Mitochondrial dysfunction in Parkinson’s disease: a possible target for neuroprotection

Abstract

Mitochondria are dynamic organelles which are required for maintaining cellular homeostasis. Thus, it is not surprising that irregularities in mitochondrial function result in cellular damage and are linked with neurodegenerative diseases, such as Parkinson’s disease. Evidence that mitochondrial dysfunction is key to the pathogenesis of Parkinson’s disease is founded in studies in post-mortem tissue from patients with Parkinson’s disease, and also from genetic studies stemming from patients with familial Parkinson’s disease. Whether triggered by environmental or genetic factors, mitochondrial dysfunction occurs early in the pathogenic process, and is central to Parkinson’s disease pathology. As such, targeting the mitochondria to slow or halt disease progression is an attractive strategy for disease-modifying agents in Parkinson’s disease. Indeed, several therapies which target the mitochondria have been investigated as neuroprotective treatments for Parkinson’s disease. This review will discuss the evidence supporting mitochondrial dysfunction in Parkinson’s disease pathology as well as treatment strategies that target the mitochondria.

Keywords

Parkinson’s disease / mitochondria / oxidative stress / lysosome / UPS

References

[1] Albani D, Polito L, Batelli S, De Mauro S, Fracasso C, Martelli G, Colombo L, Manzoni C, Salmona M, Caccia S, Negro A, Forloni G (2009). The SIRT1 activator resveratrol protects SK-N-BE cells from oxidative stress and against toxicity caused by alpha-synuclein or amyloid-beta (1-42) peptide. J Neurochem, 110(5): 1445–1456

[2] Andres R H, Huber A W, Schlattner U, Pérez-Bouza A, Krebs S H, Seiler R W, Wallimann T, Widmer H R (2005). Effects of creatine treatment on the survival of dopaminergic neurons in cultured fetal ventral mesencephalic tissue. Neuroscience, 133(3): 701–713

[3] Andres-Mateos E, Perier C, Zhang L, Blanchard-Fillion B, Greco T M, Thomas B, Ko H S, Sasaki M, Ischiropoulos H, Przedborski S, Dawson T M, Dawson V L (2007). DJ-1 gene deletion reveals that DJ-1 is an atypical peroxiredoxin-like peroxidase. Proc Natl Acad Sci USA, 104(37): 14807–14812

[4] Bedford L, Hay D, Devoy A, Paine S, Powe D G, Seth R, Gray T, Topham I, Fone K, Rezvani N, Mee M, Soane T, Layfield R, Sheppard P W, Ebendal T, Usoskin D, Lowe J, Mayer R J(2008). Depletion of 26S proteasomes in mouse brain neurons causes neurodegeneration and Lewy-like inclusions resembling human pale bodies. J Neurosci, 28: 8189–8198

[5] Beher D, Wu J, Cumine S, Kim K W, Lu S C, Atangan L, Wang M (2009). Resveratrol is not a direct activator of SIRT1 enzyme activity. Chem Biol Drug Des, 74(6): 619–624

[6] Bender A, Krishnan K J, Morris C M, Taylor G A, Reeve A K, Perry R H, Jaros E, Hersheson J S, Betts J, Klopstock T, Taylor R W, Turnbull D M (2006). High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease. Nat Genet, 38(5): 515–517

[7] Bernheimer H, Birkmayer W, Hornykiewicz O, Jellinger K, Seitelberger F (1973). Brain dopamine and the syndromes of Parkinson and Huntington. Clinical, morphological and neurochemical correlations. J Neurol Sci, 20(4): 415–455

[8] Blackinton J, Lakshminarasimhan M, Thomas K J, Ahmad R, Greggio E, Raza A S, Cookson M R, Wilson M A (2009). Formation of a stabilized cysteine sulfinic acid is critical for the mitochondrial function of the parkinsonism protein DJ-1. J Biol Chem, 284(10): 6476–6485

[9] Bové J, Zhou C, Jackson-Lewis V, Taylor J, Chu Y, Rideout H J, Wu D C, Kordower J H, Petrucelli L, Przedborski S (2006). Proteasome inhibition and Parkinson’s disease modeling. Ann Neurol, 60(2): 260–264

[10] Brunet A, Sweeney L B, Sturgill J F, Chua K F, Greer P L, Lin Y, Tran H, Ross S E, Mostoslavsky R, Cohen H Y, Hu L S, Cheng H L, Jedrychowski M P, Gygi S P, Sinclair D A, Alt F W, Greenberg M E (2004). Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science, 303(5666): 2011–2015

[11] Canet-Avilés R M, Wilson M A, Miller D W, Ahmad R, McLendon C, Bandyopadhyay S, Baptista M J, Ringe D, Petsko G A, Cookson M R (2004). The Parkinson’s disease protein DJ-1 is neuroprotective due to cysteine-sulfinic acid-driven mitochondrial localization. Proc Natl Acad Sci USA, 101(24): 9103–9108

[12] Chan C S, Gertler T S, Surmeier D J(2010). A molecular basis for the increased vulnerability of substantia nigra dopamine neurons in aging and Parkinson's disease. Mov Disord, 25 (Suppl 1): S63–70

[13] Chan C S, Guzman J N, Ilijic E, Mercer J N, Rick C, Tkatch T, Meredith G E, Surmeier D J (2007). ‘Rejuvenation’ protects neurons in mouse models of Parkinson’s disease. Nature, 447(7148): 1081–1086

[14] Chao J, Yu M S, Ho Y S, Wang M, Chang R C (2008). Dietary oxyresveratrol prevents parkinsonian mimetic 6-hydroxydopamine neurotoxicity. Free Radic Biol Med, 45(7): 1019–1026

[15] Chartier-Harlin M C, Kachergus J, Roumier C, Mouroux V, Douay X, Lincoln S, Levecque C, Larvor L, Andrieux J, Hulihan M, Waucquier N, Defebvre L, Amouyel P, Farrer M, Destée A (2004). Alpha-synuclein locus duplication as a cause of familial Parkinson’s disease. Lancet, 364(9440): 1167–1169

[16] Cherra S J 3rd, Steer E, Gusdon A M, Kiselyov K, Chu C T (2013). Mutant LRRK2 elicits calcium imbalance and depletion of dendritic mitochondria in neurons. Am J Pathol, 182(2): 474–484

[17] Chinta S J, Mallajosyula J K, Rane A, Andersen J K (2010). Mitochondrial α-synuclein accumulation impairs complex I function in dopaminergic neurons and results in increased mitophagy in vivo. Neurosci Lett, 486(3): 235–239

[18] Ciron C, Lengacher S, Dusonchet J, Aebischer P, Schneider B L (2012). Sustained expression of PGC-1α in the rat nigrostriatal system selectively impairs dopaminergic function. Hum Mol Genet, 21(8): 1861–1876

[19] Clark I E, Dodson M W, Jiang C, Cao J H, Huh J R, Seol J H, Yoo S J, Hay B A, Guo M (2006). Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin. Nature, 441(7097): 1162–1166

[20] Cole N B, Murphy D D (2002). The cell biology of alpha-synuclein: a sticky problem? Neuromolecular Med, 1(2): 95–109

[21] Cookson M R (2003). Parkin’s substrates and the pathways leading to neuronal damage. Neuromolecular Med, 3(1): 1–13

[22] Couzin J (2007). Clinical research. Testing a novel strategy against Parkinson’s disease. Science, 315(5820): 1778

[23] Cuervo A M, Stefanis L, Fredenburg R, Lansbury P T, Sulzer D (2004). Impaired degradation of mutant alpha-synuclein by chaperone-mediated autophagy. Science, 305(5688): 1292–1295

[24] Dauer W, Przedborski S (2003). Parkinson’s disease: mechanisms and models. Neuron, 39(6): 889–909

[25] Devi L, Raghavendran V, Prabhu B M, Avadhani N G, Anandatheerthavarada H K (2008). Mitochondrial import and accumulation of alpha-synuclein impair complex I in human dopaminergic neuronal cultures and Parkinson disease brain. J Biol Chem, 283(14): 9089–9100

[26] Donmez G, Arun A, Chung C Y, McLean P J, Lindquist S, Guarente L(2012). SIRT1 protects against alpha-synuclein aggregation by activating molecular chaperones. J Neurosci, 32: 124–132

[27] Dorsey E R, Constantinescu R, Thompson J P, Biglan K M, Holloway R G, Kieburtz K, Marshall F J, Ravina B M, Schifitto G, Siderowf A, Tanner C M (2007). Projected number of people with Parkinson disease in the most populous nations, 2005 through 2030. Neurology, 68(5): 384–386

[28] Dryanovski D I, Guzman J N, Xie Z, Galteri D J, Volpicelli-Daley L A, Lee V M, Miller R J, Schumacker P T, Surmeier D J (2013). Calcium entry and alpha-synuclein inclusions elevate dendritic mitochondrial oxidant stress in dopaminergic neurons. J Neurosci, 33(24): 10154–10164

[29] Ekstrand M I, Terzioglu M, Galter D, Zhu S, Hofstetter C, Lindqvist E, Thams S, Bergstrand A, Hansson F S, Trifunovic A, Hoffer B, Cullheim S, Mohammed A H, Olson L, Larsson N G (2007). Progressive parkinsonism in mice with respiratory-chain-deficient dopamine neurons. Proc Natl Acad Sci USA, 104(4): 1325–1330

[30] Esteves A R, Lu J, Rodova M, Onyango I, Lezi E, Dubinsky R, Lyons K E, Pahwa R, Burns J M, Cardoso S M, Swerdlow R H (2010). Mitochondrial respiration and respiration-associated proteins in cell lines created through Parkinson’s subject mitochondrial transfer. J Neurochem, 113(3): 674–682

[31] Exner N, Lutz A K, Haass C, Winklhofer K F (2012). Mitochondrial dysfunction in Parkinson’s disease: molecular mechanisms and pathophysiological consequences. EMBO J, 31(14): 3038–3062

[32] Ferretta A, Gaballo A, Tanzarella P, Piccoli C, Capitanio N, Nico B, Annese T, Di Paola M, Dell’aquila C, De Mari M, Ferranini E, Bonifati V, Pacelli C, Cocco T (2014). Effect of resveratrol on mitochondrial function: implications in parkin-associated familiar Parkinson’s disease. Biochim Biophys Acta, 1842(7): 902–915

[33] Frye R A (2000). Phylogenetic classification of prokaryotic and eukaryotic Sir2-like proteins. Biochem Biophys Res Commun, 273(2): 793–798

[34] Fuchs J, Nilsson C, Kachergus J, Munz M, Larsson E M, Schüle B, Langston J W, Middleton F A, Ross O A, Hulihan M, Gasser T, Farrer M J (2007). Phenotypic variation in a large Swedish pedigree due to SNCA duplication and triplication. Neurology, 68(12): 916–922

[35] Gautier C A, Kitada T, Shen J (2008). Loss of PINK1 causes mitochondrial functional defects and increased sensitivity to oxidative stress. Proc Natl Acad Sci USA, 105(32): 11364–11369

[36] Gerhart-Hines Z, Rodgers J T, Bare O, Lerin C, Kim S H, Mostoslavsky R, Alt F W, Wu Z, Puigserver P (2007). Metabolic control of muscle mitochondrial function and fatty acid oxidation through SIRT1/PGC-1alpha. EMBO J, 26(7): 1913–1923

[37] Gispert S, Ricciardi F, Kurz A, Azizov M, Hoepken H H, Becker D, Voos W, Leuner K, Müller W E, Kudin A P, Kunz W S, Zimmermann A, Roeper J, Wenzel D, Jendrach M, García-Arencíbia M, Fernández-Ruiz J, Huber L, Rohrer H, Barrera M, Reichert A S, Rüb U, Chen A, Nussbaum R L, Auburger G (2009). Parkinson phenotype in aged PINK1-deficient mice is accompanied by progressive mitochondrial dysfunction in absence of neurodegeneration. PLoS ONE, 4(6): e5777

[38] Goedert M (2001). Alpha-synuclein and neurodegenerative diseases. Nat Rev Neurosci, 2(7): 492–501

[39] Goldberg M S, Fleming S M, Palacino J J, Cepeda C, Lam H A, Bhatnagar A, Meloni E G, Wu N, Ackerson L C, Klapstein G J, Gajendiran M, Roth B L, Chesselet M F, Maidment N T, Levine M S, Shen J (2003). Parkin-deficient mice exhibit nigrostriatal deficits but not loss of dopaminergic neurons. J Biol Chem, 278(44): 43628–43635

[40] Gómez-Sánchez R, Gegg M E, Bravo-San Pedro J M, Niso-Santano M, Alvarez-Erviti L, Pizarro-Estrella E, Gutiérrez-Martín Y, Alvarez-Barrientos A, Fuentes J M, González-Polo R A, Schapira A H (2014). Mitochondrial impairment increases FL-PINK1 levels by calcium-dependent gene expression. Neurobiol Dis, 62: 426–440

[41] González-Polo R, Niso-Santano M, Morán J M, Ortiz-Ortiz M A, Bravo-San Pedro J M, Soler G, Fuentes J M (2009). Silencing DJ-1 reveals its contribution in paraquat-induced autophagy. J Neurochem, 109(3): 889–898

[42] Good C H, Hoffman A F, Hoffer B J, Chefer V I, Shippenberg T S, Backman C M, Larsson N G, Olson L, Gellhaar S, Galter D, Lupica C R(2011). Impaired nigrostriatal function precedes behavioral deficits in a genetic mitochondrial model of Parkinson's disease. FASEB J, 25:1333–1344

[43] Greenamyre J T, Betarbet R, Sherer T B (2003). The rotenone model of Parkinson’s disease: genes, environment and mitochondria. Parkinsonism Relat Disord, 9(Suppl 2): S59–S64

[44] Greene J C, Whitworth A J, Kuo I, Andrews L A, Feany M B, Pallanck L J (2003). Mitochondrial pathology and apoptotic muscle degeneration in Drosophila parkin mutants. Proc Natl Acad Sci USA, 100(7): 4078–4083

[45] Greggio E, Jain S, Kingsbury A, Bandopadhyay R, Lewis P, Kaganovich A, van der Brug M P, Beilina A, Blackinton J, Thomas K J, Ahmad R, Miller D W, Kesavapany S, Singleton A, Lees A, Harvey R J, Harvey K, Cookson M R (2006). Kinase activity is required for the toxic effects of mutant LRRK2/dardarin. Neurobiol Dis, 23(2): 329–341

[46] Gu G, Reyes P E, Golden G T, Woltjer R L, Hulette C, Montine T J, Zhang J (2002). Mitochondrial DNA deletions/rearrangements in parkinson disease and related neurodegenerative disorders. J Neuropathol Exp Neurol, 61(7): 634–639

[47] Guardia-Laguarta C, Area-Gomez E, Rub C, Liu Y, Magrane J, Becker D, Voos W, Schon E A, Przedborski S(2014). alpha-Synuclein is localized to mitochondria-associated ER membranes. J Neurosc, 34: 249–259

[48] Guzman J N, Sanchez-Padilla J, Wokosin D, Kondapalli J, Ilijic E, Schumacker P T, Surmeier D J (2010). Oxidant stress evoked by pacemaking in dopaminergic neurons is attenuated by DJ-1. Nature, 468(7324): 696–700

[49] Haas R H, Nasirian F, Nakano K, Ward D, Pay M, Hill R, Shults C W (1995). Low platelet mitochondrial complex I and complex II/III activity in early untreated Parkinson’s disease. Ann Neurol, 37(6): 714–722

[50] Hayashi Y, Yoshida M, Yamato M, Ide T, Wu Z, Ochi-Shindou M, Kanki T, Kang D, Sunagawa K, Tsutsui H, Nakanishi H(2008). Reverse of age-dependent memory impairment and mitochondrial DNA damage in microglia by an overexpression of human mitochondrial transcription factor a in mice. J Neurosci, 28: 8624–8634

[51] Healy D G, Abou-Sleiman P M, Casas J P, Ahmadi K R, Lynch T, Gandhi S, Muqit M M, Foltynie T, Barker R, Bhatia K P, Quinn N P, Lees A J, Gibson J M, Holton J L, Revesz T, Goldstein D B, Wood N W (2006). UCHL-1 is not a Parkinson’s disease susceptibility gene. Ann Neurol, 59(4): 627–633

[52] Höglinger G U, Carrard G, Michel P P, Medja F, Lombès A, Ruberg M, Friguet B, Hirsch E C (2003). Dysfunction of mitochondrial complex I and the proteasome: interactions between two biochemical deficits in a cellular model of Parkinson’s disease. J Neurochem, 86(5): 1297–1307

[53] Howitz K T, Bitterman K J, Cohen H Y, Lamming D W, Lavu S, Wood J G, Zipkin R E, Chung P, Kisielewski A, Zhang L L, Scherer B, Sinclair D A (2003). Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature, 425(6954): 191–196

[54] Ikebe S, Tanaka M, Ozawa T (1995). Point mutations of mitochondrial genome in Parkinson’s disease. Brain Res Mol Brain Res, 28(2): 281–295

[55] Imai Y, Soda M, Takahashi R (2000). Parkin suppresses unfolded protein stress-induced cell death through its E3 ubiquitin-protein ligase activity. J Biol Chem, 275(46): 35661–35664

[56] Inden M, Taira T, Kitamura Y, Yanagida T, Tsuchiya D, Takata K, Yanagisawa D, Nishimura K, Taniguchi T, Kiso Y, Yoshimoto K, Agatsuma T, Koide-Yoshida S, Iguchi-Ariga S M, Shimohama S, Ariga H (2006). PARK7 DJ-1 protects against degeneration of nigral dopaminergic neurons in Parkinson’s disease rat model. Neurobiol Dis, 24(1): 144–158

[57] Irrcher I, Aleyasin H, Seifert E L, Hewitt S J, Chhabra S, Phillips M, Lutz A K, Rousseaux M W, Bevilacqua L, Jahani-Asl A, Callaghan S, MacLaurin J G, Winklhofer K F, Rizzu P, Rippstein P, Kim R H, Chen C X, Fon E A, Slack R S, Harper M E, McBride H M, Mak T W, Park D S (2010). Loss of the Parkinson’s disease-linked gene DJ-1 perturbs mitochondrial dynamics. Hum Mol Genet, 19(19): 3734–3746

[58] Itier J M, Ibanez P, Mena M A, Abbas N, Cohen-Salmon C, Bohme G A, Laville M, Pratt J, Corti O, Pradier L, Ret G, Joubert C, Periquet M, Araujo F, Negroni J, Casarejos M J, Canals S, Solano R, Serrano A, Gallego E, Sanchez M, Denefle P, Benavides J, Tremp G, Rooney T A, Brice A, Garcia de Yebenes J (2003). Parkin gene inactivation alters behaviour and dopamine neurotransmission in the mouse. Hum Mol Genet, 12(18): 2277–2291

[59] Jin F, Wu Q, Lu Y F, Gong Q H, Shi J S (2008). Neuroprotective effect of resveratrol on 6-OHDA-induced Parkinson’s disease in rats. Eur J Pharmacol, 600(1-3): 78–82

[60] Juhn M S, Tarnopolsky M(1998). Oral creatine supplementation and athletic performance: a critical review. Clin J Sport Med, 8: 286–297

[61] Kakefuda K, Fujita Y, Oyagi A, Hyakkoku K, Kojima T, Umemura K, Tsuruma K, Shimazawa M, Ito M, Nozawa Y, Hara H (2009). Sirtuin 1 overexpression mice show a reference memory deficit, but not neuroprotection. Biochem Biophys Res Commun, 387(4): 784–788

[62] Katzenschlager R, Lees A J (2002). Treatment of Parkinson’s disease: levodopa as the first choice. J Neurol, 249(Suppl 2): II19–II24

[63] Keeney P M, Quigley C K, Dunham L D, Papageorge C M, Iyer S, Thomas R R, Schwarz K M, Trimmer P A, Khan S M, Portell F R, Bergquist K E, Bennett J P Jr (2009). Mitochondrial gene therapy augments mitochondrial physiology in a Parkinson’s disease cell model. Hum Gene Ther, 20(8): 897–907

[64] Kim R H, Smith P D, Aleyasin H, Hayley S, Mount M P, Pownall S, Wakeham A, You-Ten A J, Kalia S K, Horne P, Westaway D, Lozano A M, Anisman H, Park D S, Mak T W (2005). Hypersensitivity of DJ-1-deficient mice to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine (MPTP) and oxidative stress. Proc Natl Acad Sci USA, 102(14): 5215–5220

[65] Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y, Minoshima S, Yokochi M, Mizuno Y, Shimizu N (1998). Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature, 392(6676): 605–608

[66] Kitada T, Pisani A, Porter D R, Yamaguchi H, Tscherter A, Martella G, Bonsi P, Zhang C, Pothos E N, Shen J (2007). Impaired dopamine release and synaptic plasticity in the striatum of PINK1-deficient mice. Proc Natl Acad Sci USA, 104(27): 11441–11446

[67] Klivenyi P, Gardian G, Calingasan N Y, Yang L, Beal M F(2003). Additive neuroprotective effects of creatine and a cyclooxygenase 2 inhibitor against dopamine depletion in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease. J Mol Neurosci, MN 21: 191–198

[68] Klivenyi P, Calingasan N Y, Starkov A, Stavrovskaya I G, Kristal B S, Yang L, Wieringa B, Beal M F (2004). Neuroprotective mechanisms of creatine occur in the absence of mitochondrial creatine kinase. Neurobiol Dis, 15(3): 610–617

[69] Klivenyi P, Siwek D, Gardian G, Yang L, Starkov A, Cleren C, Ferrante R J, Kowall N W, Abeliovich A, Beal M F (2006). Mice lacking alpha-synuclein are resistant to mitochondrial toxins. Neurobiol Dis, 21(3): 541–548

[70] Kones R(2010). Mitochondrial therapy for Parkinson's disease: neuroprotective pharmaconutrition may be disease-modifying. Clin pharmacol, 2: 185–198

[71] Kordower J H, Kanaan N M, Chu Y, Suresh Babu R, Stansell J 3rd, Terpstra B T, Sortwell C E, Steece-Collier K, Collier T J (2006). Failure of proteasome inhibitor administration to provide a model of Parkinson’s disease in rats and monkeys. Ann Neurol, 60(2): 264–268

[72] Kraytsberg Y, Kudryavtseva E, McKee A C, Geula C, Kowall N W, Khrapko K (2006). Mitochondrial DNA deletions are abundant and cause functional impairment in aged human substantia nigra neurons. Nat Genet, 38(5): 518–520

[73] Krebiehl G, Ruckerbauer S, Burbulla L F, Kieper N, Maurer B, Waak J, Wolburg H, Gizatullina Z, Gellerich F N, Woitalla D, Riess O, Kahle P J, Proikas-Cezanne T, Krüger R (2010). Reduced basal autophagy and impaired mitochondrial dynamics due to loss of Parkinson’s disease-associated protein DJ-1. PLoS ONE, 5(2): e9367

[74] Krüger R, Kuhn W, Müller T, Woitalla D, Graeber M, Kösel S, Przuntek H, Epplen J T, Schöls L, Riess O (1998). Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson’s disease. Nat Genet, 18(2): 106–108

[75] Lakshminarasimhan M, Rauh D, Schutkowski M, Steegborn C (2013). Sirt1 activation by resveratrol is substrate sequence-selective. Aging (Albany NY), 5(3): 151–154

[76] Langston J W, Ballard P, Tetrud J W, Irwin I (1983). Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis. Science, 219(4587): 979–980

[77] Leroy E, Boyer R, Auburger G, Leube B, Ulm G, Mezey E, Harta G, Brownstein M J, Jonnalagada S, Chernova T, Dehejia A, Lavedan C, Gasser T, Steinbach P J, Wilkinson K D, Polymeropoulos M H (1998). The ubiquitin pathway in Parkinson’s disease. Nature, 395(6701): 451–452

[78] Li C, Beal M F (2005). Leucine-rich repeat kinase 2: a new player with a familiar theme for Parkinson’s disease pathogenesis. Proc Natl Acad Sci USA, 102(46): 16535–16536

[79] Li X, Kazgan N (2011). Mammalian sirtuins and energy metabolism. Int J Biol Sci, 7(5): 575–587

[80] Lim K L (2007). Ubiquitin-proteasome system dysfunction in Parkinson’s disease: current evidence and controversies. Expert Rev Proteomics, 4(6): 769–781

[81] Lin T K, Chen S D, Chuang Y C, Lin H Y, Huang C R, Chuang J H, Wang P W, Huang S T, Tiao M M, Chen J B, Liou C W (2014). Resveratrol partially prevents rotenone-induced neurotoxicity in dopaminergic SH-SY5Y cells through induction of heme oxygenase-1 dependent autophagy. Int J Mol Sci, 15(1): 1625–1646

[82] Liu D, Gharavi R, Pitta M, Gleichmann M, Mattson M P (2009). Nicotinamide prevents NAD⁺ depletion and protects neurons against excitotoxicity and cerebral ischemia: NAD⁺ consumption by SIRT1 may endanger energetically compromised neurons. Neuromolecular Med, 11(1): 28–42

[83] Liu G, Zhang C, Yin J, Li X, Cheng F, Li Y, Yang H, Uéda K, Chan P, Yu S (2009). alpha-Synuclein is differentially expressed in mitochondria from different rat brain regions and dose-dependently down-regulates complex I activity. Neurosci Lett, 454(3): 187–192

[84] Lu K T, Ko M C, Chen B Y, Huang J C, Hsieh C W, Lee M C, Chiou R Y, Wung B S, Peng C H, Yang Y L (2008). Neuroprotective effects of resveratrol on MPTP-induced neuron loss mediated by free radical scavenging. J Agric Food Chem, 56(16): 6910–6913

[85] Lutz A K, Exner N, Fett M E, Schlehe J S, Kloos K, Lämmermann K, Brunner B, Kurz-Drexler A, Vogel F, Reichert A S, Bouman L, Vogt-Weisenhorn D, Wurst W, Tatzelt J, Haass C, Winklhofer K F (2009). Loss of parkin or PINK1 function increases Drp1-dependent mitochondrial fragmentation. J Biol Chem, 284(34): 22938–22951

[86] Marques O, Outeiro T F (2012). Alpha-synuclein: from secretion to dysfunction and death. Cell Death Dis, 3(7): e350

[87] Matthews R T, Ferrante R J, Klivenyi P, Yang L, Klein A M, Mueller G, Kaddurah-Daouk R, Beal M F (1999). Creatine and cyclocreatine attenuate MPTP neurotoxicity. Exp Neurol, 157(1): 142–149

[88] McLelland G L, Soubannier V, Chen C X, McBride H M, Fon E A (2014). Parkin and PINK1 function in a vesicular trafficking pathway regulating mitochondrial quality control. EMBO J, 33(4): 282–295

[89] McNaught K S, Perl D P, Brownell A L, Olanow C W (2004). Systemic exposure to proteasome inhibitors causes a progressive model of Parkinson’s disease. Ann Neurol, 56(1): 149–162

[90] Minakawa E N, Yamakado H, Tanaka A, Uemura K, Takeda S, Takahashi R (2013). Chicken DT40 cell line lacking DJ-1, the gene responsible for familial Parkinson’s disease, displays mitochondrial dysfunction. Neurosci Res, 77(4): 228–233

[91] Moisoi N, Fedele V, Edwards J, Martins L M (2014). Loss of PINK1 enhances neurodegeneration in a mouse model of Parkinson’s disease triggered by mitochondrial stress. Neuropharmacology, 77: 350–357

[92] Morais V A, Haddad D, Craessaerts K, De Bock P J, Swerts J, Vilain S, Aerts L, Overbergh L, Grünewald A, Seibler P, Klein C, Gevaert K, Verstreken P, De Strooper B (2014). PINK1 loss-of-function mutations affect mitochondrial complex I activity via NdufA10 ubiquinone uncoupling. Science, 344(6180): 203–207

[93] Mortiboys H, Johansen K K, Aasly J O, Bandmann O (2010). Mitochondrial impairment in patients with Parkinson disease with the G2019S mutation in LRRK2. Neurology, 75(22): 2017–2020

[94] Mortiboys H, Thomas K J, Koopman W J, Klaffke S, Abou-Sleiman P, Olpin S, Wood N W, Willems P H, Smeitink J A, Cookson M R, Bandmann O (2008). Mitochondrial function and morphology are impaired in parkin-mutant fibroblasts. Ann Neurol, 64(5): 555–565

[95] Mudò G, Mäkelä J, Di Liberto V, Tselykh T V, Olivieri M, Piepponen P, Eriksson O, Mälkiä A, Bonomo A, Kairisalo M, Aguirre J A, Korhonen L, Belluardo N, Lindholm D (2012). Transgenic expression and activation of PGC-1α protect dopaminergic neurons in the MPTP mouse model of Parkinson’s disease. Cell Mol Life Sci, 69(7): 1153–1165

[96] Murray A M, Weihmueller F B, Marshall J F, Hurtig H I, Gottleib G L, Joyce J N (1995). Damage to dopamine systems differs between Parkinson’s disease and Alzheimer’s disease with parkinsonism. Ann Neurol, 37(3): 300–312

[97] Narendra D, Tanaka A, Suen D F, Youle R J (2008). Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J Cell Biol, 183(5): 795–803

[98] Neuspiel M, Schauss A C, Braschi E, Zunino R, Rippstein P, Rachubinski R A, Andrade-Navarro M A, McBride H M(2008). Cargo-selected transport from the mitochondria to peroxisomes is mediated by vesicular carriers. Curr Biol, CB 18: 102–108

[99] Ng C H, Mok S Z, Koh C, Ouyang X, Fivaz M L, Tan E K, Dawson V L, Dawson T M, Yu F, Lim K L(2009). Parkin protects against LRRK2 G2019S mutant-induced dopaminergic neurodegeneration in Drosophila. J Neurosci, 29: 11257–11262

[100] NINDS NET-PD Investigators (2006). A randomized, double-blind, futility clinical trial of creatine and minocycline in early Parkinson disease. Neurology, 66(5): 664–671

[101] Nishiyama S, Shitara H, Nakada K, Ono T, Sato A, Suzuki H, Ogawa T, Masaki H, Hayashi J, Yonekawa H (2010). Over-expression of Tfam improves the mitochondrial disease phenotypes in a mouse model system. Biochem Biophys Res Commun, 401(1): 26–31

[102] Niu J, Yu M, Wang C, Xu Z (2012). Leucine-rich repeat kinase 2 disturbs mitochondrial dynamics via Dynamin-like protein. J Neurochem, 122(3): 650–658

[103] Noack H, Bednarek T, Heidler J, Ladig R, Holtz J, Szibor M (2006). TFAM-dependent and independent dynamics of mtDNA levels in C2C12 myoblasts caused by redox stress. Biochim Biophys Acta, 1760(2): 141–150

[104] O’Donnell K C, Lulla A, Stahl M C, Wheat N D, Bronstein J M, Sagasti A (2014). Axon degeneration and PGC-1α-mediated protection in a zebrafish model of α-synuclein toxicity. Dis Model Mech, 7(5): 571–582

[105] Orenstein S J, Kuo S H, Tasset I, Arias E, Koga H, Fernandez-Carasa I, Cortes E, Honig L S, Dauer W, Consiglio A, Raya A, Sulzer D, Cuervo A M (2013). Interplay of LRRK2 with chaperone-mediated autophagy. Nat Neurosci, 16(4): 394–406

[106] Pacholec M, Bleasdale J E, Chrunyk B, Cunningham D, Flynn D, Garofalo R S, Griffith D, Griffor M, Loulakis P, Pabst B, Qiu X, Stockman B, Thanabal V, Varghese A, Ward J, Withka J, Ahn K (2010). SRT1720, SRT2183, SRT1460, and resveratrol are not direct activators of SIRT1. J Biol Chem, 285(11): 8340–8351

[107] Papkovskaia T D, Chau K Y, Inesta-Vaquera F, Papkovsky D B, Healy D G, Nishio K, Staddon J, Duchen M R, Hardy J, Schapira A H, Cooper J M (2012). G2019S leucine-rich repeat kinase 2 causes uncoupling protein-mediated mitochondrial depolarization. Hum Mol Genet, 21(19): 4201–4213

[108] Pardo P S, Mohamed J S, Lopez M A, Boriek A M (2011). Induction of Sirt1 by mechanical stretch of skeletal muscle through the early response factor EGR1 triggers an antioxidative response. J Biol Chem, 286(4): 2559–2566

[109] Parihar M S, Parihar A, Fujita M, Hashimoto M, Ghafourifar P (2008). Mitochondrial association of alpha-synuclein causes oxidative stress. Cell Mol Life Sci, 65(7-8): 1272–1284

[110] Park J, Kim S Y, Cha G H, Lee S B, Kim S, Chung J (2005). Drosophila DJ-1 mutants show oxidative stress-sensitive locomotive dysfunction. Gene, 361: 133–139

[111] Park J, Lee S B, Lee S, Kim Y, Song S, Kim S, Bae E, Kim J, Shong M, Kim J M, Chung J (2006). Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin. Nature, 441(7097): 1157–1161

[112] Parker W D Jr, Boyson S J, Parks J K (1989). Abnormalities of the electron transport chain in idiopathic Parkinson’s disease. Ann Neurol, 26(6): 719–723

[113] Pesah Y, Pham T, Burgess H, Middlebrooks B, Verstreken P, Zhou Y, Harding M, Bellen H, Mardon G (2004). Drosophila parkin mutants have decreased mass and cell size and increased sensitivity to oxygen radical stress. Development, 131(9): 2183–2194

[114] Ping H X, Shepard P D (1999). Blockade of SK-type Ca²⁺-activated K⁺ channels uncovers a Ca²⁺-dependent slow afterdepolarization in nigral dopamine neurons. J Neurophysiol, 81(3): 977–984

[115] Polymeropoulos M H, Lavedan C, Leroy E, Ide S E, Dehejia A, Dutra A, Pike B, Root H, Rubenstein J, Boyer R, Stenroos E S, Chandrasekharappa S, Athanassiadou A, Papapetropoulos T, Johnson W G, Lazzarini A M, Duvoisin R C, Di Iorio G, Golbe L I, Nussbaum R L (1997). Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science, 276(5321): 2045–2047

[116] Poole A C, Thomas R E, Andrews L A, McBride H M, Whitworth A J, Pallanck L J (2008). The PINK1/Parkin pathway regulates mitochondrial morphology. Proc Natl Acad Sci USA, 105(5): 1638–1643

[117] Ramirez A, Heimbach A, Gründemann J, Stiller B, Hampshire D, Cid L P, Goebel I, Mubaidin A F, Wriekat A L, Roeper J, Al-Din A, Hillmer A M, Karsak M, Liss B, Woods C G, Behrens M I, Kubisch C (2006). Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase. Nat Genet, 38(10): 1184–1191

[118] Ramonet D, Daher J P, Lin B M, Stafa K, Kim J, Banerjee R, Westerlund M, Pletnikova O, Glauser L, Yang L, Liu Y, Swing D A, Beal M F, Troncoso J C, McCaffery J M, Jenkins N A, Copeland N G, Galter D, Thomas B, Lee M K, Dawson T M, Dawson V L, Moore D J (2011). Dopaminergic neuronal loss, reduced neurite complexity and autophagic abnormalities in transgenic mice expressing G2019S mutant LRRK2. PLoS ONE, 6(4): e18568

[119] Richfield E K, Thiruchelvam M J, Cory-Slechta D A, Wuertzer C, Gainetdinov R R, Caron M G, Di Monte D A, Federoff H J (2002). Behavioral and neurochemical effects of wild-type and mutated human alpha-synuclein in transgenic mice. Exp Neurol, 175(1): 35–48

[120] Saha S, Guillily M D, Ferree A, Lanceta J, Chan D, Ghosh J, Hsu C H, Segal L, Raghavan K, Matsumoto K, Hisamoto N, Kuwahara T, Iwatsubo T, Moore L, Goldstein L, Cookson M, Wolozin B(2009). LRRK2 modulates vulnerability to mitochondrial dysfunction in Caenorhabditis elegans. J Neurosci, 29: 9210–9218

[121] Sakata E, Yamaguchi Y, Kurimoto E, Kikuchi J, Yokoyama S, Yamada S, Kawahara H, Yokosawa H, Hattori N, Mizuno Y, Tanaka K, Kato K (2003). Parkin binds the Rpn10 subunit of 26S proteasomes through its ubiquitin-like domain. EMBO Rep, 4(3): 301–306

[122] Sarafian T A, Ryan C M, Souda P, Masliah E, Kar U K, Vinters H V, Mathern G W, Faull K F, Whitelegge J P, Watson J B (2013). Impairment of mitochondria in adult mouse brain overexpressing predominantly full-length, N-terminally acetylated human α-synuclein. PLoS ONE, 8(5): e63557PMID:23667637

[123] Scarffe L A, Stevens D A, Dawson V L, Dawson T M (2014). Parkin and PINK1: much more than mitophagy. Trends Neurosci, 37(6): 315–324

[124] Schapira A H, Cooper J M, Dexter D, Jenner P, Clark J B, Marsden C D (1989). Mitochondrial complex I deficiency in Parkinson’s disease. Lancet, 1(8649): 1269

[125] Shavali S, Brown-Borg H M, Ebadi M, Porter J (2008). Mitochondrial localization of alpha-synuclein protein in alpha-synuclein overexpressing cells. Neurosci Lett, 439(2): 125–128

[126] Shimura H, Hattori N, Kubo S, Mizuno Y, Asakawa S, Minoshima S, Shimizu N, Iwai K, Chiba T, Tanaka K, Suzuki T (2000). Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase. Nat Genet, 25(3): 302–305

[127] Shin J H, Ko H S, Kang H, Lee Y, Lee Y I, Pletinkova O, Troconso J C, Dawson V L, Dawson T M (2011). PARIS (ZNF746) repression of PGC-1α contributes to neurodegeneration in Parkinson’s disease. Cell, 144(5): 689–702

[128] Simon D K, Lin M T, Zheng L, Liu G J, Ahn C H, Kim L M, Mauck W M, Twu F, Beal M F, Johns D R (2004). Somatic mitochondrial DNA mutations in cortex and substantia nigra in aging and Parkinson’s disease. Neurobiol Aging, 25(1): 71–81

[129] Snyder H, Mensah K, Theisler C, Lee J, Matouschek A, Wolozin B (2003). Aggregated and monomeric alpha-synuclein bind to the S6′ proteasomal protein and inhibit proteasomal function. J Biol Chem, 278(14): 11753–11759

[130] Song D D, Shults C W, Sisk A, Rockenstein E, Masliah E (2004). Enhanced substantia nigra mitochondrial pathology in human alpha-synuclein transgenic mice after treatment with MPTP. Exp Neurol, 186(2): 158–172

[131] Soubannier V, McLelland G L, Zunino R, Braschi E, Rippstein P, Fon E A, McBride H M(2012). A vesicular transport pathway shuttles cargo from mitochondria to lysosomes. Curr Biol, CB 22: 135–141

[132] Spillantini M G, Crowther R A, Jakes R, Hasegawa M, Goedert M (1998). alpha-Synuclein in filamentous inclusions of Lewy bodies from Parkinson’s disease and dementia with lewy bodies. Proc Natl Acad Sci USA, 95(11): 6469–6473

[133] Spillantini M G, Schmidt M L, Lee V M, Trojanowski J Q, Jakes R, Goedert M (1997). Alpha-synuclein in Lewy bodies. Nature, 388(6645): 839–840

[134] St-Pierre J, Drori S, Uldry M, Silvaggi J M, Rhee J, Jäger S, Handschin C, Zheng K, Lin J, Yang W, Simon D K, Bachoo R, Spiegelman B M (2006). Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators. Cell, 127(2): 397–408

[135] Su Y C, Qi X (2013). Inhibition of excessive mitochondrial fission reduced aberrant autophagy and neuronal damage caused by LRRK2 G2019S mutation. Hum Mol Genet, 22(22): 4545–4561

[136] Sulzer D, Zecca L (2000). Intraneuronal dopamine-quinone synthesis: a review. Neurotox Res, 1(3): 181–195

[137] Surmeier D J (2007). Calcium, ageing, and neuronal vulnerability in Parkinson’s disease. Lancet Neurol, 6(10): 933–938

[138] Surmeier D J, Guzman J N, Sanchez-Padilla J (2010). Calcium, cellular aging, and selective neuronal vulnerability in Parkinson’s disease. Cell Calcium, 47(2): 175–182

[139] Taira T, Saito Y, Niki T, Iguchi-Ariga S M, Takahashi K, Ariga H (2004). DJ-1 has a role in antioxidative stress to prevent cell death. EMBO Rep, 5(2): 213–218

[140] Tanaka M, Kim Y M, Lee G, Junn E, Iwatsubo T, Mouradian M M (2004). Aggresomes formed by alpha-synuclein and synphilin-1 are cytoprotective. J Biol Chem, 279(6): 4625–4631

[141] Valente E M, Abou-Sleiman P M, Caputo V, Muqit M M, Harvey K, Gispert S, Ali Z, Del Turco D, Bentivoglio A R, Healy D G, Albanese A, Nussbaum R, González-Maldonado R, Deller T, Salvi S, Cortelli P, Gilks W P, Latchman D S, Harvey R J, Dallapiccola B, Auburger G, Wood N W (2004). Hereditary early-onset Parkinson’s disease caused by mutations in PINK1. Science, 304(5674): 1158–1160

[142] Valente E M, Salvi S, Ialongo T, Marongiu R, Elia A E, Caputo V, Romito L, Albanese A, Dallapiccola B, Bentivoglio A R (2004). PINK1 mutations are associated with sporadic early-onset parkinsonism. Ann Neurol, 56(3): 336–341

[143] van der Horst A, Tertoolen L G, de Vries-Smits L M, Frye R A, Medema R H, Burgering B M (2004). FOXO4 is acetylated upon peroxide stress and deacetylated by the longevity protein hSir2(SIRT1). J Biol Chem, 279(28): 28873–28879

[144] Vaquero A, Scher M, Erdjument-Bromage H, Tempst P, Serrano L, Reinberg D (2007). SIRT1 regulates the histone methyl-transferase SUV39H1 during heterochromatin formation. Nature, 450(7168): 440–444

[145] Vaquero A, Scher M, Lee D, Erdjument-Bromage H, Tempst P, Reinberg D (2004). Human SirT1 interacts with histone H1 and promotes formation of facultative heterochromatin. Mol Cell, 16(1): 93–105

[146] Wang X, Winter D, Ashrafi G, Schlehe J, Wong Y L, Selkoe D, Rice S, Steen J, LaVoie M J, Schwarz T L (2011). PINK1 and Parkin target Miro for phosphorylation and degradation to arrest mitochondrial motility. Cell, 147(4): 893–906

[147] Wang X, Yan M H, Fujioka H, Liu J, Wilson-Delfosse A, Chen S G, Perry G, Casadesus G, Zhu X (2012). LRRK2 regulates mitochondrial dynamics and function through direct interaction with DLP1. Hum Mol Genet, 21(9): 1931–1944

[148] Wareski P, Vaarmann A, Choubey V, Safiulina D, Liiv J, Kuum M, Kaasik A (2009). PGC-1alpha and PGC-1beta regulate mitochondrial density in neurons. J Biol Chem, 284(32): 21379–21385

[149] West A B, Moore D J, Biskup S, Bugayenko A, Smith W W, Ross C A, Dawson V L, Dawson T M (2005). Parkinson’s disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity. Proc Natl Acad Sci USA, 102(46): 16842–16847

[150] Westerheide S D, Anckar J, Stevens S M Jr, Sistonen L, Morimoto R I (2009). Stress-inducible regulation of heat shock factor 1 by the deacetylase SIRT1. Science, 323(5917): 1063–1066

[151] Winslow A R, Chen C W, Corrochano S, Acevedo-Arozena A, Gordon D E, Peden A A, Lichtenberg M, Menzies F M, Ravikumar B, Imarisio S, Brown S, O’Kane C J, Rubinsztein D C (2010). α-Synuclein impairs macroautophagy: implications for Parkinson’s disease. J Cell Biol, 190(6): 1023–1037

[152] Wood-Kaczmar A, Gandhi S, Yao Z, Abramov A Y, Miljan E A, Keen G, Stanyer L, Hargreaves I, Klupsch K, Deas E, Downward J, Mansfield L, Jat P, Taylor J, Heales S, Duchen M R, Latchman D, Tabrizi S J, Wood N W (2008). PINK1 is necessary for long term survival and mitochondrial function in human dopaminergic neurons. PLoS ONE, 3(6): e2455

[153] Xilouri M, Vogiatzi T, Vekrellis K, Park D, Stefanis L (2009). Abberant alpha-synuclein confers toxicity to neurons in part through inhibition of chaperone-mediated autophagy. PLoS ONE, 4(5): e5515

[154] Yang S R, Wright J, Bauter M, Seweryniak K, Kode A, Rahman I (2007). Sirtuin regulates cigarette smoke-induced proinflammatory mediator release via RelA/p65 NF-kappaB in macrophages in vitro and in rat lungs in vivo: implications for chronic inflammation and aging. Am J Physiol Lung Cel l Mol Physiol, 292(2): L567–L576

[155] Yeung F, Hoberg J E, Ramsey C S, Keller M D, Jones D R, Frye R A, Mayo M W (2004). Modulation of NF-kappaB-dependent transcription and cell survival by the SIRT1 deacetylase. EMBO J, 23(12): 2369–2380

[156] Yong-Kee C J, Salomonczyk D, Nash J E (2011). Development and validation of a screening assay for the evaluation of putative neuroprotective agents in the treatment of Parkinson’s disease. Neurotox Res, 19(4): 519–526

[157] Yong-Kee C J, Sidorova E, Hanif A, Perera G, Nash J E (2012). Mitochondrial dysfunction precedes other sub-cellular abnormalities in an in vitro model linked with cell death in Parkinson’s disease. Neurotox Res, 21(2): 185–194

[158] Zarranz J J, Alegre J, Gómez-Esteban J C, Lezcano E, Ros R, Ampuero I, Vidal L, Hoenicka J, Rodriguez O, Atarés B, Llorens V, Gomez Tortosa E, del Ser T, Muñoz D G, de Yebenes J G (2004). The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia. Ann Neurol, 55(2): 164–173

[159] Zhang L, Shimoji M, Thomas B, Moore D J, Yu S W, Marupudi N I, Torp R, Torgner I A, Ottersen O P, Dawson T M, Dawson V L (2005). Mitochondrial localization of the Parkinson’s disease related protein DJ-1: implications for pathogenesis. Hum Mol Genet, 14(14): 2063–2073

[160] Zhang N Y, Tang Z, Liu C W (2008). alpha-Synuclein protofibrils inhibit 26 S proteasome-mediated protein degradation: understanding the cytotoxicity of protein protofibrils in neurodegenerative disease pathogenesis. J Biol Chem, 283(29): 20288–20298

[161] Zheng B, Liao Z, Locascio J J, Lesniak K A, Roderick S S, Watt M L, Eklund A C, Zhang-James Y, Kim P D, Hauser M A, Grünblatt E, Moran L B, Mandel S A, Riederer P, Miller R M, Federoff H J, Wüllner U, Papapetropoulos S, Youdim M B, Cantuti-Castelvetri I, Young A B, Vance J M, Davis R L, Hedreen J C, Adler C H, Beach T G, Graeber M B, Middleton F A, Rochet J C, Scherzer C R, Global P D G E C, and the Global PD Gene Expression (GPEX) Consortium (2010). PGC-1α, a potential therapeutic target for early intervention in Parkinson’s disease. Sci Transl Med, 2(52): 52ra73

Compliance with ethics guidelines

Dr. Joanne Nash, Dr. Jacqueline Gleave and Mr. Peter Perri declare that they have no conflict of interest. This manuscript is a review article and does not involve a research protocol requiring approval by the relevant institutional review board or ethics committee.

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