Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Immediate Communication
  • Published:

Mitochondrial dysfunction in schizophrenia: evidence for compromised brain metabolism and oxidative stress

Molecular Psychiatry volume 9, pages 684–697 (2004)Cite this article

Abstract

The etiology and pathophysiology of schizophrenia remain unknown. A parallel transcriptomics, proteomics and metabolomics approach was employed on human brain tissue to explore the molecular disease signatures. Almost half the altered proteins identified by proteomics were associated with mitochondrial function and oxidative stress responses. This was mirrored by transcriptional and metabolite perturbations. Cluster analysis of transcriptional alterations showed that genes related to energy metabolism and oxidative stress differentiated almost 90% of schizophrenia patients from controls, while confounding drug effects could be ruled out. We propose that oxidative stress and the ensuing cellular adaptations are linked to the schizophrenia disease process and hope that this new disease concept may advance the approach to treatment, diagnosis and disease prevention of schizophrenia and related syndromes.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

Similar content being viewed by others

References

  1. Middleton FA, Mirnics K, Pierri JN, Lewis DA, Levitt P . Gene expression profiling reveals alterations of specific metabolic pathways in schizophrenia. J Neurosci 2002; 22: 2718–2729.

    Article  CAS  Google Scholar 

  2. Hakak Y . Genome-wide expression analysis reveals dysregulation of myelination-related genes in chronic schizophrenia. Proc Natl Acad Sci USA 2001; 98: 4746–4751.

    Article  CAS  Google Scholar 

  3. Torrey EF, Webster M, Knable M, Johnston N, Yolken RH . The stanley foundation brain collection and neuropathology consortium. Schizophr Res 2000; 44: 151–155.

    Article  CAS  Google Scholar 

  4. Alban A, David SO, Bjorkesten L, Andersson C, Sloge E, Lewis S et al. A novel experimental design for comparative two-dimensional gel analysis: two-dimensional difference gel electrophoresis incorporating a pooled internal standard. Proteomics 2003; 3: 36–44.

    Article  CAS  Google Scholar 

  5. Griffin JL, Bollard M, Nicholson JK, Bhakoo K . Spectral profiles of cultured neuronal and glial cells derived from HRMAS (1)H NMR spectroscopy. NMR Biomed 2002; 15: 375–384.

    Article  CAS  Google Scholar 

  6. Ryan MM, Huffaker SJ, Webster MJ, Wayland M, Freeman T, Bahn S . Application and optimization of microarray technologies for human post-mortem brain studies. Biol Psychiatry 2003; 55: 329–336.

    Article  Google Scholar 

  7. Irizarry RA, Hobbs B, Collin F, Beazer-Barclay YD, Antonellis KJ, Scherf U et al. Exploration, normalization and summaries of high density oligonucleotide array probe level data. Biostatistics 2003; 4: 249–264.

    Article  Google Scholar 

  8. Rosner B . Percentage points for a generalized ESD many-outlier procedure. Technometrics 1983; 25: 165–172.

    Article  Google Scholar 

  9. Akaike H . Information theory and an extension of the maximum likelihood principle. Second Internatioanl Symposium on Information Theory. Akademiai Kiado, Budapest, 1973 pp 267–281.

    Google Scholar 

  10. Ihaka R, Gentleman R . A language for data analysis and graphics. J Comp Graph Stat 1996; 5: 299–314.

    Google Scholar 

  11. Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM et al. Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat Genet 2000; 25: 25–29.

    CAS  PubMed  Google Scholar 

  12. Taylor SW, Fahy E, Zhang B, Glenn GM, Warnock DE, Wiley S et al. Characterization of the human heart mitochondrial proteome. Nat Biotechnol 2003; 21: 281–286.

    Article  CAS  Google Scholar 

  13. Goswami S, Sheets NL, Zavadil J et al. Spectrum and range of oxidative stress responses of human lens epithelial cells to H2O2 insult. Invest Ophthalmol Vis Sci 2003; 44: 2084–2093.

    Article  Google Scholar 

  14. Horie S, Ishii H, Itoh S, Suga T . The noninvolvement of MDH as NAD-oxidoreductase shuttle in rat liver peroxisomes. Biochem Int 1984; 8: 353–359.

    CAS  PubMed  Google Scholar 

  15. Fujii J, Ikeda Y . Advances in our understanding of peroxiredoxin, a multifunctional, mammalian redox protein. Redox Rep 2002; 7: 123–130.

    Article  CAS  Google Scholar 

  16. Koerkamp MG, Rep M, Bussemaker HJ, Hardy GP, Mul A, Piekarska K et al. Dissection of transient oxidative stress response in Saccharomyces cerevisiae by using DNA microarrays. Mol Biol Cell 2002; 13: 2783–2794.

    Article  CAS  Google Scholar 

  17. Brown GK . Pyruvate dehydrogenase E1 alpha deficiency. J Inherit Metab Dis 1992; 15: 625–633.

    Article  CAS  Google Scholar 

  18. Hertz L, Dienel GA . Energy metabolism in the brain. Int Rev Neurobiol 2002; 51: 1–102.

    Article  CAS  Google Scholar 

  19. Michaelis T, Helms G, Frahm J . Metabolic alterations in brain autopsies: proton NMR identification of free glycerol. NMR Biomed 1996; 9: 121–124.

    Article  CAS  Google Scholar 

  20. Sebastian S, Kenkare UW . Stimulation of brain hexokinase gene expression by recombinant brain insulin-like growth factor in C6 glial cells. Exp Cell Res 1999; 246: 243–247.

    Article  CAS  Google Scholar 

  21. Guan J, Williams CE, Skinner SJ, Mallard EC, Gluckman PD . The effects of insulin-like growth factor (IGF)-1, IGF-2, and des-IGF-1 on neuronal loss after hypoxic-ischemic brain injury in adult rats: evidence for a role for IGF binding proteins. Endocrinology 1996; 137: 893–898.

    Article  CAS  Google Scholar 

  22. Roth AD, Leisewitz AV, Jung JE, Cassina P, Barbeito L, Inestrosa NC et al. PPAR gamma activators induce growth arrest and process extension in B12 oligodendrocyte-like cells and terminal differentiation of cultured oligodendrocytes. J Neurosci Res 2003; 72: 425–435.

    Article  CAS  Google Scholar 

  23. Tkachev D, Mimmack ML, Ryan MM, Wayland M, Freeman T, Jones PB et al. Oligodendrocyte dysfunction in schizophrenia and bipolar disorder. Lancet 2003; 362: 798–805.

    Article  CAS  Google Scholar 

  24. Nagarajan R, Svaren J, Le N, Araki T, Watson M, Milbrandt J . EGR2 mutations in inherited neuropathies dominant-negatively inhibit myelin gene expression. Neuron 2001; 30: 355–368.

    Article  CAS  Google Scholar 

  25. Nagarajan R, Le N, Mahoney H, Araki T, Milbrandt J . Deciphering peripheral nerve myelination by using Schwann cell expression profiling. Proc Natl Acad Sci USA 2002; 99: 8998–9003.

    Article  CAS  Google Scholar 

  26. Ramsay RR, Gandour RD, van der Leij FR . Molecular enzymology of carnitine transfer and transport. Biochim Biophys Acta 2001; 1546: 21–43.

    Article  CAS  Google Scholar 

  27. Heininger K . The cerebral glucose-fatty acid cycle: evolutionary roots, regulation, and (patho)physiological importance. Int Rev Neurobiol 2002; 51: 103–158.

    Article  CAS  Google Scholar 

  28. Sipos I, Tretter L, Adam-Vizi V . Quantitative relationship between inhibition of respiratory complexes and formation of reactive oxygen species in isolated nerve terminals. J Neurochem 2003; 84: 112–118.

    Article  CAS  Google Scholar 

  29. Carper DA, Sun JK, Iwata T, Zigler Jr JS, Ibaraki N, Lin LR et al. Oxidative stress induces differential gene expression in a human lens epithelial cell line. Invest Ophthalmol Vis Sci 1999; 40: 400–406.

    CAS  PubMed  Google Scholar 

  30. Cabiscol E, Piulats E, Echave P, Herrero E, Ross J . Oxidative stress promotes specific protein damage in Saccharomyces cerevisiae. J Biol Chem 2000; 275: 27393–27398.

    CAS  PubMed  Google Scholar 

  31. Blass JP . Glucose/mitochondria in neurological conditions. Int Rev Neurobiol 2002; 51: 325–376.

    Article  CAS  Google Scholar 

  32. Gardner PR, Nguyen DD, White CW . Aconitase is a sensitive and critical _target of oxygen poisoning in cultured mammalian cells and in rat lungs. Proc Natl Acad Sci USA 1994; 91: 12248–12252.

    Article  CAS  Google Scholar 

  33. Saransaari P, Oja SS . Taurine and neural cell damage. Amino Acids 2000; 19: 509–526.

    Article  CAS  Google Scholar 

  34. Dringen R, Hirrlinger J . Glutathione pathways in the brain. Biol Chem 2003; 384: 505–516.

    Article  CAS  Google Scholar 

  35. Berggren M, Gallegos A, Gasdaska JR, Gasdaska PY, Warneke J, Powis G . Thioredoxin and thioredoxin reductase gene expression in human tumors and cell lines, and the effects of serum stimulation and hypoxia. Anticancer Res 1996; 16: 3459–3466.

    CAS  PubMed  Google Scholar 

  36. Das KD, White CW . Redox systems of the cell: possible links and implications. Proc Natl Acad Sci USA 2002; 99: 9617–9618.

    Article  CAS  Google Scholar 

  37. Kang SW, Chae HZ, Seo MS, Kim K, Baines IC, Rhee SG . Mammalian peroxiredoxin isoforms can reduce hydrogen peroxide generated in response to growth factors and tumor necrosis factor-alpha. J Biol Chem 1998; 273: 6297–6302.

    Article  CAS  Google Scholar 

  38. Maier CM, Chan PH . Role of superoxide dismutases in oxidative damage and neurodegenerative disorders. Neuroscientist 2002; 8: 323–334.

    Article  CAS  Google Scholar 

  39. Demchenko IT, Oury TD, Crapo JD, Piantadosi CA . Regulation of the brain's vascular responses to oxygen. Circ Res 2002; 91: 1031–1037.

    Article  CAS  Google Scholar 

  40. Wheeler MD, Katuna M, Smutney OM et al. Comparison of the effect of adenoviral delivery of three superoxide dismutase genes against hepatic ischemia–reperfusion injury. Hum Gene Ther 2001; 12: 2167–2177.

    Article  CAS  Google Scholar 

  41. Campagne MV, Thibodeaux H, van Bruggen N, Cairns B, Lowe DG . Increased binding activity at an antioxidant-responsive element in the metallothionein-1 promoter and rapid induction of metallothionein-1 and -2 in response to cerebral ischemia and reperfusion. J Neurosci 2000; 20: 5200–5207.

    Article  Google Scholar 

  42. Emerson MR, Samson FE, Pazdernik TL . Effects of hypoxia preconditioning on expression of metallothionein-1,2 and heme oxygenase-1 before and after kainic acid-induced seizures. Cell Mol Biol (Noisy-le-grand) 2000; 46: 619–626.

    CAS  Google Scholar 

  43. Webster KA . Evolution of the coordinate regulation of glycolytic enzyme genes by hypoxia. J Exp Biol 2003; 206(part 17): 2911–2922.

    Article  CAS  Google Scholar 

  44. Wenger RH . Cellular adaptation to hypoxia: O2-sensing protein hydroxylases, hypoxia-inducible transcription factors, and O2-regulated gene expression. FASEB J 2002; 16: 1151–1162.

    Article  CAS  Google Scholar 

  45. Heidbreder M, Frohlich F, Johren O, Dendorfer A, Qadri F, Dominiak P . Hypoxia rapidly activates HIF-3alpha mRNA expression. FASEB J 2003; 17: 1541–1543.

    Article  CAS  Google Scholar 

  46. Sharp FR, Bergeron M, Bernaudin M . Hypoxia-inducible factor in brain. Adv Exp Med Biol 2001; 502: 273–291.

    Article  CAS  Google Scholar 

  47. Harris AL . Hypoxia—a key regulatory factor in tumour growth. Nat Rev Cancer 2002; 2: 38–47.

    Article  CAS  Google Scholar 

  48. Sakanaka M, Wen TC, Matsuda S, Masuda S, Morishita E, Nagao M et al. In vivo evidence that erythropoietin protects neurons from ischemic damage. Proc Natl Acad Sci USA 1998; 95: 4635–4640.

    Article  CAS  Google Scholar 

  49. Aversa A, Basciani S, Visca P, Arizzi M, Gnessi L, Frajese G et al. Platelet-derived growth factor (PDGF) and PDGF receptors in rat corpus cavernosum: changes in expression after transient in vivo hypoxia. J Endocrinol 2001; 170: 395–402.

    Article  CAS  Google Scholar 

  50. Cheng B, Mattson MP . PDGFs protect hippocampal neurons against energy deprivation and oxidative injury: evidence for induction of antioxidant pathways. J Neurosci 1995; 15: 7095–7104.

    Article  CAS  Google Scholar 

  51. Iihara K, Sasahara M, Hashimoto N, Hazama F . Induction of platelet-derived growth factor beta-receptor in focal ischemia of rat brain. J Cereb Blood Flow Metab 1996; 16: 941–949.

    Article  CAS  Google Scholar 

  52. Sakai Y, Furuichi M, Takahashi M, Mishima M, Iwai S, Shirakawa M et al. A molecular basis for the selective recognition of 2-hydroxy-dATP and 8-oxo-dGTP by human MTH1. J Biol Chem 2002; 277: 8579–8587.

    Article  CAS  Google Scholar 

  53. Parikh V, Khan MM, Mahadik SP . Differential effects of antipsychotics on expression of antioxidant enzymes and membrane lipid peroxidation in rat brain. J Psychiatr Res 2003; 37: 43–51.

    Article  Google Scholar 

  54. Peres M, Bourgeois D, Roussel S, Lefur Y, Devoulon P, Remy C et al. Two-dimensional 1H spectroscopic imaging for evaluating the local metabolic response to focal ischemia in the conscious rat. NMR Biomed 1992; 5: 11–19.

    Article  CAS  Google Scholar 

  55. Ryan MC, Collins P, Thakore JH . Impaired fasting glucose tolerance in first-episode, drug-naive patients with schizophrenia. Am J Psychiatry 2003; 160: 284–289.

    Article  Google Scholar 

  56. Henderson DC, Ettinger ER . Schizophrenia and diabetes. Int Rev Neurobiol 2002; 51: 481–501.

    Article  CAS  Google Scholar 

  57. Chambers CB, Lee JM, Troncoso JC, Reich S, Muma NA . Overexpression of four-repeat tau mRNA isoforms in progressive supranuclear palsy but not in Alzheimer's disease. Ann Neurol 1999; 46: 325–332.

    Article  CAS  Google Scholar 

  58. Barrier L . Evidence that acidosis alters the high-affinity dopamine uptake in rat striatal slices and synaptosomes by different mechanisms partially related to oxidative damage. Neurochem Int 2003; 42: 27–34.

    Article  CAS  Google Scholar 

  59. Fedorovich SV, Kaler GV, Konev SV . Effect of low pH on glutamate uptake and release in isolated presynaptic endings from rat brain. Neurochem Res 2003; 28: 715–721.

    Article  CAS  Google Scholar 

  60. Rae C . Is pH a biochemical marker of IQ? Proc R Soc Lond Ser B 1996; 263: 1061–1064.

    Article  CAS  Google Scholar 

  61. Hakak Y, Walker JR, Li C et al. Genome-wide expression analysis reveals dysregulation of myelination-related genes in chronic schizophrenia. Proc Natl Acad Sci USA 2001; 98: 4746–4751.

    Article  CAS  Google Scholar 

  62. Brockmann K . Succinate in dystrophic white matter; a proton magnetic resonance spectroscopy finding characteristics for complex II deficiency. Ann Neurol 2002; 52: 38–46.

    Article  CAS  Google Scholar 

  63. Jacobson AM, Samson JA, Weinger K, Ryan CM . Diabetes, the brain, and behavior: is there a biological mechanism underlying the association between diabetes and depression? Int Rev Neurobiol 2002; 51: 455–479.

    Article  Google Scholar 

  64. Mootha VK . PGC-1 alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet 2003; 34: 267–273.

    Article  CAS  Google Scholar 

  65. Ben-Shachar D . Mitochondrial dysfunction in schizophrenia: a possible linkage to dopamine. J Neurochem 2002; 83: 1241–1251.

    Article  CAS  Google Scholar 

  66. van Lookeren Campagne M, Thibodeaux H, van Bruggen N, Cairns B, Gerlai R, Palmer JT et al. Evidence for a protective role of metallothionein-1 in focal cerebral ischemia. Proc Natl Acad Sci USA 1999; 96: 12870–12875.

    Article  CAS  Google Scholar 

  67. Shi Y, Pritchard Jr. KA, Holman P, Rafiee P, Griffith OW, Kalyanaraman B et al. Chronic myocardial hypoxia increases nitric oxide synthase and decreases caveolin-3. Free Radic Biol Med 2000; 29: 695–703.

    Article  CAS  Google Scholar 

  68. Flavin MP, Yang Y, Ho G . Hypoxia forebrain cholinergic neuron injury: role of glucose, excitatory amino acid receptors and nitric oxide. Neurosci Lett 1993; 164: 5–8.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This research was supported by the Stanley Medical Research Institute (SMRI) and the donations of the Stanley brain collection courtesy of Drs Michael B Knable, E Fuller Torrey, Maree J Webster, Serge Weis and Robert H Yolken. The Department of Psychiatry gratefully acknowledges SMRI center support. We thank all other members of the Bahn laboratory for intellectual and practical input. Many thanks to Professors Peter Jones and Steve O’Rahilly and Dr Husseini Manji for valuable input and discussions and Dr Vivian Lee for help with gene ontology analysis. Sudhakaran Prabakaran is supported through a Nehru and Cambridge Commonwealth Trust scholarship, Dmitri Tkachev through a Darwin Trust scholarship, Janie Swatton is a Community Fund/Alzheimer Research Trust fellow and Stephen Huffaker is supported by the National Institutes of Health-Cambridge Health Science Scholars Program. We thank Drs Brian Sweatman and John Haselden of GlaxoSmithKline, Ware, UK for generous access to high-resolution NMR facilities. We also thank MRC genservice for hybridisation of the arrays.

Author information

Author notes

  1. S Prabakaran, J E Swatton, M M Ryan and S J Huffaker: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Neurobiology, Babraham Institute, Cambridge, UK

    S Prabakaran, J E Swatton, M M Ryan, S J Huffaker, JT-J Huang, D Tkachev, M L Mimmack & S Bahn

  2. Department of Psychiatry, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK

    S Prabakaran, J E Swatton, M M Ryan, S J Huffaker, JT-J Huang, D Tkachev, M L Mimmack & S Bahn

  3. Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Sanger Building, Cambridge, UK

    J L Griffin

  4. MRC Rosalind Franklin Centre for Genomics Research (formerly MRC Human Genome Mapping Project Resource Centre), Hinxton, Cambridge, UK

    M Wayland, T Freeman & F Dudbridge

  5. Department of Biochemistry, Cambridge Centre for Proteomics, University of Cambridge, Cambridge, UK

    K S Lilley, N A Karp & S Hester

  6. Stanley Division of Developmental Neurovirology, Johns Hopkins School of Medicine, Baltimore, MD, USA

    R H Yolken

  7. Department of Psychiatry, Stanley Laboratory of Brain Research, Uniformed Services University for the Health Sciences, Bethesda, MD, USA

    M J Webster & E F Torrey

Authors
  1. S Prabakaran
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J E Swatton
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M M Ryan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. S J Huffaker
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. JT-J Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J L Griffin
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. M Wayland
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. T Freeman
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. F Dudbridge
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. K S Lilley
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. N A Karp
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. S Hester
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. D Tkachev
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. M L Mimmack
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. R H Yolken
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. M J Webster
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. E F Torrey
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. S Bahn
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to S Bahn.

Additional information

Supplementary Information accompanies the paper on Molecular Pyschiatry website (http://www.nature.com/mp)

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Prabakaran, S., Swatton, J., Ryan, M. et al. Mitochondrial dysfunction in schizophrenia: evidence for compromised brain metabolism and oxidative stress. Mol Psychiatry 9, 684–697 (2004). https://doi.org/10.1038/sj.mp.4001511

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.mp.4001511

Keywords

Search

Advanced search

Quick links

  NODES
Association 1
COMMUNITY 1
INTERN 3
Note 2
Project 1