Mitochondrial dysfunction, a new marker warning of neuropsychiatric disorder risk: evidence from genetics and...

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.

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.

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.

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.