• The mitochondrial lipid homeostasis of SZ was systematically depicted. • Elevated oxidized lipids and AA deficiency identified as key mitochondrial pathology in CIAS. • Six-week AA intervention alleviates cognitive deficits in SZ. • AA supplementation restores mitochondrial lipid homeostasis. • AA supplementation activates mitophagy and suppresses ferroptosis in SZ. While mitochondrial dysfunction is implicated in schizophrenia, comprehensive understanding of mitochondrial lipid dysregulation in disease pathogenesis remains limited. To elucidate lipid-driven mitochondrial pathology in schizophrenia and developing nutritional interventions to ameliorate cognitive impairment in schizophrenia through mitochondrial lipid homeostasis restoration. Here, this study investigated a total of 93 schizophrenia patients (61.3% male) and 34 matched healthy controls (41.2% male). Comprehensive mitochondrial lipidomic analyses using ultrahigh performance liquid chromatography-mass spectrometry were conducted to characterize pathological alterations in patients. Building on identification of arachidonic acid (AA) deficiency in schizophrenia-related cognitive impairment, we conducted a six-week nutritional intervention to evaluate AA supplementation’s therapeutic potential. Integrated mitochondrial lipidomic and transcriptomic profiling was performed to explore AA intervention-induced molecular changes and underlying mechanisms. Comparative analyses demonstrated significantly perturbed mitochondrial lipid profiles in schizophrenia patients, characterized by elevated oxidized lipids and AA deficiency. These metabolic disturbances exhibited strong positive correlations with cognitive impairment severity. Six-week AA supplementation improved cognitive performance through enhanced reaction speed, increased memory accuracy, and reduced decision-making errors. Concurrently, AA intervention restored mitochondrial lipid homeostasis by eliminating excessive levels of oxidative lipids. Enrichment analysis highlights key molecular pathways changed in mitophagy and ROS-induced ferroptosis. Our study identifies mitochondrial lipid dyshomeostasis as a pathological hallmark in schizophrenia and clarifies that AA supplementation may restore lipid balance, alongside with coordinating activation of mitophagy and ferroptosis suppression. These molecular corrections underlie the clinical efficacy of cognitive improvements, positioning mitochondrial lipid modulation as a promising therapeutic strategy for schizophrenia.
Gao et al. (Sun,) studied this question.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: