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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

Abstract

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.

Keywords

Schizophrenia Mitochondria Complex I Dopamine Specificity protein 1 (Sp1) 

Notes

Acknowledgments

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.

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© 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

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