Elevated serum circulating cell-free mitochondrial DNA in amyotrophic lateral sclerosis

Background and Purpose

The substantial role of inflammation in amyotrophic lateral sclerosis (ALS) is gaining support from recent research. Studies indicate that circulating cell-free mitochondrial DNA (ccf-mtDNA) can activate the immune system and is associated with neurodegenerative diseases. This research was designed to quantify ccf-mtDNA levels in the serum of ALS patients.

Methods

The medical records of ALS patients were reviewed. Serum ccf-mtDNA levels of patients with ALS (n = 62) and age-matched healthy controls (n = 46) were measured and compared. Additionally, serum interleukin-6 (IL-6) levels were measured using an enzyme-linked immunosorbent assay in 26 ALS patients. Correlations between variables were analyzed.

Results

Serum ccf-mtDNA was notably higher in the patients with ALS. When stratified by genotype, the superoxide dismutase 1 (SOD1) mutation group showed the greatest increase in ccf-mtDNA levels relative to other ALS patients. Among all 108 individuals, a cut-off set at 1.1 × 10⁵ mtDNA copies on a receiver-operating characteristic curve identified patients with ALS with 80.7% sensitivity and 50.0% specificity; the area under the curve was 0.69 (p < 0.001). Furthermore, serum ccf-mtDNA levels correlated negatively with the progression rate of ALS (ΔFS; rs = −0.26, p = 0.044), but not the ALSFRS-R score (rs = 0.06, p = 0.625). Importantly, the correlation between ccf-mtDNA and ΔFS was more pronounced in the SOD1 mutation group (rs = −0.62, p = 0.018). Lastly, a significant positive association was observed between serum ccf-mtDNA levels and IL-6 levels in ALS (r s= 0.41, p = 0.038).

Conclusion

Our study found increased serum ccf-mtDNA in ALS patients, suggesting a link to inflammatory processes and disease mechanism. Moreover, ccf-mtDNA could be an indicator for ALS progression, especially in those with the SOD1 mutation.