Journal of Neural Transmission

, Volume 116, Issue 11, pp 1383–1396 | Cite as

The interplay between mitochondrial complex I, dopamine and Sp1 in schizophrenia

  • Dorit Ben-ShacharEmail author
Basic Neurosciences, Genetics and Immunology - Review Article


Schizophrenia is currently believed to result from variations in multiple genes, each contributing a subtle effect, which combines with each other and with environmental stimuli to impact both early and late brain development. At present, schizophrenia clinical heterogeneity as well as the difficulties in relating cognitive, emotional and behavioral functions to brain substrates hinders the identification of a disease-specific anatomical, physiological, molecular or genetic abnormality. Mitochondria play a pivotal role in many essential processes, such as energy production, intracellular calcium buffering, transmission of neurotransmitters, apoptosis and ROS production, all either leading to cell death or playing a role in synaptic plasticity. These processes have been well established as underlying altered neuronal activity and thereby abnormal neuronal circuitry and plasticity, ultimately affecting behavioral outcomes. The present article reviews evidence supporting a dysfunction of mitochondria in schizophrenia, including mitochondrial hypoplasia, impairments in the oxidative phosphorylation system (OXPHOS) as well as altered mitochondrial-related gene expression. Abnormalities in mitochondrial complex I, which plays a major role in controlling OXPHOS activity, are discussed. Among them are schizophrenia specific as well as disease-state-specific alterations in complex I activity in the peripheral tissue, which can be modulated by DA. In addition, CNS and peripheral abnormalities in the expression of three of complex I subunits, associated with parallel alterations in their transcription factor, specificity protein 1 (Sp1) are reviewed. Finally, this review discusses the question of disease specificity of mitochondrial pathologies and suggests that mitochondria dysfunction could cause or arise from anomalities in processes involved in brain connectivity.


Schizophrenia Mitochondria Complex I Dopamine Specificity protein 1 (Sp1) 



We acknowledge Rachel Karry (Ph.D.) and Natalie Dror who performed the molecular studies in postmortem specimens and blood cells, Hanit Brenner-Lavie (Ph.D.), Predrag Ljubuncic (Ph.D.), Haifa Gazawi (M.Sc.) and Rosa Zuk (M.Sc.) who performed the studies on complex I activity and characterized its interaction with DA. We acknowledge the assistance of Alon Reshef (MD), Ala Sheinkman MD, Marina Mazar (MD) and Zvi Kirsh (MD) for their contribution to blood samples collection and the clinical characterization of the patients and Ehud Klein (MD) for supervising the clinical part of the studies. Postmortem brain specimens were provided from the Stanley Foundation Neuropathology Consortium (Bethesda, MD). This project was supported by the by grants from The Chief Scientist Israel Ministry of Health, The Stanley Medical Research Institute grant and The NARSAD Independent Investigator Award.


  1. Albensi BC, Sullivan PG, Thompson MB, Scheff SW, Mattson MP (2000) Cyclosporin ameliorates traumatic brain-injury-induced alterations of hippocampal synaptic plasticity. Exp Neurol 162:385–389PubMedCrossRefGoogle Scholar
  2. Aleman A, Bocker KBE, Hijman R, Kahn RS (2002) Hallucinations in schizophrenia: imbalance between imagery and perception. Schizophr Res 57:315–316PubMedCrossRefGoogle Scholar
  3. Altar CA, Jurata LW, Charles V, Lemire A, Liu P, Bukhman Y, Young TA, Bullard J, Yokoe H, Webster MJ, Knable MB, Brockman JA (2005) Deficient hippocampal neuron expression of proteasome, ubiquitin, and mitochondrial genes in multiple schizophrenia cohorts. Biol Psychiatry 58:85–96PubMedCrossRefGoogle Scholar
  4. Amar S, Shamir A, Ovadia O, Blanaru M, Reshef A, Kremer I, Rietschel M, Schulze TG, Maier W, Belmaker RH, Ebstein RP, Agam G, Mishmar D (2007) Mitochondrial DNA HV lineage increases the susceptibility to schizophrenia among Israeli Arabs. Schizophr Res 94:354–358PubMedCrossRefGoogle Scholar
  5. Andreasen NC, OwLeary DS, Flaum M, Nopoulos P, Watkins G, Boles Ponto LLB, Hichwa RD (1997) Hypofrontality in schizophrenia: disturbed dysfunctional circuits in neuroleptic-naive patients. Lancet 349:1730–1734PubMedCrossRefGoogle Scholar
  6. Baethge C, Baldessarini RJ, Freudenthal K, Streeruwitz A, Bauer M, Bschor T (2005) Hallucinations in bipolar disorder: characteristics and comparison to unipolar depression and schizophrenia. Bipolar Disord 7:136–145PubMedCrossRefGoogle Scholar
  7. Balijepalli S, Boyd MR, Ravindranath V (1999) Inhibition of mitochondrial complex I by haloperidol: the role of thiol oxidation. Neuropsychopharmacol 38:567–577Google Scholar
  8. Bao L, Avshalumov MV, Rice ME (2005) Partial mitochondrial inhibition causes striatal dopamine release suppression and medium spiny neuron depolarization via H2O2 elevation, not ATP depletion. J Neurosci 25:10029–10040PubMedCrossRefGoogle Scholar
  9. Barnes J, Howard RJ, Senior C, Brammer M, Bullmore ET, Simmons A, Woodruff P, David AS (2000) Cortical activity during rotational and linear transformations. Neuropsychologia 38:1148–1156PubMedCrossRefGoogle Scholar
  10. Belogrudov G, Hatefi Y (1994) Catalytic sector of complex I (NADH:ubiquinone oxidoreductase): subunit stoichiometry and substrate-induced conformation changes. Biochemistry 33:4571–4576PubMedCrossRefGoogle Scholar
  11. Belogrudov GI, Hatefi Y (1996) Intersubunit interactions in the bovine mitochondrial complex I as revealed by ligand blotting. Biochem Biophys Res Commun 227:135–139PubMedCrossRefGoogle Scholar
  12. Ben-Shachar D (2002) Mitochondrial dysfunction in schizophrenia: a possible linkage to dopamine. J Neurochem 83:1241–1251PubMedCrossRefGoogle Scholar
  13. Ben-Shachar D, Karry R (2007) Sp1 expression is disrupted in schizophrenia; a possible mechanism for the abnormal expression of mitochondrial complex I genes, NDUFV1 and NDUFV2. PLoS One 2:e817PubMedCrossRefGoogle Scholar
  14. Ben-Shachar D, Karry R (2008) Neuroanatomical pattern of mitochondrial complex I pathology varies between schizophrenia, bipolar disorder and major depression. PLoS One 3:e3676PubMedCrossRefGoogle Scholar
  15. Ben-Shachar D, Zuk R, Glinka Y (1995) Dopamine neurotoxicity: inhibition of mitochondrial respiration. J Neurochem 64:718–723PubMedGoogle Scholar
  16. Ben-Shachar D, Zuk R, Gazawi H, Reshef A, Sheinkman A, Klein E (1999) Increased mitochondrial complex I activity in platelets of schizophrenic patients. Int J Neuropsychopharmacol 2:245–253PubMedCrossRefGoogle Scholar
  17. Ben-Shachar D, Zuk R, Gazawi H, Ljubuncic P (2004) Dopamine toxicity involves mitochondrial complex I inhibition: implications to dopamine-related neuropsychiatric disorders. Biochem Pharmacol 67:1965–1974PubMedCrossRefGoogle Scholar
  18. Ben-Shachar D, Bonne O, Chisin R, Klein E, Lester H, Aharon-Peretz J, Yona I, Freedman N (2007) Cerebral glucose utilization and platelet mitochondrial complex I activity in schizophrenia: a FDG-PET study. Prog Neuropsychopharmacol Biol Psychiatry 31:807–813PubMedCrossRefGoogle Scholar
  19. Berman SB, Hastings TG (1999) Dopamine oxidation alters mitochondrial respiration and induces permeability transition in brain mitochondria: implications for Parkinson’s disease. J Neurochem 73:1127–1137PubMedCrossRefGoogle Scholar
  20. Bertolino A, Frye M, Callicott JH, Mattay VS, Rakow R, Shelton-Repella J, Post R, Weinberger DR (2003) Neuronal pathology in the hippocampal area of patients with bipolar disorder: a study with proton magnetic resonance spectroscopic imaging. Biol Psychiatry 53:906–913PubMedCrossRefGoogle Scholar
  21. Black JE, Zelazny AM, Greenough WT (1991) Capillary and mitochondrial support of neural plasticity in adult rat visual cortex. Exp Neurol 111:204–209PubMedCrossRefGoogle Scholar
  22. Breier A, Su TP, Saunders R, Carson RE, Kolachana BA, de Bartolomeis A, Weinberger DR, Weisenfeld N, Malhotra AK, Eckelman WC, Pickar D (1997) Schizophrenia is associated with elevated amphetamine-induced synaptic dopamine concentrations: evidence from a novel positron emission tomography method. Proc Natl Acad Sci USA 94:2569–2574PubMedCrossRefGoogle Scholar
  23. Brenner-Lavie H, Klein E, Zuk R, Gazawi H, Ljubuncic P, Ben-Shachar D (2008) Dopamine modulates mitochondrial function in viable SH-SY5Y cells possibly via its interaction with complex I: relevance to dopamine pathology in schizophrenia. Biochim Biophys Acta 1777:173–185PubMedCrossRefGoogle Scholar
  24. Brenner-Lavie H, Klein E, Ben-Shachar D (2009) Mitochondrial complex I as a novel target for intraneuronal DA: modulation of respiration in intact cells. Biochem Pharmacol 78:85–95PubMedCrossRefGoogle Scholar
  25. Brodin L, Bakeeva L, Shupliakov O (1999) Presynaptic mitochondria and the temporal pattern of neurotransmitter release. Philos Trans R Soc Lond B Biol Sci 354:365–372PubMedCrossRefGoogle Scholar
  26. Buchsbaum MS (1990) The frontal lobes, basal ganglia and temporal lobes as sites for schizophrenia. Schizophr Bull 16:377–387PubMedGoogle Scholar
  27. Buchsbaum MS, Hazlett EA (1998) Positron emission tomography studies of abnormal glucose metabolism in schizophrenia. Schizophr Bull 24:343–346PubMedGoogle Scholar
  28. Burkhardt C, Kelly JP, Lim YH, Filley CM, Parker WD (1993) Neuroleptic medications inhibit complex I of the electron transport chain. Ann Neurol 33:512–517PubMedCrossRefGoogle Scholar
  29. Burnett BB, Gardner A, Boles RG (2005) Mitochondrial inheritance in depression, dysmotility and migraine? J Affect Disord 88:109–116PubMedCrossRefGoogle Scholar
  30. Calabresi P, Gubellini P, Picconi B, Centonze D, Pisani A, Bonsi P, Greengard P, Hipskind RA, Borrelli E, Bernardi G (2001) Inhibition of mitochondrial complex II induces a long-term potentiation of NMDA-mediated synaptic excitation in the striatum requiring endogenous dopamine. J Neurosci 20:5110–5120Google Scholar
  31. Cannon M, Jones PB, Murray RM (2002) Obstetric complications and schizophrenia: historical and meta-analytic review. Am J Psychiatry 159:1080–1092PubMedCrossRefGoogle Scholar
  32. Carlsson A (1988) The current status of the dopamine hypothesis of schizophrenia. Neuropsychopharmacol 1:179–186CrossRefGoogle Scholar
  33. Carter CS, Perlstein W, Ganguli R, Brar J, Mintun M, Cohen JD (1998) Functional hypofrontality and working memory dysfunction in schizophrenia. Am J Psychiatry 155:1285–1287PubMedGoogle Scholar
  34. Cavelier L, Jazin E, Eriksson I, Prince J, Bave B, Oreland L, Gyllensten U (1995) Decreased cytochrome c oxidase activity and lack of age related accumulation of mtDNA in brain of schizophrenics. Genomics 29:217–228PubMedCrossRefGoogle Scholar
  35. Chan P, Di Monte DA, Luo JJ, DeLanney LE, Irwin I, Langston JW (1994) Rapid ATP loss caused by methamphetamine in the mouse striatum: relationship between energy impairment and dopaminergic neurotoxicity. J Neurochem 62:2484–2487PubMedGoogle Scholar
  36. Chaturvedi RK, Beal MF (2008) Mitochondrial approaches for neuroprotection. Ann N Y Acad Sci 1147:395–412PubMedCrossRefGoogle Scholar
  37. Chen Y, Sharma RP, Costa RH, Costa E, Grayson DR (2002) On the epigenetic regulation of the human reelin promoter. Nucleic Acids Res 30:2930–2939PubMedCrossRefGoogle Scholar
  38. Clason T, Zickermann V, Ruiz T, Brandt U, Radermacher M (2007) Direct localization of the 51 and 24 kDa subunits of mitochondrial complex I by three-dimensional difference imaging. J Struct Biol 159:433–442PubMedCrossRefGoogle Scholar
  39. Cohen G, Farooqui R, Kesler N (1997) Parkinson’s disease: a new link between monoamine oxidase and mitochondrial electron flow. Proc Natl Acad Sci USA 94:4890–4894PubMedCrossRefGoogle Scholar
  40. Coupland NJ, Ogilvie CJ, Hegadoren KM, Seres P, Hanstock CC, Allen PS (2005) Decreased prefrontal Myo-inositol in major depressive disorder. Biol Psychiatry 57:1526–1534PubMedCrossRefGoogle Scholar
  41. Daley E, Wilkie D, Loesch A, Hargreaves IP, Kendall DA, Pilkington GJ, Bates TE (2005) Chlorimipramine: a novel anticancer agent with a mitochondrial target. Biochem Biophys Res Commun 328:623–632PubMedCrossRefGoogle Scholar
  42. Davey GP, Peuchen S, Clark JB (1998) Energy thresholds in brain mitochondria: potential involvement in neurodegeneration. J Biol Chem 273:12753–12757PubMedCrossRefGoogle Scholar
  43. Davis KL, Kann RS, Ko G, Davidson M (1991) Dopamine in schizophrenia: a review and reconceptualization. Am J Psychiatry 148:1474–1486PubMedGoogle Scholar
  44. Deicken RF, Johnson C, Pegues M (2000) Proton magnetic resonance spectroscopy of the human brain in schizophrenia. Rev Neurosci 11:147–158PubMedGoogle Scholar
  45. Dingman CW, McGlashan TH (1986) Discriminating characteristics of suicides. Chestnut Lodge follow-up sample including patients with affective disorder, schizophrenia and schizoaffective disorder. Acta Psychiatr Scand 74:91–97PubMedCrossRefGoogle Scholar
  46. Dror N, Klein E, Karry R, Sheinkman A, Kirsh Z, Mazor M, Tzukerman M, Ben-Shachar D (2002) State dependent alterations in mitochondrial complex I activity in platelets: a potential peripheral marker for schizophrenia. Mol Psychiatry 7:995–1001PubMedCrossRefGoogle Scholar
  47. Fecke W, Sled VD, Ohnishi T, Weiss H (1994) Disruption of the gene encoding the NADH-binding subunit of NADH: ubiquinone oxidoreductase in Neurospora crassa. Formation of a partially assembled enzyme without FMN and the iron–sulphur cluster N-3. Eur J Biochem 220:551–558PubMedCrossRefGoogle Scholar
  48. Feinberg AP (2007) Phenotypic plasticity and the epigenetics of human disease. Nature 447:433–440PubMedCrossRefGoogle Scholar
  49. Frith C, Dolan RJ (1997) Brain mechanisms associated with top–down processes in perception. Philos Trans R Soc Lond B Biol Sci 352:1221–1230PubMedCrossRefGoogle Scholar
  50. Fujimoto T, Nakano T, Takano T, Hokazono Y, Asakura T, Tsuji T (1992) Study of chronic schizophrenics using 31P magnetic resonance chemical shift imaging. Acta Psychiatr Scand 86:455–462PubMedCrossRefGoogle Scholar
  51. Fukuzako H, Fukuzako T, Hashiguchi T, Kodama S, Takigawa M, Fujimoto T (1999) Changes in levels of phosphorus metabolites in temporal lobes of drug-naive schizophrenic patients. Am J Psychiatry 156:1205–1208PubMedGoogle Scholar
  52. Goffart S, Wiesner RJ (2003) Regulation and co-ordination of nuclear gene expression during mitochondrial biogenesis. Exp Physiol 88:33–40PubMedCrossRefGoogle Scholar
  53. Guo X, Macleod GT, Wellington A, Hu F, Panchumarthi S, Schoenfield M, Marin L, Charlton MP, Atwood HL, Zinsmaier KE (2005) The GTPase dMiro is required for axonal transport of mitochondria to Drosophila synapses. Neuron 47:379–393PubMedCrossRefGoogle Scholar
  54. Gur RE, Resnick SM, Alavi A, Gur RC, Caroff S, Dann R, Silver FL, Saykin AJ, Chwluk JB, Kudhner M (1987) Regional brain function in schizophrenia II: repeated evaluation with positron emission tomography. Arch Gen Psychiatry 44:126–129PubMedGoogle Scholar
  55. Harrison PJ (1999) The neuropathology of schizophrenia. A critical review of the data and their interpretation. Brain 122(Pt 4):593–624PubMedCrossRefGoogle Scholar
  56. Harrison PJ, Weinberger DR (2005) Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Mol Psychiatry 10:40–68 (image 45)PubMedCrossRefGoogle Scholar
  57. Hatefi Y (1985) The mitochondrial electron transport and oxidative phosphorylation system. Annu Rev Biochem 54:1015–1069PubMedCrossRefGoogle Scholar
  58. Hazlett EA, Buchsbaum MS, Byne W, Wei TC, Spiegel-Cohen J, Geneve C, Kinderlehrer R, Haznedar MM, Shihabuddin L, Siever LJ (1999) Three-dimensional analysis with MRI and PET of the size, shape, and function of the thalamus in the schizophrenia spectrum. Am J Psychiatry 156:1190–1199PubMedGoogle Scholar
  59. Hazlett EA, Buchsbaum MS, Jeu LA, Nenadic I, Fleischman MB, Shihabuddin L, Haznedar MM, Harvey PD (2000) Hypofrontality in unmedicated schizophrenia patients studied with PET during performance of a serial verbal learning tasks. Schizophr Res 43:33–46PubMedCrossRefGoogle Scholar
  60. Hevner RF, Wong-Riley M (1991) Neuronal expression of nuclear and mitochondrial genes for cytochrome oxidase (CO) subunits analyzed by in situ hybridization: comparison with CO activity and protein. J Neurosci 11:1942–1958PubMedGoogle Scholar
  61. Iwamoto K, Bundo M, Kato T (2005) Altered expression of mitochondria-related genes in postmortem brains of patients with bipolar disorder or schizophrenia, as revealed by large-scale DNA microarray analysis. Hum Mol Genet 14:241–253PubMedCrossRefGoogle Scholar
  62. Izumi Y, Sawada H, Yamamoto N, Kume T, Katsuki H, Shimohama S, Akaike A (2005) Iron accelerates the conversion of dopamine-oxidized intermediates into melanin and provides protection in SH-SY5Y cells. J Neurosci Res 82:126–137PubMedCrossRefGoogle Scholar
  63. Jakob H, Beckmann H (1989) Gross and histological criteria for developmental disorders in brains of schizophrenics. J R Soc Med 82:466–469PubMedGoogle Scholar
  64. Jayakumar PN, Venkatasubramanian G, Keshavan MS, Srinivas JS, Gangadhar BN (2006) MRI volumetric and 31P MRS metabolic correlates of caudate nucleus in antipsychotic-naive schizophrenia. Acta Psychiatr Scand 114:346–351PubMedCrossRefGoogle Scholar
  65. Jensen JE, Miller J, Williamson PC, Neufeld RW, Menon RS, Malla A, Manchanda R, Schaefer B, Densmore M, Drost DJ (2006) Grey and white matter differences in brain energy metabolism in first episode schizophrenia: 31P-MRS chemical shift imaging at 4 Tesla. Psychiatry Res 146:127–135PubMedCrossRefGoogle Scholar
  66. Kaminska B, Kaczmarek L, Larocque S, Chaudhuri A (1997) Activity-dependent regulation of cytochrome b gene expression in monkey visual cortex. J Comp Neurol 379:271–282PubMedCrossRefGoogle Scholar
  67. Kang JS, Tian JH, Pan PY, Zald P, Li C, Deng C, Sheng ZH (2008) Docking of axonal mitochondria by syntaphilin controls their mobility and affects short-term facilitation. Cell 132:137–148PubMedCrossRefGoogle Scholar
  68. Karry R, Klein E, Ben Shachar D (2004) Mitochondrial complex I subunits expression is altered in schizophrenia: a postmortem study. Biol Psychiatry 55:676–684PubMedCrossRefGoogle Scholar
  69. Kato T (2005) Mitochondrial dysfunction in bipolar disorder: from 31P-magnetic resonance spectroscopic findings to their molecular mechanisms. Int Rev Neurobiol 63:21–40PubMedCrossRefGoogle Scholar
  70. Kato T (2007) Mitochondrial dysfunction as the molecular basis of bipolar disorder: therapeutic implications. CNS Drugs 21:1–11PubMedCrossRefGoogle Scholar
  71. Kato T, Takahashi S, Shioiri T, Inubushi T (1992) Brain phosphorous metabolism in depressive disorders detected by phosphorus-31 magnetic resonance spectroscopy. J Affect Disord 26:223–230PubMedCrossRefGoogle Scholar
  72. Kato T, Kunugi H, Nanko S, Kato N (2001) Mitochondrial DNA polymorphisms in bipolar disorder. J Affect Disord 62:151–164PubMedCrossRefGoogle Scholar
  73. Khan FH, Sen T, Maiti AK, Jana S, Chatterjee U, Chakrabarti S (2005) Inhibition of rat brain mitochondrial electron transport chain activity by dopamine oxidation products during extended in vitro incubation: implications for Parkinson’s disease. Biochim Biophys Acta 1741:65–74PubMedGoogle Scholar
  74. Kim JJ, Mohamed S, Andreasen NC, O’Leary DS, Watkins GL, Boles Ponto LL, Hichwa RD (2000) Regional neural dysfunctions in chronic schizophrenia studied with positron emission tomography. Am J Psychiatry 157:542–548PubMedCrossRefGoogle Scholar
  75. Kishimoto H, Yamada K, Iseki E, Kosaka K, Okoshi T (1998) Brain imaging of affective disorders and schizophrenia. Psychiatry Clin Neurosci 52:S212–S214PubMedCrossRefGoogle Scholar
  76. Kolomeet NS, Uranova NA (1999) Synaptic contacts in schizophrenia: studies using immunocytochemical identification of dopaminergic neurons. Neurosci Behav Physiol 29:217–221CrossRefGoogle Scholar
  77. Kolomeets NS, Uranova N (2009) Ultrastructural abnormalities of astrocytes in the hippocampus in schizophrenia and duration of illness: a postmortem morphometric study. World J Biol Psychiatry 99999:1–11CrossRefGoogle Scholar
  78. Konradi C, Eaton M, MacDonald ML, Walsh J, Benes FM, Heckers S (2004) Molecular evidence for mitochondrial dysfunction in bipolar disorder. Arch Gen Psychiatry 61:300–308PubMedCrossRefGoogle Scholar
  79. Kumar A, Thomas A, Lavretsky H, Yue K, Huda A, Curran J, Venkatraman T, Estanol L, Mintz J, Mega M, Toga A (2002) Frontal white matter biochemical abnormalities in late-life major depression detected with proton magnetic resonance spectroscopy. Am J Psychiatry 159:630–636PubMedCrossRefGoogle Scholar
  80. Kung L, Roberts RC (1999) Mitochondrial pathology in human schizophrenic striatum: a postmortem ultrastructural study. Synapse 31:67–75PubMedCrossRefGoogle Scholar
  81. Lahti AC, Holcomb HH, Medoff DR, Weiler MA, Tamminga CA, Carpenter WT Jr (2001) Abnormal patterns of regional cerebral blood flow in schizophrenia with primary negative symptoms during an effortful auditory recognition task. Am J Psychiatry 158:1797–1808PubMedCrossRefGoogle Scholar
  82. Laruelle M, Abi-Dargham A, Gil R, Kegeles L, Innis R (1999) Increased dopamine transmission in schizophrenia: relationship to illness phase. Biol Psychiatry 46:56–72PubMedCrossRefGoogle Scholar
  83. LaVoie MJ, Hastings TG (1999) Dopamine quinone formation and protein modification associated with the striatal neurotoxicity of methamphetamine: evidence against a role for extracellular dopamine. J Neurosci 19:1484–1491PubMedGoogle Scholar
  84. Li Z, Okamoto K, Hayashi Y, Sheng M (2004) The importance of dendritic mitochondria in the morphogenesis and plasticity of spines and synapses. Cell 119:873–887PubMedCrossRefGoogle Scholar
  85. Liu A, Zhuang Z, Hoffman PW, Bai G (2003) Functional analysis of the rat N-methyl-d-aspartate receptor 2A promoter: multiple transcription starts points, positive regulation by Sp factors, and translational regulation. J Biol Chem 278:26423–26434PubMedCrossRefGoogle Scholar
  86. Ma L, Song L, Radoi GE, Harrison NL (2004) Transcriptional regulation of the mouse gene encoding the alpha-4 subunit of the GABAA receptor. J Biol Chem 279:40451–40461PubMedCrossRefGoogle Scholar
  87. Madhavarao CN, Chinopoulos C, Chandrasekaran K, Namboodiri MA (2003) Characterization of the N-acetylaspartate biosynthetic enzyme from rat brain. J Neurochem 86:824–835PubMedCrossRefGoogle Scholar
  88. Manoach DS, Press DZ, Thangaraj V, Searl MM, Goff DC, Halpern E, Saper CB, Warach S (1999) Schizophrenic subjects activate dorsolateral prefrontal cortex during a working memory task, as measured by fMRI. Biol Psychiatry 45:1128–1137PubMedCrossRefGoogle Scholar
  89. Martorell L, Segues T, Folch G, Valero J, Joven J, Labad A, Vilella E (2006) New variants in the mitochondrial genomes of schizophrenic patients. Eur J Hum Genet 14:520–528PubMedCrossRefGoogle Scholar
  90. Mattson MP (1999) Establishment and plasticity of neuronal polarity. J Neurosci 57:577–589CrossRefGoogle Scholar
  91. Maurer I, Zierz S, Moller H (2001) Evidence for a mitochondrial oxidative phosphorylation defect in brains from patients with schizophrenia. Schizophr Res 48:125–136PubMedCrossRefGoogle Scholar
  92. McGlashan TH (1988) A selective review of recent North American long-term follow-up studies of schizophrenia. Schizophr Bull 14:515–542PubMedGoogle Scholar
  93. McGlashan TH, Fenton WS (1992) The positive/negative distinction in schizophrenia: review of natural history validators. Arch Gen Psychiatry 49:63–72PubMedGoogle Scholar
  94. McMahon FJ, Chen YS, Patel S, Kokoszka J, Brown MD, Torroni A, DePaulo JR, Wallace DC (2000) Mitochondrial DNA sequence diversity in bipolar affective disorder. Am J Psychiatry 157:1058–1064PubMedCrossRefGoogle Scholar
  95. Mehler-Wex C, Duvigneau JC, Hartl RT, Ben-Shachar D, Warnke A, Gerlach M (2006) Increased mRNA levels of the mitochondrial complex I 75-kDa subunit : a potential peripheral marker of early onset schizophrenia? Eur Child Adolesc Psychiatry 15:504–507PubMedCrossRefGoogle Scholar
  96. Middleton FA, Mirnics K, Pierri JN, Lewis DA, Levitt P (2002) Gene expression profiling reveals alterations of specific metabolic pathways in schizophrenia. J Neurosci 22:2718–2729PubMedGoogle Scholar
  97. Mizino Y, Suzuki K, Ohta S (1990) Postmortem changes in mitochondrial respiratory enzymes in brain and a preliminary observation in Parkinson’s disease. J Neurol Sci 96:49–57CrossRefGoogle Scholar
  98. Muir WJ, Pickard BS, Blackwood DH (2008) Disrupted-in-Schizophrenia-1. Curr Psychiatry Rep 10:140–147PubMedCrossRefGoogle Scholar
  99. Mulcrone J, Whatley SA, Ferrier IN, Marchbanks RM (1995) A study of altered gene expression in frontal cortex from schizophrenic patients using differential screening. Schizophr Res 14:203–213PubMedCrossRefGoogle Scholar
  100. Ohnishi T, Ragan CI, Hatefi Y (1985) EPR studies of iron–sulfur clusters in isolated subunits and subfractions of NADH-ubiquinone oxidoreductase. J Biol Chem 260:2782–2788PubMedGoogle Scholar
  101. Okamoto S, Sherman K, Bai G, Lipton SA (2002) Effect of the ubiquitous transcription factors, SP1 and MAZ, on NMDA receptor subunit type 1 (NR1) expression during neuronal differentiation. Brain Res Mol Brain Res 107:89–96PubMedCrossRefGoogle Scholar
  102. Phillips LJ, Francey SM, Edwards J, McMurray N (2007) Stress and psychosis: towards the development of new models of investigation. Clin Psychol Rev 27:307–317PubMedCrossRefGoogle Scholar
  103. Potkin SG, Alva G, Fleming K, Anand R, Keator D, Carreon D, Doo M, Jin Y, Wu JC, Fallon JH (2002) A PET study of the pathophysiology of negative symptoms in schizophrenia. Positron emission tomography. Am J Psychiatry 157:227–237CrossRefGoogle Scholar
  104. Prabakaran S, Swatton JE, Ryan MM, Huffaker SJ, Huang JT, Griffin JL, Wayland M, Freeman T, Dudbridge F, Lilley KS, Karp NA, Hester S, Tkachev D, Mimmack ML, Yolken RH, Webster MJ, Torrey EF, Bahn S (2004) Mitochondrial dysfunction in schizophrenia: evidence for compromised brain metabolism and oxidative stress. Mol Psychiatry 9:684–697 (see also 643)PubMedCrossRefGoogle Scholar
  105. Prince JA, Yassin MS, Oreland L (1998) A histochemical demonstration of altered cytochrome oxidase activity in the rat brain by neuroleptics. Eur Neuropsychopharmacol 8:1–6PubMedCrossRefGoogle Scholar
  106. Prince JA, Blennow K, Gottfries CG, Karlsson I, Oreland L (1999) Mitochondrial function in differentially altered in the basal ganglia of chronic schizophrenics. Neuropsychopharmacol 21:372–379CrossRefGoogle Scholar
  107. Prince JA, Harro J, Blennow K, Gottfries CG, Karlsson I, Oreland L (2000) Putamen mitochondrial energy metabolism is highly correlated to emotional and intellectual impairment in schizophrenics. Neuropsychopharmacol 22:284–292CrossRefGoogle Scholar
  108. Przedborski S, Jackson-Lewis V, Muthane U, Jiang H, Ferreria M, Naini AB, Fahn S (1993) Chronic levodopa administration alters cerebral mitochondrial respiratory chain activity. Ann Neurol 34:715–723PubMedCrossRefGoogle Scholar
  109. Ragan CI, Galante YM, Hatefi Y (1982) Purification of three iron–sulfur proteins from the iron-protein fragment of mitochondrial NADH-ubiquinone oxidoreductase. Biochemistry 21:2518–2524PubMedCrossRefGoogle Scholar
  110. Reddy R, Keshavan MS (2003) Phosphorus magnetic resonance spectroscopy: its utility in examining the membrane hypothesis of schizophrenia. Prostaglandins Leukot Essent Fatty Acids 69:401–405PubMedCrossRefGoogle Scholar
  111. Rollins B, Martin MV, Sequeira PA, Moon EA, Morgan LZ, Watson SJ, Schatzberg A, Akil H, Myers RM, Jones EG, Wallace DC, Bunney WE, Vawter MP (2009) Mitochondrial variants in schizophrenia, bipolar disorder, and major depressive disorder. PLoS One 4:e4913PubMedCrossRefGoogle Scholar
  112. Seeman P (1987) Dopamine receptors and the dopamine hypothesis of schizophrenia. Synapse 1:133–152PubMedCrossRefGoogle Scholar
  113. Shao L, Martin MV, Watson SJ, Schatzberg A, Akil H, Myers RM, Jones EG, Bunney WE, Vawter MP (2008) Mitochondrial involvement in psychiatric disorders. Ann Med 40:281–295PubMedCrossRefGoogle Scholar
  114. Shenton ME, Dickey CC, Frumin M, McCarley RW (2001) A review of MRI findings in schizophrenia. Schizophr Res 49:1–52PubMedCrossRefGoogle Scholar
  115. Sherman SM, Spear PD (1982) Organization of visual pathways in normal and visually deprived cats. Physiol Rev 62:738–755PubMedGoogle Scholar
  116. Shifman S, Bronstein M, Sternfeld M, Pisante-Shalom A, Lev-Lehman E, Weizman A, Reznik I, Spivak B, Grisaru N, Karp L, Schiffer R, Kotler M, Strous RD, Swartz-Vanetik M, Knobler HY, Shinar E, Beckmann JS, Yakir B, Risch N, Zak NB, Darvasi A (2002) A Highly Significant Association between a COMT Haplotype and Schizophrenia. Am J Hum Genet 71:1296–1302PubMedCrossRefGoogle Scholar
  117. Shih JC, Grimsby J, Chen K, Zhu QS (1993) Structure and promoter organization of the human monoamine oxidase A and B genes. J Psychiatry Neurosci 18:25–32PubMedGoogle Scholar
  118. Souza ME, Polizello AC, Uyemura SA, Castro-Silva O, Curti C (1994) Effect of fluoxetine on rat liver mitochondria. Biochem Pharmacol 48:535–541PubMedCrossRefGoogle Scholar
  119. Stefansson H, Thorgeirsson TE, Gulcher JR, Stefansson K (2003) Neuregulin 1 in schizophrenia: out of Iceland. Mol Psychiatry 8:639–640PubMedCrossRefGoogle Scholar
  120. Stork C, Renshaw PF (2005) Mitochondrial dysfunction in bipolar disorder: evidence from magnetic resonance spectroscopy research. Mol Psychiatry 10:900–919PubMedCrossRefGoogle Scholar
  121. Stowers RS, Megeath LJ, Gorska-Andrzejak J, Meinertzhagen IA, Schwarz TL (2002) Axonal transport of mitochondria to synapses depends on Milton, a novel Drosophila protein. Neuron 36:1063–1077PubMedCrossRefGoogle Scholar
  122. Suske G (1999) The Sp-family of transcription factors. Gene 238:291–300PubMedCrossRefGoogle Scholar
  123. Szabo G, Katarova Z, Kortvely E, Greenspan RJ, Urban Z (1996) Structure and the promoter region of the mouse gene encoding the 67-kD form of glutamic acid decarboxylase. DNA Cell Biol 15:1081–1091PubMedCrossRefGoogle Scholar
  124. Tamminga CA, Thaker GK, Buchanan R, Kirkpatrick B, Alphs LD, Chase TN, Carpenter WT (1992) Limbic system abnormalities identified in schizophrenia using positron emission tomography with fluorodeoxyglucose and neocortical alterations with deficit syndrome. Arch Gen Psychiatry 49:522–530PubMedGoogle Scholar
  125. Tsankova N, Renthal W, Kumar A, Nestler EJ (2007) Epigenetic regulation in psychiatric disorders. Nat Rev Neurosci 8:355–367PubMedCrossRefGoogle Scholar
  126. Uranova NA, Aganova EA (1989) Ultrastructure of synapses of the anterior limbic cortex in schizophrenia. Zh Nevropatol Psikhiatr Im S S Korsakova 89:56–59PubMedGoogle Scholar
  127. Uranova N, Orlovskaya D, Vikhreva O, Zimina I, Kolomeets N, Vostrikov V, Rachmanova V (2001) Electron microscopy of oligodendroglia in severe mental illness. Brain Res Bull 55:597–610PubMedCrossRefGoogle Scholar
  128. Van Laar VS, Dukes AA, Cascio M, Hastings TG (2008) Proteomic analysis of rat brain mitochondria following exposure to dopamine quinone: implications for Parkinson disease. Neurobiol Dis 29:477–489PubMedCrossRefGoogle Scholar
  129. van Winkel R, Stefanis NC, Myin-Germeys I (2008) Psychosocial stress and psychosis: a review of the neurobiological mechanisms and the evidence for gene–stress interaction. Schizophr Bull 34:1095–1105PubMedCrossRefGoogle Scholar
  130. Vawter MP, Tomita H, Meng F, Bolstad B, Li J, Evans S, Choudary P, Atz M, Shao L, Neal C, Walsh DM, Burmeister M, Speed T, Myers R, Jones EG, Watson SJ, Akil H, Bunney WE (2006) Mitochondrial-related gene expression changes are sensitive to agonal-pH state: implications for brain disorders. Mol Psychiatry 11(615):663–679CrossRefGoogle Scholar
  131. Verstreken P, Ly CV, Venken KJ, Koh TW, Zhou Y, Bellen HJ (2005) Synaptic mitochondria are critical for mobilization of reserve pool vesicles at Drosophila neuromuscular junctions. Neuron 47:365–378PubMedCrossRefGoogle Scholar
  132. Volz HR, Riehemann S, Maurer I, Smesny S, Sommer M, Rzanny R, Holstein W, Czekalla J, Sauer H (2000) Reduced phosphodiesters and high-energy phosphates in the frontal lobe of schizophrenic patients: a 31P chemical shift spectroscopic-imaging study. Biol Psychiatry 47:954–961PubMedCrossRefGoogle Scholar
  133. Washizuka S, Kametani M, Sasaki T, Tochigi M, Umekage T, Kohda K, Kato T (2006) Association of mitochondrial complex I subunit gene NDUFV2 at 18p11 with schizophrenia in the Japanese population. Am J Med Genet B Neuropsychiatr Genet 141:301–304Google Scholar
  134. Weeber EJ, Levy M, Sampson MJ, Anflous K, Armstrong DL, Brown SE, Sweatt JD, Craigen WJ (2002) The role of mitochondrial porins and the permeability transition pore in learning and synaptic plasticity. J Biol Chem 277:18891–18897PubMedCrossRefGoogle Scholar
  135. Weinbach EC, Costa JL, Nelson BD, Claggett CE, Hundal T, Bradley D, Morris SJ (1986) Effects of tricyclic antidepressant drugs on energy-linked reactions in mitochondria. Biochem Pharmacol 35:1445–1451PubMedCrossRefGoogle Scholar
  136. Weinberger DR, Egan MF, Bertolino A, Callicott JH, Mattay VS, Lipska BK, Berman KF, Goldberg TE (2001) Prefrontal neurons and the genetics of schizophrenia. Biol Psychiatry 50:825–844PubMedCrossRefGoogle Scholar
  137. Whatley SA, Curi D, Marchbanks RM (1996) Mitochondrial involvement in schizophrenia and other functional psychoses. Neuroch Res 21:995–1004CrossRefGoogle Scholar
  138. Whatley SA, Curi D, Das Gupta F (1998) Superoxide, neuroleptics and the ubiquinone and cytochrome b5 reductases in brain and lymphocytes from normals and schizophrenic patients. Mol Psychiatry 3:227–237PubMedCrossRefGoogle Scholar
  139. Wolkin A, Jaeger J, Brodie JD, Wolf AP, Fowler J, Rotrosen J, Gomez-Mont F, Cancro R (1985) Persistence of cerebral metabolic abnormalities in chronic schizophrenia as determined by positron emission tomography. Am J Psychiatry 142:564–571PubMedGoogle Scholar
  140. Wong-Riley M (1989) Cytochrome c oxidase: an endogenous metabolic marker for neuronal activity. Trends Neurosci 12:94–101PubMedCrossRefGoogle Scholar
  141. Wright IC, Rabe-Hesketh S, Woodruff PW, David AS, Murray RM, Bullmore ET (2000) Meta-analysis of regional brain volumes in schizophrenia. Am J Psychiatry 157:16–25PubMedGoogle Scholar
  142. Yang C, Silver B, Ellis SR, Mower GD (2001) Bidirectional regulation of mitochondrial gene expression during developmental neuroplasticity of visual cortex. Biochem Biophys Res Commun 287:1070–1074PubMedCrossRefGoogle Scholar
  143. Yildiz-Yesiloglu A, Ankerst DP (2006) Review of 1H magnetic resonance spectroscopy findings in major depressive disorder: a meta-analysis. Psychiatry Res 147:1–25PubMedCrossRefGoogle Scholar
  144. Zaid A, Li R, Luciakova K, Barath P, Nery S, Nelson BD (1999) On the role of the general transcription factor Sp1 in the activation and repression of diverse mammalian oxidative phosphorylation genes. J Bioenerg Biomembr 31:129–135PubMedCrossRefGoogle Scholar
  145. Zickermann V, Zwicker K, Tocilescu MA, Kerscher S, Brandt U (2007) Characterization of a subcomplex of mitochondrial NADH:ubiquinone oxidoreductase (complex I) lacking the flavoprotein part of the N-module. Biochim Biophys Acta 1767:393–400PubMedCrossRefGoogle Scholar
  146. Zubin J, Spring B (1977) Vulnerability––a new view of schizophrenia. J Abnorm Psychol 86:103–126PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  1. 1.Laboratory of Psychobiology, Department of PsychiatryRambam Medical Center and Faculty of Medicine, Rappaport Family Institute for Research in the Medical Sciences, Technion IITHaifaIsrael

Personalised recommendations