Melatonin as a radioprotectant against mitochondrial damage.

Abstract

Purpose: Conventional radioprotectants are designed to be administered before radiation exposure, while few have been identified that are effective when administered post-exposure. Irradiation generates intracellular reactive oxygen species (ROS) that induce mitochondrial damage, causing the release of mitochondrial contents into the cell cytoplasm and ensuing cell death. This mitochondrial damage occurs a few hours after radiation exposure, so mitochondria-targeted radioprotection can be effective when administered post-exposure. Here, we examined the efficacies of the glutathione (GSH) peroxidase activators melatonin and mitoEbselen-2 against radiation-induced mitochondrial damage.

Materials and methods: Human TIG-3 fibroblasts were exposed to ionizing radiation (IR), and cGAS-positive cytosolic DNA was detected by immunostaining with double-strand DNA and cGAS antibodies as an indicator of mitochondrial (mt)DNA leakage. Mitochondrial membrane potential (Δψm) was also measured using JC-1, while radiation-induced senescence was detected by β-gal staining. Mice were exposed to whole-body irradiation with or without melatonin treatment to assess radioprotective efficacy in vivo.

Results: Radiation exposure induced mitochondrial damage in TIG-3 cells as evidenced by cytosolic mtDNA leakage, Δψm depolarization, and accelerated cellular senescence. Melatonin and mitoEbselen-2 protected against both irradiation-induced and H₂O₂-induced mitochondrial damage, suggesting that these agents act as ROS scavengers. Melatonin also maintained Δψm after irradiation and inhibited cellular senescence. However, prolonged mitoEbselen-2 treatment indicated potential cytotoxicity as shown by Δψm loss. Melatonin mitigated the release of exosome mtDNA into the plasma of mice, as well as radiation-induced damage to blood cells and testicular tissue.

Conclusions: Melatonin can protect against irradiation-induced mitochondrial damage, suggesting utility for mitigating the health effects of accidental radiation exposure.