Ann Gen Psychiatry. 2025 Oct 22;24(1):64. doi: 10.1186/s12991-025-00604-7.
ABSTRACT
BACKGROUND: Mitochondrial dysfunction has been implicated in the pathogenesis of a variety of neuropsychiatric disorders, but its causal role remains unclear. Mitochondrial DNA copy number (mtDNA-CN) and methylmalonic acid (MMA) are well-recognized biomarkers of mitochondrial function, but their association with psychiatric disorders has not yet been fully assessed.
METHODS: We performed two-step two-sample Mendelian randomization (MR) analyses using genome-wide association study (GWAS) data to assess causal associations between mtDNA-CN and 13 major neuropsychiatric disorders. In addition, we conducted a cross-sectional analysis using National Health and Nutrition Examination Survey (NHANES) data 2011-2014 to examine the association between serum MMA levels and cognitive impairment and depressive symptoms to further validate the correctness and robustness of the results of the MR analysis.
RESULTS: MR analysis showed a significant negative causal effect of mtDNA-CN on bipolar disorder, Alzheimer’s disease, dementia, depressive symptoms, and autism spectrum disorders (OR ranged from 0.15 to 0.84, all p < 0.05). Reverse MR analysis showed that only depressive symptoms had a significant causal effect on reducing mtDNA-CN. NHANES analysis further showed that higher MMA levels were significantly associated with an increased risk of cognitive impairment (OR = 1.56, p = 0.036) and depression (OR = 1.53, p = 0.020), suggesting that mitochondrial dysfunction and neuropsychiatric disorders have a close association.
CONCLUSION: The mitochondrial function biomarkers mtDNA-CN and MMA are expected to be potential therapeutic targets for depression and cognitive dysfunction, emphasizing the need for mitochondrial function monitoring and interventions in future therapies targeting neuropsychiatric disorders.
PMID:41126246 | DOI:10.1186/s12991-025-00604-7
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