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

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.

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

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.