New insights into the mechanisms of mitochondrial preconditioning-triggered neuroprotection

Current Pharmaceutical Design

Volumn 17, Issue 31, 2011, Pages 3381-3389

  Correia, Sónia C ^a,b   Cardoso, Susana ^a,b   Santos, Renato X ^a,b   Carvalho, Cristina ^a,b   Santos, Maria S ^a,b   Perry, George ^c,d   Smith, Mark A ^c   Moreira, Paula I ^a,e  

^a UNIVERSITY OF COIMBRA   (Portugal)

^b UNIVERSITY OF COIMBRA   (Portugal)

^c CASE WESTERN RESERVE UNIVERSITY   (United States)

^d UNIVERSITY OF TEXAS AT SAN ANTONIO   (United States)

^e UNIVERSITY OF COIMBRA   (Portugal)

Author keywords

Mitochondria; Mitochondria turnover; Mitochondrial dynamics; Neuroprotection; Preconditioning; Reactive oxygen species

Indexed keywords

1 METHYL 4 PHENYLPYRIDINIUM; 2 MORPHOLINO 8 PHENYLCHROMONE; 5 HYDROXYDECANOIC ACID; ACETYLCYSTEINE; ADENOSINE TRIPHOSPHATE SENSITIVE POTASSIUM CHANNEL; DEFEROXAMINE; DIAZOXIDE; GLIBENCLAMIDE; HEAT SHOCK PROTEIN 70; HYPOXIA INDUCIBLE FACTOR 1ALPHA; HYPOXIA INDUCIBLE FACTOR 1BETA; I KAPPA B KINASE BETA; MANGANESE SUPEROXIDE DISMUTASE; MITOCHONDRIAL PROTEIN; MITOFUSIN 1; NICOTINAMIDE ADENINE DINUCLEOTIDE; NUCLEAR RESPIRATORY FACTOR 1; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA COACTIVATOR 1ALPHA; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA COACTIVATOR 1BETA; PHOSPHATIDYLINOSITOL 3 KINASE; PROTEIN BAK; PROTEIN BAX; PROTEIN BCL 2; PROTEIN BCL XL; PROTEIN KINASE C; REACTIVE OXYGEN METABOLITE; RESVERATROL; SIRTUIN 1; SUCCINATE DEHYDROGENASE; UNCOUPLING PROTEIN 2;

APOPTOSIS; ARTICLE; AUTOPHAGY; BIOGENESIS; HUMAN; MITOCHONDRIAL MEMBRANE POTENTIAL; MITOCHONDRION; NEUROPROTECTION; PRIORITY JOURNAL;

CENTRAL NERVOUS SYSTEM DISEASES; HUMANS; ISCHEMIC PRECONDITIONING; MITOCHONDRIA; NEUROPROTECTIVE AGENTS; REACTIVE OXYGEN SPECIES; SIGNAL TRANSDUCTION;

EID: 80055089996     PISSN: 13816128     EISSN: 18734286     Source Type: Journal    
DOI: 10.2174/138161211798072490     Document Type: Article

References (124)

1. Wiegand F, Liao W, Busch C, et al. Respiratory chain inhibition induces tolerance to focal cerebral ischemia. J Cereb Blood Flow Metab 1999; 19(11): 1229-37.
2. Dahl NA, Balfour WM. Prolonged Anoxic Survival Due to Anoxia Pre-Exposure: Brain Atp, Lactate, and Pyruvate. Am J Physiol 1964; 207: 452-6.
3. Chopp M, Chen H, Ho KL, et al. Transient hyperthermia protects against subsequent forebrain ischemic cell damage in the rat. Neu-rology 1989; 39(10): 1396-8.
4. Schurr A, Reid KH, Tseng MT, West C, Rigor BM. Adaptation of adult brain tissue to anoxia and hypoxia in vitro. Brain Res 1986; 374(2): 244-8.
5. Kitagawa K, Matsumoto M, Kuwabara K, et al. 'Ischemic toler- ance' phenomenon detected in various brain regions. Brain Res 1991; 561(2): 203-11.
6. Stagliano NE, Perez-Pinzon MA, Moskowitz MA, Huang PL. Focal ischemic preconditioning induces rapid tolerance to middle cerebral artery occlusion in mice. J Cereb Blood Flow Metab 1999; 19(7): 757-61.
7. Xu GP, Dave KR, Vivero R, Schmidt-Kastner R, Sick TJ, Perez- Pinzon MA. Improvement in neuronal survival after ischemic pre-conditioning in hippocampal slice cultures. Brain Res 2002; 952(2): 153-8.
8. Bruer U, Weih MK, Isaev NK, et al. Induction of tolerance in rat cortical neurons: hypoxic preconditioning. FEBS Lett 1997; 414(1): 117-21.
9. Moncayo J, de Freitas GR, Bogousslavsky J, Altieri M, van Melle G. Do transient ischemic attacks have a neuroprotective effect? Neurology 2000; 54(11): 2089-94.
10. Cadet JL, Krasnova IN. Cellular and molecular neurobiology of brain preconditioning. Mol Neurobiol 2009; 39(1): 50-61.
11. Kirino T. Ischemic tolerance. J Cereb Blood Flow Metab 2002; 22(11): 1283-96.
12. Gidday JM. Cerebral preconditioning and ischaemic tolerance. Nat Rev Neurosci 2006; 7(6): 437-48.
13. Barone FC, White RF, Spera PA, et al. Ischemic preconditioning and brain tolerance: temporal histological and functional outcomes, protein synthesis requirement, and interleukin-1 receptor antagonist and early gene expression. Stroke 1998; 29(9): 1937-50.
14. Stenzel-Poore MP, Stevens SL, King JS, Simon RP. Precondition-ing reprograms the response to ischemic injury and primes the emergence of unique endogenous neuroprotective phenotypes: a speculative synthesis. Stroke 2007 38(2 Suppl): 680-5.
15. Busija DW, Gaspar T, Domoki F, Katakam PV, Bari F. Mitochon-drial-mediated suppression of ROS production upon exposure of neurons to lethal stress: mitochondrial targeted preconditioning. Adv Drug Deliv Rev 2008; 60(13-14): 1471-7.
16. Chen H, Chan DC. Mitochondrial dynamics--fusion, fission, movement, and mitophagy--in neurodegenerative diseases. Hum Mol Genet 2009; 18(R2): R169-76.
17. Mattson MP, Gleichmann M, Cheng A. Mitochondria in neuroplas- ticity and neurological disorders. Neuron 2008; 60(5): 748-66.
18. Perez-Pinzon MA, Dave KR, Raval AP. Role of reactive oxygen species and protein kinase C in ischemic tolerance in the brain. An-tioxid Redox Signal 2005; 7(9-10): 1150-7.
19. Duchen MR. Roles of mitochondria in health and disease. Diabetes 2004; 53 Suppl 1: S96-102.
20. Dirnagl U, Meisel A. Endogenous neuroprotection: mitochondria as gateways to cerebral preconditioning? Neuropharmacology 2008; 55(3): 334-44.
21. Ravati A, Ahlemeyer B, Becker A, Klumpp S, Krieglstein J. Pre-conditioning-induced neuroprotection is mediated by reactive oxy-gen species and activation of the transcription factor nuclear factor-kappaB. J Neurochem 2001; 78(4): 909-19.
22. Ravati A, Ahlemeyer B, Becker A, Krieglstein J. Preconditioning-induced neuroprotection is mediated by reactive oxygen species. Brain Res 2000; 866(1-2): 23-32.
23. Jou MJ. Pathophysiological and pharmacological implications of mitochondria-targeted reactive oxygen species generation in astro-cytes. Adv Drug Deliv Rev 2008; 60(13-14): 1512-26.
24. Dirnagl U, Becker K, Meisel A. Preconditioning and tolerance against cerebral ischaemia: from experimental strategies to clinical use. Lancet Neurol 2009; 8(4): 398-412.
25. Furuichi T, Liu W, Shi H, Miyake M, Liu KJ. Generation of hy-drogen peroxide during brief oxygen-glucose deprivation induces preconditioning neuronal protection in primary cultured neurons. J Neurosci Res 2005; 79(6): 816-24.
26. Simerabet M, Robin E, Aristi I, et al. Preconditioning by an in situ administration of hydrogen peroxide: involvement of reactive oxy-gen species and mitochondrial ATP-dependent potassium channel in a cerebral ischemia-reperfusion model. Brain Res 2008; 1240:177-84.
27. Horiguchi T, Kis B, Rajapakse N, Shimizu K, Busija DW. Opening of mitochondrial ATP-sensitive potassium channels is a trigger of 3-nitropropionic acid-induced tolerance to transient focal cerebral ischemia in rats. Stroke 2003; 34(4): 1015-20.
28. Gaspar T, Domoki F, Lenti L, et al. Immediate neuronal precondi-tioning by NS1619. Brain Res 2009; 1285: 196-207.
29. Gaspar T, Snipes JA, Busija AR, et al. ROS-independent precondi-tioning in neurons via activation of mitoK(ATP) channels by BMS-191095. J Cereb Blood Flow Metab 2008; 28(6): 1090-103.
30. Correia SC, Moreira PI. Hypoxia-inducible factor 1: a new hope to counteract neurodegeneration? J Neurochem 2010; 112(1): 1-12.
31. Bell EL, Klimova TA, Eisenbart J, et al. The Qo site of the mito-chondrial complex III is required for the transduction of hypoxic signaling via reactive oxygen species production. J Cell Biol 2007;177(6): 1029-36.
32. Guzy RD, Hoyos B, Robin E, et al. Mitochondrial complex III is required for hypoxia-induced ROS production and cellular oxygen sensing. Cell Metab 2005; 1(6): 401-8.
33. Chandel NS, Maltepe E, Goldwasser E, Mathieu CE, Simon MC, Schumacker PT. Mitochondrial reactive oxygen species trigger hy-poxia-induced transcription. Proc Natl Acad Sci USA 1998;95(20): 11715-20.
34. Liu J, Narasimhan P, Yu F, Chan PH. Neuroprotection by hypoxic preconditioning involves oxidative stress-mediated expression of hypoxia-inducible factor and erythropoietin. Stroke 2005; 36(6):1264-9.
35. Chang S, Jiang X, Zhao C, Lee C, Ferriero DM. Exogenous low dose hydrogen peroxide increases hypoxia-inducible factor-1alpha protein expression and induces preconditioning protection against ischemia in primary cortical neurons. Neurosci Lett 2008; 441(1):134-8.
36. Bajgar R, Seetharaman S, Kowaltowski AJ, Garlid KD, Paucek P. Identification and properties of a novel intracellular (mitochon-drial) ATP-sensitive potassium channel in brain. J Biol Chem 2007;276(36): 33369-74.
37. Debska G, May R, Kicinska A, Szewczyk A, Elger CE, Kunz WS. Potassium channel openers depolarize hippocampal mitochondria. Brain Res 2001; 892(1): 42-50.
38. Kulawiak B, Bednarczyk P. Reconstitution of brain mitochondria inner membrane into planar lipid bilayer. Acta Neurobiol Exp (Wars) 2005; 65(3): 271-6.
39. Garlid KD, Paucek P, Yarov-Yarovoy V, et al. Cardioprotective effect of diazoxide and its interaction with mitochondrial ATP-sensitive K channels. Possible mechanism of cardioprotection. Circ Res 1997; 81(6): 1072-82.
40. Szewczyk A, Wojtczak L. Mitochondria as a pharmacological target. Pharmacol Rev 2002; 54(1): 101-27.
41. + channel in the mitochondrial inner membrane. Nature 1991; 352(6332): 244-7.
42. Hausenloy DJ, Maddock HL, Baxter GF, Yellon DM. Inhibiting mitochondrial permeability transition pore opening: a new para-digm for myocardial preconditioning? Cardiovasc Res 2002; 55(3): 534-43.
43. Javadov SA, Clarke S, Das M, Griffiths EJ, Lim KH, Halestrap AP. Ischaemic preconditioning inhibits opening of mitochondrial per-meability transition pores in the reperfused rat heart. J Physiol 2003; 549(Pt 2): 513-24.
44. Halestrap AP, Clarke SJ, Khaliulin I. The role of mitochondria in protection of the heart by preconditioning. Biochim Biophys Acta 2007; 1767(8): 1007-31.
45. Samavati L, Monick MM, Sanlioglu S, Buettner GR, Oberley LW, Hunninghake GW. Mitochondrial K(ATP) channel openers activate the ERK kinase by an oxidant-dependent mechanism. Am J Physiol Cell Physiol 2002; 283(1): C273-81.
46. Domoki F, Perciaccante JV, Veltkamp R, Bari F, Busija DW. Mi-tochondrial potassium channel opener diazoxide preserves neu-ronal-vascular function after cerebral ischemia in newborn pigs. Stroke 1999; 30(12): 2713-8.
47. Kis B, Nagy K, Snipes JA, et al. The mitochondrial K(ATP) chan-nel opener BMS-191095 induces neuronal preconditioning. Neu- roreport 2004; 15(2): 345-9.
48. Larsson NG, Clayton DA. Molecular genetic aspects of human mitochondrial disorders. Annu Rev Genet 1995; 29: 151-78.
49. Grivell LA. Mitochondrial DNA. Small, beautiful and essential. Nature 1989; 341(6243): 569-71.
50. Lee HC, Wei YH. Mitochondrial biogenesis and mitochondrial DNA maintenance of mammalian cells under oxidative stress. Int J Biochem Cell Biol 2005; 37(4): 822-34.
51. St-Pierre J, Drori S, Uldry M, et al. Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coac-tivators. Cell 2006; 127(2): 397-408.
52. Scarpulla RC. Transcriptional activators and coactivators in the nuclear control of mitochondrial function in mammalian cells. Gene 2002; 286(1): 81-9.
53. Andersson U, Scarpulla RC. Pgc-1-related coactivator, a novel, serum-inducible coactivator of nuclear respiratory factor 1-dependent transcription in mammalian cells. Mol Cell Biol 2001; 21(11): 3738-49.
54. Lin J, Handschin C, Spiegelman BM. Metabolic control through the PGC-1 family of transcription coactivators. Cell Metab 2005;1(6): 361-70.
55. Scarpulla RC. Nuclear control of respiratory chain expression by nuclear respiratory factors and PGC-1-related coactivator. Ann N Y Acad Sci 2008; 1147: 321-34.
56. Gutsaeva DR, Carraway MS, Suliman HB, et al. Transient hypoxia stimulates mitochondrial biogenesis in brain subcortex by a neu-ronal nitric oxide synthase-dependent mechanism. J Neurosci 2008; 28(9): 2015-24.
57. Yin W, Signore AP, Iwai M, Cao G, Gao Y, Chen J. Rapidly in-creased neuronal mitochondrial biogenesis after hypoxic-ischemic brain injury. Stroke 2008; 39(11): 3057-63.
58. Chen SD, Lin TK, Yang DI, et al. Protective effects of peroxisome proliferator-activated receptors gamma coactivator-1alpha against neuronal cell death in the hippocampal CA1 subfield after transient global ischemia. J Neurosci Res. 2010; 88(3): 605-13.
59. Yousuf S, Atif F, Ahmad M, et al. Resveratrol exerts its neuropro-tective effect by modulating mitochondrial dysfunctions and asso-ciated cell death during cerebral ischemia. Brain Res 2009; 1250: 242-53.
60. Zhang H, Schools GP, Lei T, Wang W, Kimelberg HK, Zhou M. Resveratrol attenuates early pyramidal neuron excitability impair-ment and death in acute rat hippocampal slices caused by oxygen-glucose deprivation. Exp Neurol 2008; 212(1): 44-52.
61. Chong ZZ, Maiese K. Enhanced tolerance against early and late apoptotic oxidative stress in mammalian neurons through nicoti-namidase and sirtuin mediated pathways. Curr Neurovasc Res 2008; 5(3): 159-70.
62. Della-Morte D, Dave KR, DeFazio RA, Bao YC, Raval AP, Perez-Pinzon MA. Resveratrol pretreatment protects rat brain from cere-bral ischemic damage via a sirtuin 1-uncoupling protein 2 pathway. Neuroscience 2009; 159(3): 993-1002.
63. Pallas M, Casadesus G, Smith MA, et al. Resveratrol and neurode-generative diseases: activation of SIRT1 as the potential pathway towards neuroprotection. Curr Neurovasc Res 2009; 6(1): 70-81.
64. Morris KC, Lin HW, Thompson JW, Perez-Pinzon MA. Pathways for ischemic cytoprotection: Role of sirtuins in caloric restriction, resveratrol, and ischemic preconditioning. J Cereb Blood Flow Me-tab. 2011; 31(4): 1003-19.
65. Blander G, Guarente L. The Sir2 family of protein deacetylases. Annu Rev Biochem 2004; 73: 417-35.
66. Denu JM. The Sir 2 family of protein deacetylases. Curr Opin Chem Biol 2005; 9(5): 431-40.
67. Finkel T, Deng CX, Mostoslavsky R. Recent progress in the biol-ogy and physiology of sirtuins. Nature 2009; 460(7255): 587-91.
68. Canto C, Auwerx J. PGC-1alpha, SIRT1 and AMPK, an energy sensing network that controls energy expenditure. Curr Opin Lipi-dol 2009; 20(2): 98-105.
69. Aquilano K, Vigilanza P, Baldelli S, Pagliei B, Rotilio G, Ciriolo MR. Peroxisome proliferator-activated receptor gamma co-activator 1alpha (PGC-1alpha) and sirtuin 1 (SIRT1) reside in mi-tochondria: possible direct function in mitochondrial biogenesis. J Biol Chem. 2010; 285(28): 21590-9.
70. Howitz KT, Bitterman KJ, Cohen HY, et al. Small molecule activa-tors of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 2003; 425(6954): 191-6.
71. Centeno JM, Orti M, Salom JB, Sick TJ, Perez-Pinzon MA. Nitric oxide is involved in anoxic preconditioning neuroprotection in rat hippocampal slices. Brain Res 1999; 836(1-2): 62-9.
72. Raval AP, Dave KR, Perez-Pinzon MA. Resveratrol mimics ischemic preconditioning in the brain. J Cereb Blood Flow Metab 2006; 26(9): 1141-7.
73. Tan L, Yu JT, Guan HS. Resveratrol exerts pharmacological pre-conditioning by activating PGC-1alpha. Med Hypotheses 2008; 71(5): 664-7.
74. Rodgers JT, Lerin C, Haas W, Gygi SP, Spiegelman BM, Puig-server P. Nutrient control of glucose homeostasis through a com-plex of PGC-1alpha and SIRT1. Nature 2005; 434(7029): 113-8.
75. Lagouge M, Argmann C, Gerhart-Hines Z, et al. Resveratrol im-proves mitochondrial function and protects against metabolic dis-ease by activating SIRT1 and PGC-1alpha. Cell 2006; 127(6):1109-22.
76. Wareski P, Vaarmann A, Choubey V, et al. PGC-1{alpha} and PGC-1{beta} regulate mitochondrial density in neurons. J Biol Chem 2009; 284(32): 21379-85.
77. Rane S, He M, Sayed D, et al. Downregulation of miR-199a derep-resses hypoxia-inducible factor-1alpha and Sirtuin 1 and recapitu-lates hypoxia preconditioning in cardiac myocytes. Circ Res 2009;104(7): 879-86.
78. Dioum EM, Chen R, Alexander MS, et al. Regulation of hypoxia-inducible factor 2alpha signaling by the stress-responsive deacety-lase sirtuin 1. Science 2009; 324(5932): 1289-93.
79. Meloni BP, Tilbrook PA, Boulos S, Arthur PG, Knuckey NW. Erythropoietin preconditioning in neuronal cultures: signaling, pro-tection from in vitro ischemia, and proteomic analysis. J Neurosci Res 2006; 83(4): 584-93.
80. Salih DA, Brunet A. FoxO transcription factors in the maintenance of cellular homeostasis during aging. Curr Opin Cell Biol 2008;20(2): 126-36.
81. Zhan L, Wang T, Li W, Xu ZC, Sun W, Xu E. Activation of Akt/FoxO signaling pathway contributes to induction of neuropro-tection against transient global cerebral ischemia by hypoxic pre-conditioning in adult rats. J Neurochem. 2010; 114(3): 897-908.
82. Hou J, Chong ZZ, Shang YC, Maiese K. Early apoptotic vascular signaling is determined by Sirt1 through nuclear shuttling, forkhead trafficking, bad, and mitochondrial caspase activation. Curr Neurovasc Res. 2010; 7(2): 95-112.
83. Smirnova E, Griparic L, Shurland DL, van der Bliek AM. Dy-namin-related protein Drp1 is required for mitochondrial division in mammalian cells. Mol Biol Cell 2001; 12(8): 2245-56.
84. Yoon Y, Krueger EW, Oswald BJ, McNiven MA. The mitochon-drial protein hFis1 regulates mitochondrial fission in mammalian cells through an interaction with the dynamin-like protein DLP1. Mol Cell Biol 2003; 23(15): 5409-20.
85. Koshiba T, Detmer SA, Kaiser JT, Chen H, McCaffery JM, Chan DC. Structural basis of mitochondrial tethering by mitofusin com-plexes. Science 2004; 305(5685): 858-62.
86. Cipolat S, Martins de Brito O, Dal Zilio B, Scorrano L. OPA1 requires mitofusin 1 to promote mitochondrial fusion. Proc Natl Acad Sci USA 2004; 101(45): 15927-32.
87. Chen H, Chan DC. Critical dependence of neurons on mitochon-drial dynamics. Curr Opin Cell Biol 2006; 18(4): 453-9.
88. Frederick RL, Shaw JM. Moving mitochondria: establishing distri-bution of an essential organelle. Traffic 2007; 8(12): 1668-75.
89. Knott AB, Perkins G, Schwarzenbacher R, Bossy-Wetzel E. Mito-chondrial fragmentation in neurodegeneration. Nat Rev Neurosci 2008; 9(7): 505-18.
90. Barsoum MJ, Yuan H, Gerencser AA, et al. Nitric oxide-induced mitochondrial fission is regulated by dynamin-related GTPases in neurons. EMBO J 2006; 25(16): 3900-11.
91. Bossy-Wetzel E, Barsoum MJ, Godzik A, Schwarzenbacher R, Lipton SA. Mitochondrial fission in apoptosis, neurodegeneration and aging. Curr Opin Cell Biol 2003; 15(6): 706-16.
92. Jendrach M, Mai S, Pohl S, Voth M, Bereiter-Hahn J. Short- and long-term alterations of mitochondrial morphology, dynamics and mtDNA after transient oxidative stress. Mitochondrion 2008; 8(4):293-304.
93. Brooks C, Wei Q, Feng L, et al. Bak regulates mitochondrial mor-phology and pathology during apoptosis by interacting with mito-fusins. Proc Natl Acad Sci USA 2007; 104(28): 11649-54.
94. Karbowski M, Norris KL, Cleland MM, Jeong SY, Youle RJ. Role of Bax and Bak in mitochondrial morphogenesis. Nature 2006;443(7112): 658-62.
95. Delivani P, Adrain C, Taylor RC, Duriez PJ, Martin SJ. Role for CED-9 and Egl-1 as regulators of mitochondrial fission and fusion dynamics. Mol Cell 2006; 21(6): 761-73.
96. Li H, Chen Y, Jones AF, et al. Bcl-xL induces Drp1-dependent synapse formation in cultured hippocampal neurons. Proc Natl Acad Sci USA 2008; 105(6): 2169-74.
97. Wasiak S, Zunino R, McBride HM. Bax/Bak promote sumoylation of DRP1 and its stable association with mitochondria during apop-totic cell death. J Cell Biol 2007; 177(3): 439-50.
98. Rybnikova E, Sitnik N, Gluschenko T, Tjulkova E, Samoilov MO. The preconditioning modified neuronal expression of apoptosis-related proteins of Bcl-2 superfamily following severe hypobaric hypoxia in rats. Brain Res 2006; 1089(1): 195-202.
99. Liu RG, Wang WJ, Song N, Chen YQ, Li LH. Diazoxide precondi-tioning alleviates apoptosis of hippocampal neurons induced by an-oxia-reoxygenation in vitro through up-regulation of Bcl-2/Bax protein ratio. Sheng Li Xue Bao 2006; 58(4): 345-50.
100. Dagda RK, Cherra SJ, 3rd, Kulich SM, Tandon A, Park D, Chu CT. Loss of PINK1 function promotes mitophagy through effects on oxidative stress and mitochondrial fission. J Biol Chem 2009;284(20): 13843-55.
101. Twig G, Elorza A, Molina AJ, et al. Fission and selective fusion govern mitochondrial segregation and elimination by autophagy. EMBO J 2008; 27(2): 433-46.
102. Klionsky DJ, Emr SD. Autophagy as a regulated pathway of cellu-lar degradation. Science 2000; 290(5497): 1717-21.
103. Levine B, Klionsky DJ. Development by self-digestion: molecular mechanisms and biological functions of autophagy. Dev Cell 2004; 6(4): 463-77.
104. Lee JA. Autophagy in neurodegeneration: two sides of the same coin. BMB Rep 2009; 42(6): 324-30.
105. Xilouri M, Stefanis L. Autophagy in the central nervous system: implications for neurodegenerative disorders. CNS Neurol Disord Drug Targets. 2010; 9(6): 701-19.
106. Hara T, Nakamura K, Matsui M, et al. Suppression of basal auto-phagy in neural cells causes neurodegenerative disease in mice. Na-ture 2006; 441(7095): 885-9.
107. Komatsu M, Waguri S, Chiba T, et al. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 2006; 441(7095): 880-4.
108. Levine B, Kroemer G. Autophagy in the pathogenesis of disease. Cell 2008; 132(1): 27-42.
109. Klionsky DJ. Autophagy: from phenomenology to molecular un-derstanding in less than a decade. Nat Rev Mol Cell Biol 2007; 8(11): 931-7.
110. Twig G, Shirihai OS. The Interplay Between Mitochondrial Dy-namics and Mitophagy. Antioxid Redox Signal. 2011; 14(10): 1939-51.
111. Balduini W, Carloni S, Buonocore G. Autophagy in hypoxia-ischemia induced brain injury: evidence and speculations. Auto-phagy 2009; 5(2): 221-3.
112. Park HK, Chu K, Jung KH, Lee ST, Bahn JJ, Kim M, et al. Auto-phagy is involved in the ischemic preconditioning. Neurosci Lett 2009; 451(1): 16-9.
113. Sheng R, Zhang LS, Han R, Liu XQ, Gao B, Qin ZH. Autophagy activation is associated with neuroprotection in a rat model of focal cerebral ischemic preconditioning. Autophagy 2010; 6(4).
114. Pan T, Rawal P, Wu Y, Xie W, Jankovic J, Le W. Rapamycin protects against rotenone-induced apoptosis through autophagy in-duction. Neuroscience 2009; 164(2): 541-51.
115. Pan T, Kondo S, Zhu W, Xie W, Jankovic J, Le W. Neuroprotec-tion of rapamycin in lactacystin-induced neurodegeneration via autophagy enhancement. Neurobiol Dis 2008; 32(1): 16-25.
116. Tzeng YW, Lee LY, Chao PL, Lee HC, Wu RT, Lin AM. Role of autophagy in protection afforded by hypoxic preconditioning against MPP+-induced neurotoxicity in SH-SY5Y cells. Free Radic Biol Med. 2010; 49(5): 839-46.
117. Wu Y, Li X, Xie W, Jankovic J, Le W, Pan T. Neuroprotection of deferoxamine on rotenone-induced injury via accumulation of HIF-1 alpha and induction of autophagy in SH-SY5Y cells. Neurochem Int. 2010; 57(3): 198-205.
118. Brugarolas J, Lei K, Hurley RL, et al. Regulation of mTOR func-tion in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex. Genes Dev 2004; 18(23): 2893-904.
119. Hardie DG. New roles for the LKB1-->AMPK pathway. Curr Opin Cell Biol 2005; 17(2): 167-73.
120. Zhang H, Bosch-Marce M, Shimoda LA, et al. Mitochondrial auto-phagy is an HIF-1-dependent adaptive metabolic response to hy-poxia. J Biol Chem 2008; 283(16): 10892-903.
121. Brown JE, Zeiger SL, Hettinger JC, et al. Essential role of the redox-sensitive kinase p66shc in determining energetic and oxida-tive status and cell fate in neuronal preconditioning. J Neurosci. 2010; 30(15): 5242-52.
122. Scherz-Shouval R, Shvets E, Fass E, Shorer H, Gil L, Elazar Z. Reactive oxygen species are essential for autophagy and specifi-cally regulate the activity of Atg4. EMBO J 2007; 26(7): 1749-60.
123. Elmore SP, Qian T, Grissom SF, Lemasters JJ. The mitochondrial permeability transition initiates autophagy in rat hepatocytes. FASEB J 2001; 15(12): 2286-7.
124. Priault M, Salin B, Schaeffer J, Vallette FM, di Rago JP, Martinou JC. Impairing the bioenergetic status and the biogenesis of mito-chondria triggers mitophagy in yeast. Cell Death Differ 2005; 12(12): 1613-21.