Abstract
BACKGROUND: Mitochondrial dysfunction represents a critical pathophysiological mechanism in schizophrenia, potentially linking bioenergetic impairment to synaptic dysfunction and cognitive deficits. Converging evidence suggests that deficits in oxidative phosphorylation may drive the synaptic pathology contributing to treatment-resistant cognitive and negative symptoms. OBJECTIVE: To systematically review the evidence linking mitochondrial bioenergetic dysfunction to synaptic impairment in schizophrenia, examining structural, functional, and molecular mechanisms across multiple methodological approaches. METHODS: Following PRISMA guidelines, we searched PubMed/MEDLINE, Embase, PsycINFO, and Web of Science from 2000 to 2025 for original research studies investigating mitochondrial function and synaptic dysfunction in schizophrenia. Two independent reviewers screened 2,224 articles, with 29 studies meeting inclusion criteria. Quality was assessed using the Newcastle-Ottawa Scale (median score 7/9). RESULTS: Twenty-nine studies representing 2,847 participants demonstrated consistent mitochondrial dysfunction across postmortem (n = 10), neuroimaging (n = 8), and molecular/cellular (n = 11) investigations. Postmortem studies revealed reduced complex I (18%-35%) and complex IV activity (22%-28%) in prefrontal cortex, with concurrent synaptic density reductions (27%). Neuroimaging studies demonstrated 20%-22% reductions in ATP synthesis rates correlating with cognitive deficits (r = 0.48) and negative symptoms (r = -0.42). First-episode antipsychotic-naïve patients exhibited comparable bioenergetic abnormalities, indicating primary pathophysiology rather than medication effects. Molecular studies identified impaired calcium homeostasis, oxidative stress (27%-35% glutathione reductions in synaptic compartments), and novel pseudogene regulatory mechanisms perpetuating complex I deficits. Peripheral biomarkers including platelet complex I activity and cell-free mitochondrial DNA showed disease specificity and correlation with cognitive impairment. Substantial methodological heterogeneity precluded meta-analysis but provided complementary evidence across analytical levels. CONCLUSION: Mitochondrial bioenergetic impairment represents a core, potentially modifiable pathophysiological mechanism driving synaptic dysfunction in schizophrenia. Regional specificity (prefrontal cortex, hippocampus) and cell-type selectivity (pyramidal neurons) provide mechanistic insights into cognitive symptom profiles. Early presence and progressive worsening suggest critical intervention windows. Mitochondrial-targeted therapies merit investigation as novel approaches for treatment-resistant cognitive and negative symptoms.