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Impaired mitochondrial function in psychiatric disorders

Key Points

  • Major psychiatric illnesses such as mood disorders and schizophrenia are common, chronic, recurrent mental illnesses that affect the lives and functioning of millions of individuals worldwide.

  • It is now clear that these illnesses are associated with impairments of synaptic plasticity and cellular resilience.

  • Most patients with these disorders do not have classic mitochondrial disorders, but there is a growing body of evidence to suggest that impaired mitochondrial function might have a major role in neural plasticity and cellular resilience, reducing synaptic functioning and producing long-term atrophic changes that underlie the deteriorating long-term course of these illnesses.

  • Evidence from animal models, in vitro studies, brain-imaging and post-mortem studies and genetics supports a role for mitochondria in mood disorders and schizophrenia.

  • Mood and psychotic symptoms are associated with both the rare disorders caused by mutations that directly affect mitochondrial function and the more common neurological disorders in which there is strong evidence for mitochondrial involvement.

  • Enhancing mitochondrial function may represent an important avenue for the development of novel therapeutics and also presents an opportunity for more efficient drug development.

Abstract

Major psychiatric illnesses such as mood disorders and schizophrenia are chronic, recurrent mental illnesses that affect the lives of millions of individuals. Although these disorders have traditionally been viewed as 'neurochemical diseases', it is now clear that they are associated with impairments of synaptic plasticity and cellular resilience. Although most patients with these disorders do not have classic mitochondrial disorders, there is a growing body of evidence to suggest that impaired mitochondrial function may affect key cellular processes, thereby altering synaptic functioning and contributing to the atrophic changes that underlie the deteriorating long-term course of these illnesses. Enhancing mitochondrial function could represent an important avenue for the development of novel therapeutics and also presents an opportunity for a potentially more efficient drug-development process.

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Figure 1: Mitochondrial function is at the nexus of several pathways that regulate synaptic plasticity and cellular resilience.
Figure 2: Calcium regulation by mitochondria.
Figure 3: mtDNA neuroplasticity hypothesis.
Figure 4: Investigative, pharmaceutical and nutritional compounds that target various aspects of mitochondrial function.

References

  1. 1

    Murray, C. J. & Lopez, A. D. Evidence-based health policy—lessons from the Global Burden of Disease Study. Science 274, 740–743 (1996).

    CAS  Article  PubMed  Google Scholar 

  2. 2

    Schloesser, R. J., Manji, H. K. & Martinowich, K. Suppression of adult neurogenesis leads to an increased hypothalamo-pituitary-adrenal axis response. Neuroreport 20, 553–557 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  3. 3

    Mattson, M. P., Gleichmann, M. & Cheng, A. Mitochondria in neuroplasticity and neurological disorders. Neuron 60, 748–766 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  4. 4

    Gleichmann, M. & Mattson, M. P. Neuronal calcium homeostasis and dysregulation. Antioxid. Redox. Signal. 14, 1261–1273 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  5. 5

    MacAskill, A. F., Atkin, T. A. & Kittler, J. T. Mitochondrial trafficking and the provision of energy and calcium buffering at excitatory synapses. Eur. J. Neurosci. 32, 231–240 (2010).

    Article  Google Scholar 

  6. 6

    Jonas, E. BCL-xL regulates synaptic plasticity. Mol. Interv. 6, 208–222 (2006).

    CAS  Article  PubMed  Google Scholar 

  7. 7

    Jonas, E. A. Molecular participants in mitochondrial cell death channel formation during neuronal ischemia. Exp. Neurol. 218, 203–212 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. 8

    Chen, G., Henter, I. D. & Manji, H. K. Translational research in bipolar disorder: emerging insights from genetically based models. Mol. Psychiatry 15, 883–895 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. 9

    Kato, T. Role of mitochondrial DNA in calcium signaling abnormality in bipolar disorder. Cell Calcium 44, 92–102 (2008).

    CAS  Article  PubMed  Google Scholar 

  10. 10

    Quiroz, J. A., Gray, N. A., Kato, T. & Manji, H. K. Mitochondrially mediated plasticity in the pathophysiology and treatment of bipolar disorder. Neuropsychopharmacology 33, 2551–2565 (2008).

    CAS  Article  PubMed  Google Scholar 

  11. 11

    Patergnani, S. et al. Calcium signaling around Mitochondria Associated Membranes (MAMs). Cell Commun. Signal. 9, 19 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. 12

    Massaad, C. A. & Klann, E. Reactive oxygen species in the regulation of synaptic plasticity and memory. Antioxid. Redox. Signal. 14, 2013–2054 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. 13

    Youle, R. J. & Strasser, A. The BCL-2 protein family: opposing activities that mediate cell death. Nature Rev. Mol. Cell Biol. 9, 47–59 (2008).

    CAS  Article  Google Scholar 

  14. 14

    Shoshan-Barmatz, V. & Ben-Hail, D. VDAC, a multi-functional mitochondrial protein as a pharmacological target. Mitochondrion 12, 24–34 (2012).

    CAS  Article  PubMed  Google Scholar 

  15. 15

    Ma, D. K. et al. Epigenetic choreographers of neurogenesis in the adult mammalian brain. Nature Neurosci. 13, 1338–1344 (2010).

    CAS  Article  PubMed  Google Scholar 

  16. 16

    Deng, W., Aimone, J. B. & Gage, F. H. New neurons and new memories: how does adult hippocampal neurogenesis affect learning and memory? Nature Rev. Neurosci. 11, 339–350 (2010).

    CAS  Article  Google Scholar 

  17. 17

    Hunsberger, J., Austin, D. R., Henter, I. D. & Chen, G. The neurotrophic and neuroprotective effects of psychotropic agents. Dialogues Clin. Neurosci. 11, 333–348 (2009).

    PubMed  PubMed Central  Google Scholar 

  18. 18

    Shaltiel, G., Chen, G. & Manji, H. K. Neurotrophic signaling cascades in the pathophysiology and treatment of bipolar disorder. Curr. Opin. Pharmacol. 7, 22–26 (2007).

    CAS  Article  PubMed  Google Scholar 

  19. 19

    Culmsee, C. & Mattson, M. P. p53 in neuronal apoptosis. Biochem. Biophys. Res. Commun. 331, 761–777 (2005).

    CAS  Article  PubMed  Google Scholar 

  20. 20

    Mattson, M. P., Keller, J. N. & Begley, J. G. Evidence for synaptic apoptosis. Exp. Neurol. 153, 35–48 (1998).

    CAS  Article  PubMed  Google Scholar 

  21. 21

    Glazner, G. W., Chan, S. L., Lu, C. & Mattson, M. P. Caspase-mediated degradation of AMPA receptor subunits: a mechanism for preventing excitotoxic necrosis and ensuring apoptosis. J. Neurosci. 20, 3641–3649 (2000).

    CAS  Article  PubMed  Google Scholar 

  22. 22

    Palmer, C. S., Osellame, L. D., Stojanovski, D. & Ryan, M. T. The regulation of mitochondrial morphology: Intricate mechanisms and dynamic machinery. Cell Signal. 23, 1534–1545 (2011).

    CAS  Article  PubMed  Google Scholar 

  23. 23

    Hu, D., Serrano, F., Oury, T. D. & Klann, E. Aging-dependent alterations in synaptic plasticity and memory in mice that overexpress extracellular superoxide dismutase. J. Neurosci. 26, 3933–3941 (2006).

    CAS  Article  PubMed  Google Scholar 

  24. 24

    Thiels, E. et al. Impairment of long-term potentiation and associative memory in mice that overexpress extracellular superoxide dismutase. J. Neurosci. 20, 7631–7639 (2000).

    CAS  Article  PubMed  Google Scholar 

  25. 25

    Li, Z. et al. Caspase-3 activation via mitochondria is required for long-term depression and AMPA receptor internalization. Cell 141, 859–871 (2010). This paper provides evidence of the underlying molecular mechanism linking apoptosis and synaptic depression through the mitochondrial pathway of caspase activation.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. 26

    Jiao, S. & Li, Z. Nonapoptotic function of BAD and BAX in long-term depression of synaptic transmission. Neuron 70, 758–772 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. 27

    Creson, T. K., Yuan, P., Manji, H. K. & Chen, G. Evidence for involvement of ERK, PI3K, and RSK in induction of Bcl-2 by valproate. J. Mol. Neurosci. 37, 123–134 (2009).

    CAS  Article  PubMed  Google Scholar 

  28. 28

    Murphy, A. N., Bredesen, D. E., Cortopassi, G., Wang, E. & Fiskum, G. Bcl-2 potentiates the maximal calcium uptake capacity of neural cell mitochondria. Proc. Natl Acad. Sci. USA 93, 9893–9898 (1996).

    CAS  Article  PubMed  Google Scholar 

  29. 29

    Chen, G. et al. The mood-stabilizing agents lithium and valproate robustly increase the levels of the neuroprotective protein bcl-2 in the CNS. J. Neurochem. 72, 879–882 (1999). This paper presents the novel findings of mood-stabilizing-agent-induced increases in CNS BCL-2 levels, which may have implications for the long-term treatment of various neurodegenerative disorders.

    CAS  Article  PubMed  Google Scholar 

  30. 30

    Zhou, R. et al. The anti-apoptotic, glucocorticoid receptor cochaperone protein BAG-1 is a long-term target for the actions of mood stabilizers. J. Neurosci. 25, 4493–4502 (2005).

    CAS  Article  PubMed  Google Scholar 

  31. 31

    Goodwin, F. K. & Jamison, K. R. Manic-Depressive Illness: Bipolar Disorders and Recurrent Depression 2nd edn (Oxford Univ. Press, 2007).

    Google Scholar 

  32. 32

    Maeng, S. et al. BAG1 plays a critical role in regulating recovery from both manic-like and depression-like behavioral impairments. Proc. Natl Acad. Sci. USA 105, 8766–8771 (2008). The authors present data to suggest that the level of neuronal expression of BAG1 , a common biochemical target for mood stabilizers, has a clinically relevant role in regulating recovery from stressors that can lead to the behavioural impairments associated with mood disorders. The authors suggest that therapies designed to enhance BAG1 function may lead to treatments for both the manic and depressive phases of bipolar disorders.

    CAS  Article  PubMed  Google Scholar 

  33. 33

    Demaurex, N. & Distelhorst, C. Cell biology. Apoptosis—the calcium connection. Science 300, 65–67 (2003).

    CAS  Article  Google Scholar 

  34. 34

    Malkesman, O. et al. Targeting the BH3-interacting domain death agonist to develop mechanistically unique antidepressants. Mol. Psychiatry 5 Jul 2011 (doi:10.1038/mp.2011.77).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. 35

    Hunsberger, J. G. et al. Bax inhibitor 1, a modulator of calcium homeostasis, confers affective resilience. Brain Res. 1403, 19–27 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  36. 36

    McMahon, F. J., Stine, O. C., Meyers, D. A., Simpson, S. G. & DePaulo, J. R. Patterns of maternal transmission in bipolar affective disorder. Am. J. Hum. Genet. 56, 1277–1286 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37

    Kirk, R. et al. Mitochondrial genetic analyses suggest selection against maternal lineages in bipolar affective disorder. Am. J. Hum. Genet. 65, 508–518 (1999).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  38. 38

    McMahon, F. J. et al. Mitochondrial DNA sequence diversity in bipolar affective disorder. Am. J. Psychiatry 157, 1058–1064 (2000).

    CAS  Article  PubMed  Google Scholar 

  39. 39

    Kato, T. et al. Parent-of-origin effect in transmission of bipolar disorder. Am. J. Med. Genet. 67, 546–550 (1996).

    CAS  Article  PubMed  Google Scholar 

  40. 40

    Munakata, K. et al. Mitochondrial DNA 3644T→C mutation associated with bipolar disorder. Genomics 84, 1041–1050 (2004).

    CAS  Article  PubMed  Google Scholar 

  41. 41

    Kong, Q. P. et al. Updating the East Asian mtDNA phylogeny: a prerequisite for the identification of pathogenic mutations. Hum. Mol. Genet. 15, 2076–2086 (2006).

    CAS  Article  PubMed  Google Scholar 

  42. 42

    Rollins, B. et al. Mitochondrial variants in schizophrenia, bipolar disorder, and major depressive disorder. PLoS ONE 4, e4913 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. 43

    Kato, T., Stine, O. C., McMahon, F. J. & Crowe, R. R. Increased levels of a mitochondrial DNA deletion in the brain of patients with bipolar disorder. Biol. Psychiatry 42, 871–875 (1997).

    CAS  Article  PubMed  Google Scholar 

  44. 44

    Shao, L. et al. Mitochondrial involvement in psychiatric disorders. Ann. Med. 40, 281–295 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  45. 45

    Sabunciyan, S. et al. Quantification of total mitochondrial DNA and mitochondrial common deletion in the frontal cortex of patients with schizophrenia and bipolar disorder. J. Neural Transm. 114, 665–674 (2007).

    CAS  Article  PubMed  Google Scholar 

  46. 46

    Kakiuchi, C. et al. Quantitative analysis of mitochondrial DNA deletions in the brains of patients with bipolar disorder and schizophrenia. Int. J. Neuropsychopharmacol. 8, 515–522 (2005).

    CAS  Article  PubMed  Google Scholar 

  47. 47

    Fuke, S., Kametani, M. & Kato, T. Quantitative analysis of the 4977-bp common deletion of mitochondrial DNA in postmortem frontal cortex from patients with bipolar disorder and schizophrenia. Neurosci. Lett. 439, 173–177 (2008).

    CAS  Article  PubMed  Google Scholar 

  48. 48

    Siciliano, G. et al. Autosomal dominant external ophthalmoplegia and bipolar affective disorder associated with a mutation in the ANT1 gene. Neuromuscul. Disord. 13, 162–165 (2003). This paper presents very compelling evidence for the role of deletions of mtDNA in BPD.

    CAS  Article  PubMed  Google Scholar 

  49. 49

    Suomalainen, A. et al. Multiple deletions of mitochondrial DNA in several tissues of a patient with severe retarded depression and familial progressive external ophthalmoplegia. J. Clin. Invest. 90, 61–66 (1992).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  50. 50

    Boles, R. G. et al. A high predisposition to depression and anxiety in mothers and other matrilineal relatives of children with presumed maternally inherited mitochondrial disorders. Am. J. Med. Genet. B Neuropsychiatr. Genet. 137B, 20–24 (2005).

    Article  PubMed  Google Scholar 

  51. 51

    Bergemann, E. R. & Boles, R. G. Maternal inheritance in recurrent early-onset depression. Psychiatr. Genet. 20, 31–34 (2011).

    Article  Google Scholar 

  52. 52

    Kim, M. Y., Lee, J. W., Kang, H. C., Kim, E. & Lee, D. C. Leukocyte mitochondrial DNA (mtDNA) content is associated with depression in old women. Arch. Gerontol. Geriatr. 53, e218–e221 (2011).

    CAS  Article  PubMed  Google Scholar 

  53. 53

    Kato, T., Kunugi, H., Nanko, S. & Kato, N. Mitochondrial DNA polymorphisms in bipolar disorder. J. Affect. Disord. 62, 151–164 (2001).

    CAS  Article  PubMed  Google Scholar 

  54. 54

    Washizuka, S. et al. Association of mitochondrial complex I subunit gene NDUFV2 at 18p11 with bipolar disorder in Japanese and the National Institute of Mental Health pedigrees. Biol. Psychiatry 56, 483–489 (2004).

    CAS  Article  PubMed  Google Scholar 

  55. 55

    Verge, B. et al. Mitochondrial DNA (mtDNA) and schizophrenia. Eur. Psychiatry 26, 45–56 (2011).

    CAS  Article  PubMed  Google Scholar 

  56. 56

    Warsh, J. J., Andreopoulos, S. & Li, P. P. Role of intracellular calcium signaling in the pathophysiology and pharmacotherapy of bipolar disorder: current status. Clin. Neurosci. Res. 4, 201–213 (2004).

    CAS  Article  Google Scholar 

  57. 57

    Kato, T. et al. Mechanisms of altered Ca2+ signalling in transformed lymphoblastoid cells from patients with bipolar disorder. Int. J. Neuropsychopharmacol. 6, 379–389 (2003).

    CAS  Article  PubMed  Google Scholar 

  58. 58

    Kazuno, A. A. et al. Identification of mitochondrial DNA polymorphisms that alter mitochondrial matrix pH and intracellular calcium dynamics. PLoS Genet. 2, e128 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. 59

    Naydenov, A. V., MacDonald, M. L., Ongur, D. & Konradi, C. Differences in lymphocyte electron transport gene expression levels between subjects with bipolar disorder and normal controls in response to glucose deprivation stress. Arch. Gen. Psychiatry 64, 555–564 (2007).

    Article  PubMed  Google Scholar 

  60. 60

    Cataldo, A. M. et al. Abnormalities in mitochondrial structure in cells from patients with bipolar disorder. Am. J. Pathol. 177, 575–585 (2010). This paper reports the first evidence to suggest that there is structural alteration of mitochondria in patients with bipolar disorder.

    Article  PubMed  PubMed Central  Google Scholar 

  61. 61

    Gardner, A. et al. Alterations of mitochondrial function and correlations with personality traits in selected major depressive disorder patients. J. Affect. Disord. 76, 55–68 (2003).

    CAS  Article  PubMed  Google Scholar 

  62. 62

    Machado-Vieira, R. et al. The Bcl-2 gene polymorphism rs956572AA increases inositol 1,4,5-trisphosphate receptor-mediated endoplasmic reticulum calcium release in subjects with bipolar disorder. Biol. Psychiatry 69, 344–352 (2011).

    CAS  Article  PubMed  Google Scholar 

  63. 63

    Vawter, M. P. et al. Mitochondrial-related gene expression changes are sensitive to agonal-pH state: implications for brain disorders. Mol. Psychiatry 11, 615, 663–679 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  64. 64

    Iwamoto, K., Bundo, M. & Kato, T. 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, 241–253 (2005).

    CAS  Article  PubMed  Google Scholar 

  65. 65

    Sun, X., Wang, J. F., Tseng, M. & Young, L. T. Downregulation in components of the mitochondrial electron transport chain in the postmortem frontal cortex of subjects with bipolar disorder. J. Psychiatry Neurosci. 31, 189–196 (2006).

    PubMed  PubMed Central  Google Scholar 

  66. 66

    MacDonald, M. L., Naydenov, A., Chu, M., Matzilevich, D. & Konradi, C. Decrease in creatine kinase messenger RNA expression in the hippocampus and dorsolateral prefrontal cortex in bipolar disorder. Bipolar Disord. 8, 255–264 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  67. 67

    Munakata, K., Iwamoto, K., Bundo, M. & Kato, T. Mitochondrial DNA 3243A>G mutation and increased expression of LARS2 gene in the brains of patients with bipolar disorder and schizophrenia. Biol. Psychiatry 57, 525–532 (2005).

    CAS  Article  PubMed  Google Scholar 

  68. 68

    Andreazza, A. C., Shao, L., Wang, J. F. & Young, L. T. Mitochondrial complex I activity and oxidative damage to mitochondrial proteins in the prefrontal cortex of patients with bipolar disorder. Arch. Gen. Psychiatry 67, 360–368 (2010). The results described in this post-mortem brain study suggest that impairment of mitochondrial electron-transport-chain complex I might be associated with increased protein oxidation and nitration in the prefrontal cortex of patients with BPD, but not schizophrenia. These data add to the growing evidence that mitochondrial impairment contributes to the pathogenesis of BPD.

    CAS  Article  PubMed  Google Scholar 

  69. 69

    Kim, H. W., Rapoport, S. I. & Rao, J. S. Altered expression of apoptotic factors and synaptic markers in postmortem brain from bipolar disorder patients. Neurobiol. Dis. 37, 596–603 (2010).

    CAS  Article  PubMed  Google Scholar 

  70. 70

    Kato, T. et al. Decreased brain intracellular pH measured by 31P-MRS in bipolar disorder: a confirmation in drug-free patients and correlation with white matter hyperintensity. Eur. Arch. Psychiatry Clin. Neurosci. 248, 301–306 (1998).

    CAS  Article  PubMed  Google Scholar 

  71. 71

    Kato, T. & Kato, N. Mitochondrial dysfunction in bipolar disorder. Bipolar Disord. 2, 180–190 (2000).

    CAS  Article  PubMed  Google Scholar 

  72. 72

    Jensen, J. E. et al. Triacetyluridine (TAU) decreases depressive symptoms and increases brain pH in bipolar patients. Exp. Clin. Psychopharmacol. 16, 199–206 (2008).

    CAS  Article  PubMed  Google Scholar 

  73. 73

    Moore, C. M., Christensen, J. D., Lafer, B., Fava, M. & Renshaw, P. F. Lower levels of nucleoside triphosphate in the basal ganglia of depressed subjects: a phosphorous-31 magnetic resonance spectroscopy study. Am. J. Psychiatry 154, 116–118 (1997).

    CAS  Article  PubMed  Google Scholar 

  74. 74

    Stork, C. & Renshaw, P. F. Mitochondrial dysfunction in bipolar disorder: evidence from magnetic resonance spectroscopy research. Mol. Psychiatry 10, 900–919 (2005). This review proposes a hypothesis of mitochondrial dysfunction in BPD that involves impaired oxidative phosphorylation, a resultant shift towards glycolytic energy production, a decrease in total energy production and/or substrate availability, and altered phospholipid metabolism.

    CAS  Article  PubMed  Google Scholar 

  75. 75

    Bates, T. E. et al. Inhibition of N-acetylaspartate production: implications for 1H MRS studies in vivo. Neuroreport 7, 1397–1400 (1996).

    CAS  Article  PubMed  Google Scholar 

  76. 76

    Bora, E., Fornito, A., Yucel, M. & Pantelis, C. Voxelwise meta-analysis of gray matter abnormalities in bipolar disorder. Biol. Psychiatry 67, 1097–1105 (2011).

    Article  Google Scholar 

  77. 77

    Chen, G., Huang, L. D., Jiang, Y. M. & Manji, H. K. The mood-stabilizing agent valproate inhibits the activity of glycogen synthase kinase-3. J. Neurochem. 72, 1327–1330 (1999).

    CAS  Article  PubMed  Google Scholar 

  78. 78

    Lyoo, I. K. et al. Lithium-induced gray matter volume increase as a neural correlate of treatment response in bipolar disorder: a longitudinal brain imaging study. Neuropsychopharmacology 35, 1743–1750 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  79. 79

    Rezin, G. T. et al. Inhibition of mitochondrial respiratory chain in brain of rats subjected to an experimental model of depression. Neurochem. Int. 53, 395–400 (2008).

    CAS  Article  PubMed  Google Scholar 

  80. 80

    Lucca, G. et al. Increased oxidative stress in submitochondrial particles into the brain of rats submitted to the chronic mild stress paradigm. J. Psychiatr. Res. 43, 864–869 (2009).

    Article  PubMed  Google Scholar 

  81. 81

    Gong, Y., Chai, Y., Ding, J. H., Sun, X. L. & Hu, G. Chronic mild stress damages mitochondrial ultrastructure and function in mouse brain. Neurosci. Lett. 488, 76–80 (2011).

    CAS  Article  PubMed  Google Scholar 

  82. 82

    Streck, E. L. et al. Brain creatine kinase activity in an animal model of mania. Life Sci. 82, 424–429 (2008).

    CAS  Article  PubMed  Google Scholar 

  83. 83

    Valvassori, S. S. et al. Effects of mood stabilizers on mitochondrial respiratory chain activity in brain of rats treated with d-amphetamine. J. Psychiatr. Res. 44, 903–909 (2010).

    Article  PubMed  Google Scholar 

  84. 84

    Frey, B. N. et al. Increased oxidative stress in submitochondrial particles after chronic amphetamine exposure. Brain Res. 1097, 224–229 (2006).

    CAS  Article  PubMed  Google Scholar 

  85. 85

    Freitas, T. P. et al. Evaluation of brain creatine kinase activity in an animal model of mania induced by ouabain. J. Neural Transm. 117, 149–153 (2010).

    Article  PubMed  Google Scholar 

  86. 86

    Kasahara, T. et al. Mice with neuron-specific accumulation of mitochondrial DNA mutations show mood disorder-like phenotypes. Mol. Psychiatry 11, 577–593, 523 (2006). These authors report that transgenic mice with neuron-specific accumulation of mtDNA show periodic alteration in wheel-running activity. This is the first animal model of a cyclic-activity phenotype resembling BPD.

    CAS  Article  PubMed  Google Scholar 

  87. 87

    Kasahara, T., Kubota, M., Miyauchi, T., Ishiwata, M. & Kato, T. A marked effect of electroconvulsive stimulation on behavioral aberration of mice with neuron-specific mitochondrial DNA defects. PLoS ONE 3, e1877 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. 88

    Kubota, M. et al. Abnormal Ca2+ dynamics in transgenic mice with neuron-specific mitochondrial DNA defects. J. Neurosci. 26, 12314–12324 (2006).

    CAS  Article  PubMed  Google Scholar 

  89. 89

    Kubota, M. et al. Therapeutic implications of down-regulation of cyclophilin D in bipolar disorder. Int. J. Neuropsychopharmacol. 13, 1355–1368 (2010).

    CAS  Article  PubMed  Google Scholar 

  90. 90

    Kato, T. Molecular neurobiology of bipolar disorder: a disease of 'mood-stabilizing neurons'? Trends Neurosci. 31, 495–503 (2008).

    CAS  Article  PubMed  Google Scholar 

  91. 91

    Rossignol, D. A. & Frye, R. E. Mitochondrial dysfunction in autism spectrum disorders: a systematic review and meta-analysis. Mol. Psychiatry 17, 290–314 (2012).

    CAS  Article  PubMed  Google Scholar 

  92. 92

    Jurata, L. W. et al. Altered expression of hippocampal dentate granule neuron genes in a mouse model of human 22q11 deletion syndrome. Schizophr. Res. 88, 251–259 (2006).

    Article  PubMed  Google Scholar 

  93. 93

    Ben-Shachar, D., Nadri, C., Karry, R. & Agam, G. Mitochondrial complex I subunits are altered in rats with neonatal ventral hippocampal damage but not in rats exposed to oxygen restriction at neonatal age. J. Mol. Neurosci. 38, 143–151 (2009).

    CAS  Article  PubMed  Google Scholar 

  94. 94

    Jarskog, L. F., Selinger, E. S., Lieberman, J. A. & Gilmore, J. H. Apoptotic proteins in the temporal cortex in schizophrenia: high Bax/Bcl-2 ratio without caspase-3 activation. Am. J. Psychiatry 161, 109–115 (2004).

    Article  PubMed  Google Scholar 

  95. 95

    Jarskog, L. F., Gilmore, J. H., Selinger, E. S. & Lieberman, J. A. Cortical Bcl-2 protein expression and apoptotic regulation in schizophrenia. Biol. Psychiatry 48, 641–650 (2000).

    CAS  Article  PubMed  Google Scholar 

  96. 96

    Lindholm, E. et al. Mitochondrial sequence variants in patients with schizophrenia. Eur. J. Hum. Genet. 5, 406–412 (1997).

    CAS  PubMed  Google Scholar 

  97. 97

    Martorell, L. et al. New variants in the mitochondrial genomes of schizophrenic patients. Eur. J. Hum. Genet. 14, 520–528 (2006).

    CAS  Article  PubMed  Google Scholar 

  98. 98

    Bandelt, H. J. et al. 'Distorted' mitochondrial DNA sequences in schizophrenic patients. Eur. J. Hum. Genet. 15, 400–402 (2007).

    CAS  Article  PubMed  Google Scholar 

  99. 99

    Ueno, H. et al. Analysis of mitochondrial DNA variants in Japanese patients with schizophrenia. Mitochondrion 9, 385–393 (2009).

    CAS  Article  PubMed  Google Scholar 

  100. 100

    Odawara, M. et al. Absence of association between a mitochondrial DNA mutation at nucleotide position 3243 and schizophrenia in Japanese. Hum. Genet. 102, 708–709 (1998).

    CAS  Article  PubMed  Google Scholar 

  101. 101

    Cavelier, L. et al. Decreased cytochrome-c oxidase activity and lack of age-related accumulation of mitochondrial DNA deletions in the brains of schizophrenics. Genomics 29, 217–224 (1995).

    CAS  Article  Google Scholar 

  102. 102

    Muller, D. J., Zai, C. C., Shinkai, T., Strauss, J. & Kennedy, J. L. Association between the DAOA/G72 gene and bipolar disorder and meta-analyses in bipolar disorder and schizophrenia. Bipolar Disord. 13, 198–207 (2011).

    CAS  Article  PubMed  Google Scholar 

  103. 103

    Kvajo, M., Dhilla, A., Swor, D. E., Karayiorgou, M. & Gogos, J. A. Evidence implicating the candidate schizophrenia/bipolar disorder susceptibility gene G72 in mitochondrial function. Mol. Psychiatry 13, 685–696 (2008).

    CAS  Article  PubMed  Google Scholar 

  104. 104

    Park, Y. U. et al. Disrupted-in-schizophrenia 1 (DISC1) plays essential roles in mitochondria in collaboration with Mitofilin. Proc. Natl Acad. Sci. USA 107, 17785–17790 (2010). The authors provide evidence that links DISC1 with regulation of key mitochondrial functions through interactions with mitofilin, a mitochondrial inner-membrane protein. The findings offer a possible underlying molecular mechanism to link DISC1 and mitofilin to mitochondrial function, the subsequent deregulation of which may be implicated in the pathogenesis of schizophrenia and related mood disorders.

    CAS  Article  Google Scholar 

  105. 105

    Ben-Shachar, D. et al. Cerebral glucose utilization and platelet mitochondrial complex I activity in schizophrenia: a FDG-PET study. Prog. Neuropsychopharmacol. Biol. Psychiatry 31, 807–813 (2007).

    CAS  Article  PubMed  Google Scholar 

  106. 106

    Ben-Shachar, D. et al. Increased mitochondrial complex I activity in platelets of schizophrenic patients. Int. J. Neuropsychopharmacol. 2, 245–253 (1999).

    CAS  Article  PubMed  Google Scholar 

  107. 107

    Uranova, N. et al. The ultrastructure of lymphocytes in schizophrenia. World J. Biol. Psychiatry 8, 30–37 (2007).

    Article  PubMed  Google Scholar 

  108. 108

    Rosenfeld, M., Brenner-Lavie, H., Ari, S. G., Kavushansky, A. & Ben-Shachar, D. Perturbation in mitochondrial network dynamics and in complex I dependent cellular respiration in schizophrenia. Biol. Psychiatry 69, 980–988 (2011).

    CAS  Article  PubMed  Google Scholar 

  109. 109

    Kung, L. & Roberts, R. C. Mitochondrial pathology in human schizophrenic striatum: a postmortem ultrastructural study. Synapse 31, 67–75 (1999).

    CAS  Article  PubMed  Google Scholar 

  110. 110

    Kolomeets, N. S. & Uranova, N. A. Synaptic contacts in schizophrenia: studies using immunocytochemical identification of dopaminergic neurons. Neurosci. Behav. Physiol. 29, 217–221 (1999).

    CAS  Article  PubMed  Google Scholar 

  111. 111

    Karry, R., Klein, E. & Ben Shachar, D. Mitochondrial complex I subunits expression is altered in schizophrenia: a postmortem study. Biol. Psychiatry 55, 676–684 (2004).

    CAS  Article  PubMed  Google Scholar 

  112. 112

    Ben-Shachar, D. & Karry, R. Neuroanatomical pattern of mitochondrial complex I pathology varies between schizophrenia, bipolar disorder and major depression. PLoS ONE 3, e3676 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. 113

    Burkhardt, C., Kelly, J. P., Lim, Y. H., Filley, C. M. & Parker, W. D. Jr. Neuroleptic medications inhibit complex I of the electron transport chain. Ann. Neurol. 33, 512–517 (1993).

    CAS  Article  Google Scholar 

  114. 114

    Pettegrew, J. W. et al. Alterations in brain high-energy phosphate and membrane phospholipid metabolism in first-episode, drug-naive schizophrenics. A pilot study of the dorsal prefrontal cortex by in vivo phosphorus 31 nuclear magnetic resonance spectroscopy. Arch. Gen. Psychiatry 48, 563–568 (1991).

    CAS  Article  PubMed  Google Scholar 

  115. 115

    Fujimoto, T. et al. Study of chronic schizophrenics using 31P magnetic resonance chemical shift imaging. Acta Psychiatr. Scand. 86, 455–462 (1992).

    CAS  Article  PubMed  Google Scholar 

  116. 116

    Fukuzako, H. Neurochemical investigation of the schizophrenic brain by in vivo phosphorus magnetic resonance spectroscopy. World J. Biol. Psychiatry 2, 70–82 (2001).

    CAS  Article  PubMed  Google Scholar 

  117. 117

    Honea, R., Crow, T. J., Passingham, D. & Mackay, C. E. Regional deficits in brain volume in schizophrenia: a meta-analysis of voxel-based morphometry studies. Am. J. Psychiatry 162, 2233–2245 (2005).

    Article  PubMed  Google Scholar 

  118. 118

    Steen, R. G., Mull, C., McClure, R., Hamer, R. M. & Lieberman, J. A. Brain volume in first-episode schizophrenia: systematic review and meta-analysis of magnetic resonance imaging studies. Br. J. Psychiatry 188, 510–518 (2006).

    Article  PubMed  Google Scholar 

  119. 119

    Selemon, L. D. & Rajkowska, G. Cellular pathology in the dorsolateral prefrontal cortex distinguishes schizophrenia from bipolar disorder. Curr. Mol. Med. 3, 427–436 (2003). The findings presented in this post-mortem brain study indicate that the cellular pathology in the dorsolateral prefrontal cortex differs in distinctive ways between patients with schizophrenia and those with BPD. The authors propose that the differences detected in the cellular pathology of these two disorders might account for the greater cognitive-task deficits seen in schizophrenia.

    CAS  Article  PubMed  Google Scholar 

  120. 120

    Hulshoff Pol, H. E. & Kahn, R. S. What happens after the first episode? A review of progressive brain changes in chronically ill patients with schizophrenia. Schizophr. Bull. 34, 354–366 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  121. 121

    Burchell, V. S. et al. Targeting mitochondrial dysfunction in neurodegenerative disease: Part II. Expert Opin. Ther. Targets. 14, 497–511 (2010).

    CAS  Article  PubMed  Google Scholar 

  122. 122

    Serviddio, G. et al. Principles and therapeutic relevance for targeting mitochondria in aging and neurodegenerative diseases. Curr. Pharm. Des. 17, 2036–2055 (2011).

    CAS  Article  PubMed  Google Scholar 

  123. 123

    Camara, A. K., Lesnefsky, E. J. & Stowe, D. F. Potential therapeutic benefits of strategies directed to mitochondria. Antioxid. Redox. Signal. 13, 279–347 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  124. 124

    Khanzode, S. D., Dakhale, G. N., Khanzode, S. S., Saoji, A. & Palasodkar, R. Oxidative damage and major depression: the potentialantioxidant action of selective serotonin re-uptake inhibitors. Redox Rep. 8, 365–370 (2003).

    CAS  Article  PubMed  Google Scholar 

  125. 125

    Bakare, A., Shao, L., Cui, J., Young, L. T. & Wang, J. F. Moodstabilizing drugs lamotrigine and olanzapine increase expression and activity of glutathione S-transferase in primary cultured rat cerebral cortical cells. Neurosci. Lett. 455, 70–73 (2009).

    CAS  Article  PubMed  Google Scholar 

  126. 126

    Cui, J., Shao, L., Young, L. T. & Wang, J. F. Role of glutathione in neuroprotective effects of mood stabilizing drugs lithium and valproate. Neuroscience 144, 1447–1453 (2007)

    CAS  Article  PubMed  Google Scholar 

  127. 127

    Shao, L., Cui, J., Young, L. T. & Wang, J. F. The effect of mood stabilizer lithium on expression and activity of glutathione s-transferase isoenzymes. Neuroscience 151, 518–524 (2008).

    CAS  Article  PubMed  Google Scholar 

  128. 128

    Berk, M. et al. N-acetyl cysteine for depressive symptoms in bipolar disorder—a double-blind randomized placebo-controlled trial. Biol. Psychiatry 64, 468–475 (2008).

    CAS  Article  PubMed  Google Scholar 

  129. 129

    Pieper, A. A. et al. Discovery of a proneurogenic, neuroprotective chemical. Cell 142, 39–51 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  130. 130

    Stavrovskaya, I. G. et al. Clinically approved heterocyclics act on a mitochondrial target and reduce stroke-induced pathology. J. Exp. Med. 200, 211–222 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  131. 131

    Galeotti, N., Bartolini, A. & Ghelardini, C. Blockade of intracellular calcium release induces an antidepressant-like effect in the mouse forced swimming test. Neuropharmacology 50, 309–316 (2006).

    CAS  Article  PubMed  Google Scholar 

  132. 132

    Galeotti, N., Vivoli, E., Norcini, M., Bartolini, A. & Ghelardini, C. An antidepressant behaviour in mice carrying a gene-specific InsP3R1, InsP3R2 and InsP3R3 protein knockdown. Neuropharmacology 55, 1156–1164 (2008).

    CAS  Article  PubMed  Google Scholar 

  133. 133

    Taragano, F. E., Allegri, R., Vicario, A., Bagnatti, P. & Lyketsos, C. G. A double blind, randomized clinical trial assessing the efficacy and safety of augmenting standard antidepressant therapy with nimodipine in the treatment of 'vascular depression'. Int. J. Geriatr. Psychiatry 16, 254–260 (2001).

    CAS  Article  PubMed  Google Scholar 

  134. 134

    Brunet, G. et al. Open trial of a calcium antagonist, nimodipine, in acute mania. Clin. Neuropharmacol. 13, 224–228 (1990).

    CAS  Article  PubMed  Google Scholar 

  135. 135

    Pazzaglia, P. J., Post, R. M., Ketter, T. A., George, M. S. & Marangell, L. B. Preliminary controlled trial of nimodipine in ultra-rapid cycling affective dysregulation. Psychiatry Res. 49, 257–272 (1993).

    CAS  Article  PubMed  Google Scholar 

  136. 136

    Mogilnicka, E., Czyrak, A. & Maj, J. BAY K 8644 enhances immobility in the mouse behavioral despair test, an effect blocked by nifedipine. Eur. J. Pharmacol. 151, 307–311 (1988).

    CAS  Article  PubMed  Google Scholar 

  137. 137

    Henchcliffe, C. & Beal, M. F. Mitochondrial biology and oxidative stress in Parkinson disease pathogenesis. Nature Clin. Pract. Neurol. 4, 600–609 (2008).

    CAS  Article  Google Scholar 

  138. 138

    Turner, C. & Schapira, A. H. Mitochondrial matters of the brain: the role in Huntington's disease. J. Bioenerg. Biomembr. 42, 193–198 (2010).

    CAS  Article  PubMed  Google Scholar 

  139. 139

    Galindo, M. F., Ikuta, I., Zhu, X., Casadesus, G. & Jordan, J. Mitochondrial biology in Alzheimer's disease pathogenesis. J. Neurochem. 114, 933–945 (2010).

    CAS  PubMed  Google Scholar 

  140. 140

    Woolley, J. D., Khan, B. K., Murthy, N. K., Miller, B. L. & Rankin, K. P. The diagnostic challenge of psychiatric symptoms in neurodegenerative disease: rates of and risk factors for prior psychiatric diagnosis in patients with early neurodegenerative disease. J. Clin. Psychiatry 72, 126–133 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  141. 141

    Reijnders, J. S., Ehrt, U., Weber, W. E., Aarsland, D. & Leentjens, A. F. A systematic review of prevalence studies of depression in Parkinson's disease. Mov. Disord. 23, 183–189 (2008).

    Article  PubMed  Google Scholar 

  142. 142

    Ishihara, L. & Brayne, C. A systematic review of depression and mental illness preceding Parkinson's disease. Acta Neurol. Scand. 113, 211–220 (2006).

    CAS  Article  PubMed  Google Scholar 

  143. 143

    Steinlechner, S. et al. Co-occurrence of affective and schizophrenia spectrum disorders with PINK1 mutations. J. Neurol. Neurosurg. Psychiatry 78, 532–535 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  144. 144

    Berrios, G. E. et al. Psychiatric symptoms in neurologically asymptomatic Huntington's disease gene carriers: a comparison with gene negative at risk subjects. Acta Psychiatr. Scand. 105, 224–230 (2002).

    CAS  Article  PubMed  Google Scholar 

  145. 145

    Kirkwood, S. C. et al. Longitudinal personality changes among presymptomatic Huntington disease gene carriers. Neuropsychiatry Neuropsychol. Behav. Neurol. 15, 192–197 (2002).

    PubMed  Google Scholar 

  146. 146

    Duff, K., Paulsen, J. S., Beglinger, L. J., Langbehn, D. R. & Stout, J. C. Psychiatric symptoms in Huntington's disease before diagnosis: the predict-HD study. Biol. Psychiatry 62, 1341–1346 (2007).

    Article  PubMed  Google Scholar 

  147. 147

    Paulsen, J. S., Ready, R. E., Hamilton, J. M., Mega, M. S. & Cummings, J. L. Neuropsychiatric aspects of Huntington's disease. J. Neurol. Neurosurg. Psychiatry 71, 310–314 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  148. 148

    Fiedorowicz, J. G., Mills, J. A., Ruggle, A., Langbehn, D. & Paulsen, J. S. Suicidal behavior in prodromal Huntington disease. Neurodegener. Dis. 8, 483–490 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  149. 149

    Di Maio, L. et al. Suicide risk in Huntington's disease. J. Med. Genet. 30, 293–295 (1993).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  150. 150

    Lyketsos, C. G. et al. Mental and behavioral disturbances in dementia: findings from the Cache County Study on Memory in Aging. Am. J. Psychiatry 157, 708–714 (2000).

    CAS  Article  PubMed  Google Scholar 

  151. 151

    Lyketsos, C. G. et al. Neuropsychiatric disturbance in Alzheimer's disease clusters into three groups: the Cache County study. Int. J. Geriatr. Psychiatry 16, 1043–1053 (2001).

    CAS  Article  PubMed  Google Scholar 

  152. 152

    Bassiony, M. M. et al. The relationship between delusions and depression in Alzheimer's disease. Int. J. Geriatr. Psychiatry 17, 549–556 (2002).

    Article  PubMed  Google Scholar 

  153. 153

    Zubenko, G. S. et al. A collaborative study of the emergence and clinical features of the major depressive syndrome of Alzheimer's disease. Am. J. Psychiatry 160, 857–866 (2003).

    Article  PubMed  Google Scholar 

  154. 154

    Craig, D., Mirakhur, A., Hart, D. J., McIlroy, S. P. & Passmore, A. P. A cross-sectional study of neuropsychiatric symptoms in 435 patients with Alzheimer's disease. Am. J. Geriatr. Psychiatry 13, 460–468 (2005).

    Article  PubMed  Google Scholar 

  155. 155

    Green, R. C. et al. Depression as a risk factor for Alzheimer disease: the MIRAGE Study. Arch. Neurol. 60, 753–759 (2003).

    Article  PubMed  Google Scholar 

  156. 156

    Aznar, S. & Knudsen, G. M. Depression and Alzheimer's disease: is stress the initiating factor in a common neuropathological cascade? J. Alzheimers Dis. 23, 177–193 (2011).

    Article  PubMed  Google Scholar 

  157. 157

    Barnes, D. E. & Yaffe, K. The projected effect of risk factor reduction on Alzheimer's disease prevalence. Lancet Neurol. 10, 819–828 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  158. 158

    Goosens, K. A. & Sapolsky, R. M. Stress and Glucocorticoid Contributions to Normal and Pathological Aging in Brain Aging: Models, Methods, and Mechanisms (ed. Riddle, D. R.) Ch.13 (CRC Press, Boca Raton, 2007).

    Google Scholar 

  159. 159

    Fernandez, M., Gobartt, A. L. & Balana, M. Behavioural symptoms in patients with Alzheimer's disease and their association with cognitive impairment. BMC Neurol. 10, 87 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  160. 160

    Swerdlow, R. H., Burns, J. M. & Khan, S. M. The Alzheimer's disease mitochondrial cascade hypothesis. J. Alzheimers Dis. 20 (Suppl. 2), 265–279 (2010).

    Article  CAS  PubMed Central  Google Scholar 

  161. 161

    Du, H. et al. Early deficits in synaptic mitochondria in an Alzheimer's disease mouse model. Proc. Natl Acad. Sci. USA 107, 18670–18675 (2010).

    CAS  Article  PubMed  Google Scholar 

  162. 162

    DeKosky, S. T. & Scheff, S. W. Synapse loss in frontal cortex biopsies in Alzheimer's disease: correlation with cognitive severity. Ann. Neurol. 27, 457–464 (1990).

    CAS  Article  PubMed  Google Scholar 

  163. 163

    Li, Z., Okamoto, K., Hayashi, Y. & Sheng, M. The importance of dendritic mitochondria in the morphogenesis and plasticity of spines and synapses. Cell 119, 873–887 (2004). This paper reveals the dynamic nature of dendritic mitochondria during synaptic activity and spine formation in living hippocampal neurons, and the essential and reciprocal relationship that exists in this mitochondrial–synaptic interplay. The data support a role for mitochondrial dysfunction in the characteristic synapse loss associated with neurodegenerative disorders.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  164. 164

    Baloyannis, S. J. Mitochondria are related to synaptic pathology in Alzheimer's disease. Int. J. Alzheimers Dis. 2011, 305395 (2011).

    PubMed  PubMed Central  Google Scholar 

  165. 165

    Calkins, M. J. & Reddy, P. H. Amyloid beta impairs mitochondrial anterograde transport and degenerates synapses in Alzheimer's disease neurons. Biochim. Biophys. Acta 1812, 507–513 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  166. 166

    Sydow, A. et al. Tau-induced defects in synaptic plasticity, learning, and memory are reversible in transgenic mice after switching off the toxic Tau mutant. J. Neurosci. 31, 2511–2525 (2011).

    CAS  Article  PubMed  Google Scholar 

  167. 167

    Orth, M. & Schapira, A. H. Mitochondria and degenerative disorders. Am. J. Med. Genet. 106, 27–36 (2001).

    CAS  Article  PubMed  Google Scholar 

  168. 168

    Kato, T. The other, forgotten genome: mitochondrial DNA and mental disorders. Mol. Psychiatry 6, 625–633 (2001).

    CAS  Article  PubMed  Google Scholar 

  169. 169

    Fattal, O., Link, J., Quinn, K., Cohen, B. H. & Franco, K. Psychiatric comorbidity in 36 adults with mitochondrial cytopathies. CNS Spectr. 12, 429–438 (2007).

    Article  PubMed  Google Scholar 

  170. 170

    Schapira, A. H. Mitochondrial disease. Lancet 368, 70–82 (2006).

    CAS  Article  PubMed  Google Scholar 

  171. 171

    Grover, S. et al. Mania as a first presentation in mitochondrial myopathy. Psychiatry Clin. Neurosci. 60, 774–775 (2006).

    Article  PubMed  Google Scholar 

  172. 172

    Prayson, R. A. & Wang, N. Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS) syndrome: an autopsy report. Arch. Pathol. Lab. Med. 122, 978–981 (1998).

    CAS  PubMed  Google Scholar 

  173. 173

    Oexle, K. & Zwirner, A. Advanced telomere shortening in respiratory chain disorders. Hum. Mol. Genet. 6, 905–908 (1997).

    CAS  Article  PubMed  Google Scholar 

  174. 174

    Smits, B. W. et al. Disease impact in chronic progressive external ophthalmoplegia: more than meets the eye. Neuromuscul. Disord. 21, 272–278 (2011).

    Article  PubMed  Google Scholar 

  175. 175

    Schmidt, H. D., Shelton, R. C. & Duman, R. S. Functional biomarkers of depression: diagnosis, treatment, and pathophysiology. Neuropsychopharmacology 36, 2375–2394 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  176. 176

    Du, J. et al. Dynamic regulation of mitochondrial function by glucocorticoids. Proc. Natl Acad. Sci. USA 106, 3543–3548 (2009). This is the first study to demonstrate the biphasic effects that glucocorticoids have on neuronal mitochondrial dynamics. The data also indicate the role that glucocorticoids and chronic stress might have in cellular plasticity and resilience.

    CAS  Article  Google Scholar 

  177. 177

    Capuron, L. & Miller, A. H. Immune system to brain signaling: neuropsychopharmacological implications. Pharmacol. Ther. 130, 226–238 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  178. 178

    Kato, T. Mitochondrial dysfunction as the molecular basis of bipolar disorder: therapeutic implications. CNS Drugs 21, 1–11 (2007).

    CAS  Article  PubMed  Google Scholar 

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Acknowledgements

S. Shirke (SIRO Clinpharm Pvt. Ltd., India) and W. P. Battisti (Janssen Research & Development, LLC, USA) provided editorial support for this manuscript.

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H. Manji, N. A. Di Prospero, S. Ness, M. Krams and G. Chen are employees of Janssen Research & Development, LLC, in Raritan, New Jersey, USA. T. Kato is an employee of the RIKEN Brain Science Institute in Tokyo, Japan, and M. F. Beal is an employee of Weill Medical College of Cornell University, New York, USA. All authors meet International Council of Medical Journal Editors criteria. All authors have contributed to the development of this Review and have approved the submission.

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Glossary

Mitochondrial permeability transition pore

(mPTP). A protein complex that crosses the outer and inner mitochondrial membranes. The permeability transition describes an increase in the permeability of the mitochondrial membranes to molecules of a molecular weight of less than 1,500 Daltons.

Valproate

A drug with multiple actions that is used for the treatment of seizures, bipolar disorder and migraine prophylaxis.

Learned helplessness test

A test used to measure the effects of antidepressant drugs. It is based on the phenomenon that animals cease to attempt to avoid aversive stimuli as a result of prior exposure to unavoidable stressors.

Behavioural sensitization test

A test that measures the progressive enhancement of behavioural responses to psychostimulants that is also considered to be an experimental model of the escalating increases in the severity of mania that occur over several episodes.

Tail suspension test

A test used to measure the behavioural effects of antidepressant drugs in which mice are suspended by the tip of their tail. Most mice eventually develop an immobile posture, which is thought to indicate behavioural despair. Various antidepressants and lithium reduce immobility in this test.

Forced swim test

A test used to measure the behavioural effects of antidepressant drugs in which mice are placed in a water tank. Most mice eventually develop an immobile posture, which is thought to indicate behavioural despair. Various antidepressants and lithium reduce immobility in this test.

mtDNA haplogroups

Haplogroups defined by differences in human mtDNA. Haplogroups are used to represent the major branch points on the mitochondrial phylogenetic tree.

Chronic progressive external ophthalmoplegia

(CPEO). A type of eye-movement disorder caused by mitochondrial myopathy.

Heteroplasmic

Describes a cell in which more than one type of mtDNA, including wild-type mtDNA, is present. The amount of mutant mtDNA usually correlates with the severity of mitochondrial disease.

Transmitochondrial cybrids

Hybrids of a cell line that contains no mtDNA, and platelets that contain mtDNA but no nuclear DNA. Such cybrids allow the study of mtDNA variations at the cellular level by excluding the influence of mutations in nuclear DNA.

Agonal state

State associated with agony, especially death.

Creatine kinase

An enzyme that is present in mitochondria and that catalyses the phosphorylation of creatine to creatine phosphate.

Protein carbonylation

An irreversible change resulting from oxidative damage that often leads to a loss of protein function. It is considered to be a widespread indicator of severe oxidative damage and disease-derived protein dysfunction.

Polymerase gamma

(POLG1). The catalytic subunit of mitochondrial DNA polymerase.

Adjunctive study

Study used together with the primary study. Its purpose is to assist the primary study.

Monoamine depletion

Reduction in the levels of serotonin, noradrenaline and/or dopamine in the CNS by inhibitors of key biosynthetic enzymes. The reductions are associated with anhedonia-like deficits that are insensitive to antidepressants but can be alleviated by treatment with ketamine.

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Manji, H., Kato, T., Di Prospero, N. et al. Impaired mitochondrial function in psychiatric disorders. Nat Rev Neurosci 13, 293–307 (2012). https://doi.org/10.1038/nrn3229

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