Top

Published in:

01-10-2015 | Translational Neurosciences - Original Article

Rasagiline and selegiline suppress calcium efflux from mitochondria by PK11195-induced opening of mitochondrial permeability transition pore: a novel anti-apoptotic function for neuroprotection

Authors: Yuqiu Wu, Kimiko Kazumura, Wakako Maruyama, Toshihiko Osawa, Makoto Naoi

Published in: Journal of Neural Transmission | Issue 10/2015

Abstract

Rasagiline and selegiline, inhibitors of type B monoamine oxidase (MAO-B), protect neurons from cell death in cellular and animal models. Suppression of mitochondrial membrane permeabilization and subsequent activation of apoptosis cascade, and induction of anti-apoptotic, pro-survival genes are proposed to contribute the anti-apoptotic function. Rasagiline suppresses neurotoxin- and oxidative stress-induced membrane permeabilization in isolated mitochondria, but the mechanism has been not fully clarified. In this paper, regulation of the mitochondrial permeability transition pore by rasagiline and selegiline was examined in apoptosis induced by PK11195, a ligand of the outer membrane translocator protein 18 kDa (TSPO) in SH-SY5Y cells. The pore opening was quantitatively measured using a simultaneous monitoring system for calcium (Ca²⁺) and superoxide (O₂ ⁻) (Ishibashi et al. in Biochem Biophys Res Commun 344:571–580, 2006). The association of the pore opening with Ca²⁺ efflux and ROS increase was proved by the inhibition of Bcl-2 overexpression and cyclosporine A treatment. Potency to release Ca²⁺ was correlated with the cytotoxicity of TSPO antagonists, PK11195, FGIN-1-27 and protoporphyrin IX, whereas a TSPO agonist, 4-chloro-diazepamine, did not significantly increase Ca²⁺ or cause cell death. Rasagiline and selegiline inhibited mitochondrial Ca²⁺ efflux through the mitochondrial permeability transition pore dose dependently. Ca²⁺ efflux was confirmed as the initial signal in mitochondrial apoptotic cascade, and the suppression of Ca²⁺ efflux may account for the neuroprotective function of rasagiline and selegiline. The quantitative measurement of Ca²⁺ efflux can be applied to determine anti-apoptotic activity of neuroprotective compounds. The role of mitochondrial Ca²⁺ release in neuronal death and also in neuroprotection by MAO-B inhibitors is discussed.

Akao Y, Maruyama W, Shimizu S, Yi H, Shamoto-Nagai M et al (2002) Mitochondrial permeability transition mediates apoptosis induced by N-methyl(R)salsolinol, an endogenous neurotoxin, and its inhibited by Bcl-2 and rasagiline, N-propargyl-1(R)-aminoindan. J Neurochem 82:913–923CrossRefPubMed

Azarashvili T, Grachev G, Krestinina O, Evtodienko Y, Yurkov I et al (2007) The peripheral-type benzodiazepine receptor is involved in control of Ca²⁺-induced permeability transition pore opening in rat brain mitochondria. Cell Calcium 42:27–39CrossRefPubMed

Baumgartner HK, Gerasimenko JV, Thorne C, Ferdek P, Pozzan T et al (2009) Calcium elevation in mitochondria is requirement for mitochondrial permeability transition pore (mPTP) opening. J Biol Chem 284:20796–20803PubMedCentralCrossRefPubMed

Bernardi P (1996) The permeability transition pore. Control of a cyclosporine A-sensitive mitochondrial channel involved in cell death. Biochim Biophys Acta 1275:5–9CrossRefPubMed

Bernardi P, von Stockum S (2012) The permeability transition pore as a Ca²⁺ channel: new answers to an old question. Cell Calcium 52:22–27PubMedCentralCrossRefPubMed

Bezprozvanny I, Mattson MP (2008) Neuronal calcium mishandling and the pathogenesis of Alzheimer’s disease. Trends Neurosci 31:454–463PubMedCentralCrossRefPubMed

Bonora M, Bononi A, De Marchi E, Giorgi C, Lebiedzinski M et al (2013) Role of the c subunit of the FO ATP synthase in mitochondrial permeability transition. Cell Cycle 12:674–683PubMedCentralCrossRefPubMed

Brenner C, Moulin M (2012) Physiological roles of the permeability transition pore. Circ Res 111:1222–1236CrossRef

Burke RT (2007) Programmed cell death in Parkinson’s disease. In: Koller WC, Melamed E (eds) Handbook of clinical neurology, Parkinson’s disease and related disorders, Part I, vol 83. Elsevier, Amsterdam, pp 591–605

Cassarino DS, Parks JK, Parker WD Jr, Bennett JP Jr (1999) The parkinsonian neurotoxin MPP⁺ opens the mitochondrial permeability transition pore and releases cytochrome c in isolated mitochondria via an oxidative mechanism. Biochim Biophys Acta 1453:49–62CrossRefPubMed

Chan CS, Guzman JN, Illijic E, Mercer JN, Rick C et al (2007) ‘Rejuvenation’ protects neurons in mouse models of Parkinson’s disease. Nature 447:1081–1086CrossRefPubMed

Chan CS, Gertler TS, Surmeier DJ (2009) Calcium homeostasis, selective vulnerability and Parkinson’s disease. Trends Neurosci 32:249–256CrossRefPubMed

Costantini P, Chernyak BV, Petronilli V, Berneardi P (1995) Selective inhibition of the mitochondrial permeability transition pore at the oxidation–reduction sensitive dithiol by monobromobimane. FEBS Lett 362:239–242CrossRefPubMed

Costantini P, Colonna R, Bernardi P (1998) Induction of the mitochondrial permeability transition by N-ethylmaleimide depends on secondary oxidation of critical thiol groups. Potentiation by copper-ortho-phenanthroline without dimerization of the adenine nucleotide translocator. Biochim Biophys Acta 1365:385–392CrossRefPubMed

Czerniczyniec A, Bustamante J, Lores-Arnaiz S (2006) Modulation of brain mitochondrial function by deprenyl. Neurochem Int 48:235–241CrossRefPubMed

Czerniczyniec A, Bustamante J, Lores-Arnaiz S (2007) Improvement of mouse brain mitochondrial function after deprenyl treatment. Neuroscience 144:685–693CrossRefPubMed

De Marchi U, Piertrangeli P, Marcocci L, Mondovi B, Toninello A (2003) l-Deprenyl as an inhibitor of menadione-induced permeability transition in liver mitochondria. Biochem Pharmacol 66:1749–1754CrossRefPubMed

Duchen MR (2012) Mitochondria, calcium-dependent neuronal death and neurodegenerative disease. Pfugers Arch Eur J Physiol 464:111–121CrossRef

Ebadi M, Brown-Borg H, Ren J, Sharma S, Shavali S, ReFacy HE, Carlson EC (2006) Therapeutic efficacy of selegiline in neurodegenerative disorders and neurological diseases. Curr Drug Targets 7:1513–1529CrossRefPubMed

Eriksson O, Fontaine E, Petronilli V, Bernardi P (1997) Inhibition of the mitochondrial cyclosporine A-sensitive permeability transition pore by the arginine reagent phenylglyoxal. FEBS Lett 409:361–364CrossRefPubMed

Fedrizzi L, Carafoli E (2011) Ca²⁺ dysfunction in neurodegenerative disorders: Alzheimer’s disease. BioFactors 37:189–196CrossRefPubMed

Friberg H, Wieloch T (2002) Mitochondrial permeability transition in acute neurodegeneration. Biochimie 84:241–250CrossRefPubMed

Galluzzi L, Zamzami N, Rouge T, Lemaire C, Brenner C, Kroemer G (2007) Methods for the assessment of mitochondrial permeabilization in apoptosis. Apoptosis 12:803–813CrossRefPubMed

Giacomello M, Oliveros JC, Naranjo JR, Carafoli E (2013) Neuronal Ca²⁺ dyshomeostasis in Huntington disease. Prion 7:76–84PubMedCentralCrossRefPubMed

Giorgi C, Baldassari F, Bononi A, Bononi M, Marchi ED et al (2012) Mitochondrial Ca²⁺ and apoptosis. Cell Calcium 52:36–43PubMedCentralCrossRefPubMed

Halestrap AP, Brenner C (2003) The adenine nucleotide transporter: a central component of the mitochondrial permeability transition pore and key player in cell death. Curr Med Chem 10:1507–1525CrossRefPubMed

Inaba-Hasegawa K, Akao Y, Maruyama W, Naoi M (2012) Type A monoamine oxidase is associated with induction of neuroprotective Bcl-2 by rasagiline, an inhibitor of type B monoamine oxidase. J Neural Transm 119:405–414CrossRefPubMed

Ishibashi K, Okazaki S, Hiramatsu M (2006) Simultaneous measurement of superoxide generation and intracellular Ca²⁺ concentration reveals the effect of extracellular Ca²⁺ on rapid and transient contents of superoxide generation in differentiated THP-1 cells. Biochem Biophys Res Commun 344:571–580CrossRefPubMed

Kaludercic N, Carpi A, Manabo R, Lisa FD, Paolocci N (2011) Monoamine oxidase (MAO) in the pathogenesis of heart failure and ischemia/reperfusion injury. Biochim Biophys Acta 1813:1323–1332PubMedCentralCrossRefPubMed

Kazumura K, Sato Y, Satozono H, Koike T, Tsuchiya H et al (2013) Simultaneous monitoring of superoxides and intracellular calcium ions in neutrophils by chemiluminescence: evaluation of action mechanisms of bioactive compounds in foods. J Pharm Biomed Anal 84:90–96CrossRefPubMed

Kroemer G, Galluzzi L, Brenner C (2007) Mitochondrial membrane permeabilization in cell death. Physiol Rev 87:99–163CrossRefPubMed

Kwong JQ, Davis J, Baines CP, Sargent MA, Karch J et al (2014) Genetic deletion of the mitochondrial phosphate carrier desensitizes the mitochondrial permeability transition pore and causes cardiomyopathy. Cell Death Differ 21:1209–1217PubMedCentralCrossRefPubMed

Leung AWC, Varanyuwatan 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 283:26312–26323PubMedCentralCrossRefPubMed

Magyar K (2011) Pharmacology of selegiline. Int Rev Neurobiol 100:65–84CrossRefPubMed

Martin LJ, Adams NA, Pan Y, Price A, Wong M (2011) The mitochondrial permeability transition pore regulates nitric oxide-mediated apoptosis of neurons induced by target deprivation. J Neurosci 31:359–370PubMedCentralCrossRefPubMed

Maruyama W, Naoi M (2013) “70th Birthday Professor Riederer”. Induction of glial cell-line-derived and brain-derived neurotrophic factors by rasagiline and (−)deprenyl: a way to a disease-modifying therapy? J Neural Transm 120:83–89CrossRefPubMed

Maruyama W, Akao Y, Youdim MBH, Davis BA, Naoi M (2001) Transfection-enforced Bcl-2 overexpression and an anti-Parkinson drug, rasagiline, prevent nuclear accumulation of glyceraldehyde-3-phosphate dehydrogenase induced by an endogenous dopaminergic neurotoxin, N-methyl(R)salsolinol. J Neurochem 78:727–735CrossRefPubMed

Naoi M, Maruyama W (2009) Functional mechanism of neuroprotection by inhibitors of type B monoamine oxidase in Parkinson’s disease. Expert Rev Neurother 9:1233–1250CrossRefPubMed

Naoi M, Maruyama W (2010) Monoamine oxidase inhibitors as neuroprotective agents in age-dependent neurodegenerative disorders. Curr Pharm Design 16:2799–2817CrossRef

Naoi M, Maruyama W, Akao Y, Yamaoka Y (2006) Involvement of type A monoamine oxidase in neurodegeneration: regulation of mitochondrial signaling leading to cell death or neuroprotection. J Neural Transm Suppl 71:67–77CrossRefPubMed

Naoi M, Maruyama W, Inaba-Hasegawa K (2013a) Revelation in neuroprotective functions of rasagiline and selegiline: the induction of distinct genes by different mechanisms. Expert Rev Neurother 13:671–684CrossRefPubMed

Naoi M, Maruyama W, Yi H (2013b) Rasagiline prevents apoptosis induced by PK11195, a ligand of the outer membrane translocator protein (18 kDa), in SH-SY5Y cells through suppression of cytochrome c release from mitochondria. J Neural Transm 120:1539–1551CrossRefPubMed

Orrenius S, Zhivotovsky B, Nicotera P (2003) Regulation of cell death: the calcium-apoptosis link. Nat Rev Mol Cell Biol 4:552–565CrossRefPubMed

Park D, Chiu J, Perrone GG, Dilda PJ, Hogg PJ (2012) The tumor metabolism inhibitors GSAO and PENAO react with cysteines 57 and 257 of mitochondrial adenine nucleotide translocator. Cancer Cell Int 12:11PubMedCentralCrossRefPubMed

Riederer P, Lachensmayer L, Laux G (2004) Clinical applications of MAO-inhibitors. Curr Med Chem 11:2033–2043CrossRefPubMed

Sorato E, Menazza S, Zulian A, Sabatelli P, Gualandi F et al (2014) Monoamine oxidase inhibition prevents mitochondrial dysfunction and apoptosis in myoblasts from patients with collagen VI myopathy. Free Rad Biol Med 75:40–47PubMedCentralCrossRefPubMed

Striessnig J, Koschak A, Sinnegger-Brauns MJ, Hetezenauer A, Nguyen NK et al (2006) Role of voltage-gated L-type Ca²⁺ channel isoforms for brain function. Biochem Soc Trans 34:903–909CrossRefPubMed

Tatton WG, Chalmers-Redman RM, Ju WJ, Mammen M, Carlile GW et al (2002) Propargylamines induce antiapoptotic new protein synthesis in serum- and nerve growth factor (NGF)-withdrawn, NGF-differentiated PC-12 cells. J Pharmacol Exp Ther 301:753–764CrossRefPubMed

Vaarmann A, Gandhi S, Abramov AY (2010) Dopamine induces Ca²⁺ signaling in astrocytes through reactive oxygen species generated by monoamine oxidase. J Biol Chem 285:25018–25023PubMedCentralCrossRefPubMed

Vay L, Hernandez-SanMiguel E, Lobaton CD, Moreno A, Montero M, Alzarez J (2009) Mitochondrial free [Ca²⁺] levels and the permeability transition. Cell Calcium 45:243–250CrossRefPubMed

Vila M, Przedborski S (2003) Targeting programmed cell death in neurodegenerative diseases. Nat Rev Neurosci 4:1–11CrossRef

Wadia JS, Chalmers-Redman RME, Ju WJH, Carilile GW, Phillips JL et al (1998) Mitochondrial membrane potential and nuclear changes in apoptosis caused by serum and nerve growth factor withdrawal: time course and modification by (−)-deprenyl. J Neurosci 8:932–957

Wang W, Fang H, Groom L, Cheng A, Zhang W et al (2008) Superoxide flashes in single mitochondria. Cell 134:279–290PubMedCentralCrossRefPubMed

Weinreb O, Amit T, Bar-Am O, Sagi Y, Mandel S, Youdim MB (2009) Involvement of multiple survival signal transduction pathways in the neuroprotective, neurorescue and APP processing activity of rasagiline and its propargyl moiety. J Neural Transm Suppl 70:457–465CrossRef

Wu Y, Osawa T, Kazumura K, Maruyama W, Naoi M (2015) Anti-apoptotic function of astaxanthin: prevention of mitochondrial permeability transition pore opening (in preparation)

Youdim MBH, Edmondson D, Tipton KF (2006) The therapeutic potential of monoamine oxidase inhibitors. Nat Rev Neurosci 7:295–309CrossRefPubMed

Title: Rasagiline and selegiline suppress calcium efflux from mitochondria by PK11195-induced opening of mitochondrial permeability transition pore: a novel anti-apoptotic function for neuroprotection
Authors: Yuqiu Wu
Kimiko Kazumura
Wakako Maruyama
Toshihiko Osawa
Makoto Naoi
Publication date: 01-10-2015
Publisher: Springer Vienna
Published in: Journal of Neural Transmission / Issue 10/2015
Print ISSN: 0300-9564
Electronic ISSN: 1435-1463
DOI: https://doi.org/10.1007/s00702-015-1398-0

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Rasagiline and selegiline suppress calcium efflux from mitochondria by PK11195-induced opening of mitochondrial permeability transition pore: a novel anti-apoptotic function for neuroprotection

Abstract

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 10/2015

Comparison of I-123 MIBG planar imaging and SPECT for the detection of decreased heart uptake in Parkinson disease

Heart rate variability shows different cardiovascular modulation in Parkinson’s disease patients with tremor dominant subtype compared to those with akinetic rigid dominant subtype

Glucose regulates amyloid β production via AMPK

Comparative quantitative study of ‘signature’ pathological lesions in the hippocampus and adjacent gyri of 12 neurodegenerative disorders

Assessment of the degree of asymmetry of pathological features in neurodegenerative diseases. What is the significance for brain banks?

Relevance of sonography for botulinum toxin treatment of cervical dystonia: an expert statement