Mitochondrial Oxidative Phosphorylation System (OXPHOS) Deficits in Schizophrenia

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 þ2 , 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. Abré géLes 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 rô le 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

Mitochondrial Complex I Deficiency in Schizophrenia and Bipolar Disorder and Medication Influence

“…These reductions might be the result of an overrepresentation of subjects with chronic antipsychotic medication that reduces complex I activity. To date, very few studies of deficits in complex I have been reported in medication-free subjects as reviewed [5,6,42]. The reports of a deficit in complex I are found in studies of medicated subjects, e.g.…”

“…Prior studies of the frontal cortex of subjects with BD [41] and SZ [42] have reported reductions in complex I activity. These reductions might be the result of an overrepresentation of subjects with chronic antipsychotic medication that reduces complex I activity.…”

Food Supplements Were Applied to the Mitochondrial Capacity of Retinal Cells and Oxidative Phosphorylation of Adenosine Triphosphate (ATP) Synthesis

“…The triphosphate synthetase inhibitor is, for example, oligomycin. Then, by adding an appropriate concentration of the anti-coupling agent, the mitochondria are allowed idling to limit the maximum oxygen consumption capacity of the mitochondria (Maximal Respiration) without destroying the electron transport chain of the mitochondrial inner membrane [4]. The anti-coupling agent is Carbonylcyanide-4-(trifluoromethoxy) phenylhydrazone (FCCP).…”

“…Oxidative injury and functional impairment may act an early and important role in the development of age-related macular degeneration (AMD) [2,4,5,6], Previous studies have indicated that damage to RPE through photochemical mechanisms by free radical reactions is driven by photo-excited, endogenous chromophores through the cornea and lens [2]. As we age, the yellow pigment accumulates; however, oxidative damage increases, antioxidant capacity decreases and the efficiency of self-repairing systems deteriorate during the aging process.…”

The Complex Interaction of Mitochondrial Genetics and Mitochondrial Pathways in Psychiatric Disease

“…In support of OXPHOS dysfunction in SCZ, a small parallel transcriptomic, proteomic, and metabolomic study found OXPHOS to be the most significantly downregulated pathway in patients compared to controls [74]. More details on the role of the OXPHOS pathway in the context of SCZ pathophysiology can be found in a recent review [75]. …”