Circulating cell-free mitochondrial DNA in brain health and disease: A systematic review and meta-analysis

Objectives Circulating cell-free mitochondrial DNA (ccf-mtDNA) are detectable fragments of mtDNA released from the cell as a result of mitochondrial dysfunction or apoptosis. The brain is one of the most energy demanding organs in the human body, and many neuropsychiatric and non-psychiatric neurological diseases have mitochondrial dysfunction associated with disease pathophysiology. Thus, we aimed to assess ccf-mtDNA as a potential biomarker for brain diseases.Methods We conducted a systematic review and meta-analyses of studies that examined peripheral and/or cerebrospinal fluid (CSF) ccf-mtDNA relevant to neuropsychiatric conditions, which we define as disorders of affect, behaviour and mood, and non-psychiatric neurological diseases, which consist of neurological diseases not related to psychiatry including neurodegenerative diseases.Results The results of the sensitivity analysis investigating the levels of peripheral ccf-mtDNA in neuropsychiatric studies showed no significant difference between cases and controls (Z = 1.57; p = 0.12), whereas the results of the sensitivity analysis investigating the levels of CSF ccf-mtDNA in non-psychiatric neurological diseases showed a decreasing trend in cases compared with controls (Z = 2.32; p = 0.02). Interestingly, the results indicate an overall mitochondrial stress associated mainly with non-psychiatric neurological diseases.Conclusions Our study supports the involvement of mitochondrial stress, here defined as ccf-mtDNA, in brain diseases and encourage further investigation of ccf-mtDNA among patients with brain diseases.