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Mitochondrial Oxidative Phosphorylation System (OXPHOS) Deficits in Schizophrenia: Possible Interactions with Cellular Processes - PubMed

Review

Mitochondrial Oxidative Phosphorylation System (OXPHOS) Deficits in Schizophrenia: Possible Interactions with Cellular Processes

Oded Bergman et al. Can J Psychiatry. 2016 Aug.

Abstract

Mitochondria are key players in the generation and regulation of cellular bioenergetics, producing the majority of adenosine triphosphate molecules by the oxidative phosphorylation system (OXPHOS). Linked to numerous signaling pathways and cellular functions, mitochondria, and OXPHOS in particular, are involved in neuronal development, connectivity, plasticity, and differentiation. Impairments in a variety of mitochondrial functions have been described in different general and psychiatric disorders, including schizophrenia (SCZ), a severe, chronic, debilitating illness that heavily affects the lives of patients and their families. This article reviews findings emphasizing the role of OXPHOS in the pathophysiology of SCZ. Evidence accumulated during the past few decades from imaging, transcriptomic, proteomic, and metabolomic studies points at OXPHOS deficit involvement in SCZ. Abnormalities have been reported in high-energy phosphates generated by the OXPHOS, in the activity of its complexes and gene expression, primarily of complex I (CoI). In addition, cellular signaling such as cAMP/protein kinase A (PKA) and Ca(+2), neuronal development, connectivity, and plasticity have been linked to OXPHOS function and are reported to be impaired in SCZ. Finally, CoI has been shown as a site of interaction for both dopamine (DA) and antipsychotic drugs, further substantiating its role in the pathology of SCZ. Understanding the role of mitochondria and the OXPHOS in particular may encourage new insights into the pathophysiology and etiology of this debilitating disorder.

Les mitochondries sont un acteur clé dans la génération et la régulation de la bioénergétique cellulaire, produisant la majorité des molécules ATP par le système de phosphorylation oxydative (OXPHOS). Liées à de nombreuses voies de signalisation et fonctions cellulaires, les mitochondries, et OXPHOS en particulier, sont impliqués dans le développement neuronal, la connectivité, la plasticité et la différenciation. Des déficiences d’une variété de fonctions mitochondriales ont été décrites dans différents troubles généraux et psychiatriques, dont la schizophrénie (SCZ), une maladie grave, chronique et débilitante qui affecte lourdement la vie des patients et de leur famille. Cet article passe en revue les résultats mettant l’accent sur le rôle d’OXPHOS dans la pathophysiologie de la SCZ. Les données probantes accumulées au cours des récentes décennies dans des études d’imagerie, transcriptomiques, protéomiques et métabolomiques dénoncent la participation du déficit d’OXPHOS à la SCZ. Des anomalies ont été signalées dans les phosphates à haute énergie produits par le système OXPHOS, dans l’activité de ses complexes et de son expression génétique, principalement du complexe I (CoI). En outre, la signalisation cellulaire, comme cAMP/PKA et Ca+2, le développement neuronal, la connectivité et la plasticité ont été liés à la fonction OXPHOS et sont déclarés déficients dans la SCZ. Finalement, CoI s’est avéré être un site d’interaction pour la dopamine (DA) et les antipsychotiques, ce qui étaye encore son rôle dans la pathologie de la SCZ. Comprendre le rôle des mitochondries et d’OXPHOS en particulier peut susciter de nouvelles idées pour la pathophysiologie et l’étiologie de ce trouble débilitant.

Keywords: Schizophrenia; cAMP/PKA and Ca+2 signaling; complex I; dopamine; mitochondria; neurodevelopment and plasticity; oxidative phosphorylation system.

© The Author(s) 2016.

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Conflict of interest statement

Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Figures

Figure 1.
Figure 1.

Summary of the most reproducible deficiencies in the oxidative phosphorylation system (OXPHOS) and its related cellular signaling in schizophrenia (SCZ) and bipolar disorder (BD). (A) The most frequent single-nucleotide polymorphisms (SNPs) reported in nuclear and mitochondrial DNA (nDNA and mtDNA, respectively) encoded subunits of complex I. (B) Increase and decrease in the expression of various subunits of the OXPHOS complexes. (C) Reduced and enhanced enzymatic activity of 3 complexes of the OXPHOS. (D) The respiratory chain complexes, electron transfer, and adenosine triphosphate (ATP) production. (E) The mitochondrial cAMP/protein kinase A (PKA) signaling pathway, which affects the expression of mtDNA encoded subunits of the OXPHOS complexes. (F) Altered glutamate NMDA receptor transmission and intracellular Ca2+ concentration and signaling. (G) Alterations in mitochondrial originated high-energy phosphates, lactate, and pH, indicating impaired energy production in cell or tissue. (H) Disease-related neurodevelopmental consequences of the alterations presented in A to G. Arrows indicate the direction of alteration. PCr, phosphocreatine.

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