T71. MITOCHONDRIAL DNA REARRANGEMENT BURDEN IN FIRST-EPISODE PSYCHOSIS: IMPLICATIONS FOR PSYCHIATRIC PATHOPHYSIOLOGY

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Background Accumulating evidence implicates mitochondrial DNA (mtDNA) alterations and mitochondrial dysfunction in the pathophysiology of neuropsychiatric disorders, particularly schizophrenia. Our recent findings revealed a high burden of mtDNA alterations in the postmortem brains of patients with schizophrenia compared to healthy controls, suggesting a potential role for mtDNA instability in disease mechanisms. The aim of this study is to investigate mtDNA alterations in individuals with first-episode psychosis (FEP). Methods We analyzed peripheral blood mononuclear cells from 121 patients with FEP (mean age: 23.4 years; 33.3% female) and 57 healthy controls (HCs; mean age: 22.7 years; 45.6% female), who were recruited from Early Intervention Units in Catalonia, Spain. Total mtDNA was amplified into a single, overlapping fragment using long-range PCR and sequenced on the Illumina NextSeq 2000 platform. We used the MitoSAlt pipeline (v1.1.1) to detect and quantify mtDNA rearrangements, excluding those in the d-loop, and we set the heteroplasmy threshold at 1%. Results mtDNA deletions were detected in 46.3% of FEP patients versus 1.8% of HCs (χ² = 37.289, p < 0.001). The average number of deletions in FEP patients was 6.02 compared to one in the single affected HC. The mean deletion size was 818 bp in the FEP group, with a mean heteroplasmy level of 2.5%. Notably, two FEP patients exhibited large deletions (3,867 bp and 8,892 bp), with heteroplasmy levels of 65.6% and 10.2%, respectively. Duplications were observed in 32.2% of FEP patients and 19.3% of HCs (χ² = 3.209, p = 0.073). In FEP patients, duplications averaged 2.1 per subject, with a mean size of 4,706 bp and 3.6% heteroplasmy, which was comparable to that observed in HCs. Eleven FEP patients exhibited heteroplasmy levels exceeding 5%, whereas none of the HCs did. Discussion These results suggest a higher prevalence and burden of mtDNA deletions in FEP, which supports mitochondrial dysfunction as a contributing factor in early psychosis. Targeting mitochondrial pathways could provide new therapeutic options in psychiatric care.

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