) Rasagiline: a novel anti-Parkinsonian monoamine oxidase-B inhibitor with neuroprotective activity. Prog Neurobiol 92(3):330–344

    Article  CAS  PubMed  Google Scholar 

  • Williams AC, Cartwright LS, Ramsden DB (2005) Parkinson’s disease: the first common neurological disease due to auto-intoxication? QJM 98(3):215–226

    Article  CAS  PubMed  Google Scholar 

  • Winklhofer KF, Haass C (2010) Mitochondrial dysfunction in Parkinson’s disease. Biochim Biophys Acta 802:29–4

    Article  Google Scholar 

  • Wolf BB, Green DR (1999) Suicidal tendencies: apoptotic cell death by caspase family proteinases. J Biol Chem 29:20049–20052

    Article  Google Scholar 

  • Youdim MB, Bar O, Yogev-Falach M, Weinreb O, Maruyama W, Naoi M, Amit T (2005) Rasagiline: neurodegeneration, neuroprotection, and mitochondrial permeability transition. J Neurosci Res 79(1–2):172–179

    Article  CAS  PubMed  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) Minocycline inhibits cytochrome c release and delays progression of amyotrophic lateral sclerosis in mice. Nature 417(6884):74–78

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The Grant (No. F. 30-1/2013(SA-II)/RA-2012-14-GE-WES-2400), received as Research Award (2012–14) from the University Grants Commission (UGC), New Delhi, Government of India, to Dr. Suhel Parvez, is thankfully acknowledged. Dr. Heena Tabassum is grateful to the Department of Biotechnology, Government of India, for the financial grant (DBT BioCARe Program, sanction no. BT/Bio-CARe/01/10219/2013-14). The Alexander von Humboldt Foundation, Germany, is also acknowledged for the Equipment Grant awarded to Dr. Suhel Parvez. The Department of Biotechnology, Government of India is also acknowledged for providing Junior Research Fellowship to Md Zeeshan Rasheed (DBT/JRF/14/AL/199).

Author information

Author notes

    Authors and Affiliations

    1. Department of Medical Elementology and Toxicology, Jamia Hamdard (Hamdard University), New Delhi, 110 062, India

      Md Zeeshan Rasheed, Heena Tabassum & Suhel Parvez

    2. Department of Biochemistry, Jamia Hamdard (Hamdard University), New Delhi, 110 062, India

      Heena Tabassum

    Authors
    1. Md Zeeshan Rasheed
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Heena Tabassum
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Suhel Parvez
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Suhel Parvez.

    Ethics declarations

    Conflict of interest

    The authors declare that they have no competing interests.

    Additional information

    Handling Editor: Reimer Stick

    Md Zeeshan Rasheed and Heena Tabassum contributed equally to this work.

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Rasheed, M.Z., Tabassum, H. & Parvez, S. Mitochondrial permeability transition pore: a promising target for the treatment of Parkinson’s disease. Protoplasma 254, 33–42 (2017). https://doi.org/10.1007/s00709-015-0930-2

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s00709-015-0930-2

    Keywords

    Search

    Navigation