Mitochondrial Oxidative Phosphorylation System Dysfunction in Schizophrenia

Abstract

Schizophrenia (SCZ) is a severe, chronic mental disorder of unknown etiology and limited therapeutic options. Bioenergetic deficits in the oxidative phosphorylation system (OXPHOS) during early postnatal brain development may underlie disrupted neuronal metabolism and synaptic signaling, contributing to the neurodevelopmental and behavioral disturbances observed in patients. This narrative review summarizes updated evidence linking mitochondrial-OXPHOS dysfunction to SCZ pathophysiology. The novelty lies in the focus on OXPHOS dysfunction at the enzymatic/functional level, rather than on genetic, transcriptional, or oxidative parameters. While complex I impairment has long been highlighted and proposed as a peripheral marker of the disease, recent studies also report alterations in other OXPHOS complexes and their precursors. These findings suggest that OXPHOS dysfunction is not isolated to a single enzymatic component but affects broader mitochondrial function, alongside oxidative stress, contributing to disease progression through mechanisms involving apoptosis, accelerated aging, and synaptic deterioration. OXPHOS dysfunction in both central and peripheral tissues further supports its relevance to SCZ. Overall, the literature points to mitochondrial OXPHOS abnormalities as a significant biological feature of SCZ. Whether these alterations are causal factors or consequences of disease processes remains unclear. Understanding OXPHOS dysregulation may open new avenues for targeted therapies.

Keywords: OXPHOS; bioenergetics; metabolism; mitochondria; schizophrenia.

Figure 1

Upper half, mitochondrial physiology with electron transport chain and OXPHOS in the inner mitochondrial membrane, Krebs cycle providing molecules with reducing power to feed the mitochondrial respiratory chain, and intact mitochondrial genomes, located in the mitochondrial matrix. Bottom half, mitochondrial pathology with impaired mtDNA molecules, alterations in calcium homeostasis, cytochrome c release inducing apoptosis, and dysfunction of the OXPHOS generating ROS. The black warning symbols in the figure indicate the main points of dysfunction within the pathological context (at the bottom). ADP, adenosine diphosphate; ATP, adenosine triphosphate; Ca²⁺, calcium; CoQ, coenzyme Q; cyt C, cytochrome c; H⁺, hydrogen protons; H₂O, water; mtDNA, mitochondrial DNA; NAD+, nicotinamide adenine dinucleotide; NADH, reduced form of nicotinamide adenine dinucleotide; O₂, oxygen; OXPHOS: oxidative phosphorylation system; ROS: reactive oxygen species; TCA, tricarboxylic acid cycle.