Metformin Reduces Oxidative Damage in RNASEH2-Mutant Aicardi-Goutières Cells.

BACKGROUND

Aicardi-Goutières Syndrome (AGS) is a rare neuroinflammatory condition characterized by early-onset symptoms that extend outside the nervous system. Due to the rarity of the disease, the pathogenesis is not well understood, and its diagnosis and treatment remain elusive. We recently demonstrated mitochondrial abnormalities and increased reactive oxygen species (ROS) levels in lymphoblastoid cell lines (LCLs) derived from - and -mutated AGS patients. On this background, we turned our attention to metformin, the first-choice drug for type 2 diabetes, as a possible treatment acting on oxidative stress in RNASEH2-mutant AGS cells.

METHODS AND RESULTS

By means of flow cytometry, we found that metformin treatment significantly decreases ROS production in - and -mutated AGS LCLs. Of note, metformin treatment reduces the green JC-1 monomeric signal and, concurrently, increases the red JC-1 signal in both mutated LCLs, accounting for restoration of the mitochondrial membrane potential. Immunofluorescence staining shows a decrease in 8-oxoG levels only in - mutated AGS LCLs. Finally, the significant upregulation of Forkhead Box O3 (), cytochrome C somatic (), and superoxide dismutase 2 () mRNA levels in -mutated AGS LCLs after metformin treatment points to signaling as a possible mechanism to reduce oxidative stress.

CONCLUSIONS

In conclusion, even if these pilot results need to be confirmed on a larger cohort, we shed light on metformin treatment as a valid approach to ameliorate oxidative stress-related inflammation in AGS patients.