Mitochondrial Lipidomics Reveals Arachidonic Acid Deficiency as Targetable Feature in Schizophrenia
UHPLC-mass spectrometry-based mitochondrial lipidomic profiling of 93 schizophrenia patients revealed elevated oxidised lipids and arachidonic acid deficiency correlating with cognitive impairment severity. Six-week AA supplementation improved cognitive performance and restored mitochondrial lipid homeostasis. While primarily a psychiatric intervention study, the work demonstrates the diagnostic potential of mitochondrial lipid profiling for stratifying patients and monitoring treatment response.
The original study
Restoring mitochondrial lipid homeostasis with arachidonic acid supplementation to alleviate cognitive impairment in schizophrenia patients.
- Authors
- Gao Y, Wang D, Wang Q, Wang J, Li S, Lei F, et al.
- Journal
- Journal of advanced research
- PMID
- 41875945
Original abstract
INTRODUCTION: While mitochondrial dysfunction is implicated in schizophrenia, comprehensive understanding of mitochondrial lipid dysregulation in disease pathogenesis remains limited. OBJECTIVES: To elucidate lipid-driven mitochondrial pathology in schizophrenia and developing nutritional interventions to ameliorate cognitive impairment in schizophrenia through mitochondrial lipid homeostasis restoration. METHODS: 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. RESULTS: 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. CONCLUSION: 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.