Circulating Cell-Free Mitochondrial DNA in Cerebrospinal Fluid as a Biomarker for Mitochondrial Diseases

• Published in: Clinical chemistry (Baltimore, Md.) Vol. 67; no. 8; pp. 1113 - 1121
• Main Authors: Trifunov, Selena, Paredes-Fuentes, Abraham J, Badosa, Carmen, Codina, Anna, Montoya, Julio, Ruiz-Pesini, Eduardo, Jou, Cristina, Garrabou, Glòria, Grau-Junyent, Josep M, Yubero, Dèlia, Montero, Raquel, Muchart, Jordi, Ortigoza-Escobar, Juan D, O’Callaghan, Maria M, Nascimento, Andrés, Català, Albert, Garcia-Cazorla, Àngels, Jimenez-Mallebrera, Cecilia, Artuch, Rafael
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01.08.2021
• Subjects: Alanine; Biomarkers; Cerebrospinal fluid; Copy number; Deoxyribonucleic acid; Depletion; DNA; Genetic aspects; Health aspects; Lactic acid; Metabolic disorders; Mitochondrial diseases; Mitochondrial DNA; Mutation; Patients; Physiological aspects; Statistical analysis; Statistical methods; Structure-function relationships; Spain; mitochondrial diseases; droplet digital PCR; mitochondrial deletion and depletion syndromes; circulating cell-free mitochondrial DNA; cerebrospinal fluid
• ISSN: 0009-9147; 1530-8561; 1530-8561
• DOI: 10.1093/clinchem/hvab091

Abstract Background Mitochondrial diseases (MD) are genetic metabolic disorders that impair normal mitochondrial structure or function. The aim of this study was to investigate the status of circulating cell-free mitochondrial DNA (ccfmtDNA) in cerebrospinal fluid (CSF), together with other biomarkers (growth differentiation factor-15 [GDF-15], alanine, and lactate), in a cohort of 25 patients with a molecular diagnosis of MD. Methods Measurement of ccfmtDNA was performed by using droplet digital PCR. Results The mean copy number of ccfmtDNA was approximately 6 times higher in the MD cohort compared to the control group; patients with mitochondrial deletion and depletion syndromes (MDD) had the higher levels. We also detected the presence of both wild-type mtDNA and mtDNA deletions in CSF samples of patients with single deletions. Patients with MDD with single deletions had significantly higher concentrations of GDF-15 in CSF than controls, whereas patients with point mutations in mitochondrial DNA presented no statistically significant differences. Additionally, we found a significant positive correlation between ccfmtDNA levels and GDF-15 concentrations (r = 0.59, P = 0.016). Conclusion CSF ccfmtDNA levels are significantly higher in patients with MD in comparison to controls and, thus, they can be used as a novel biomarker for MD research. Our results could also be valuable to support the clinical outcome assessment of MD patients.