ATM-mediated mitochondrial damage response triggered by nuclear DNA damage in normal human lung fibroblasts

ABSTRACT

Ionizing radiation (IR) elevates mitochondrial oxidative phosphorylation (OXPHOS) in response to the energy requirement for DNA damage responses. Reactive oxygen species (ROS) released during mitochondrial OXPHOS may cause oxidative damage to mitochondria in irradiated cells. In this paper, we investigated the association between nuclear DNA damage and mitochondrial damage following IR in normal human lung fibroblasts. In contrast to low-doses of acute single radiation, continuous exposure of chronic radiation or long-term exposure of fractionated radiation (FR) induced persistent Rad51 and γ-H2AX foci at least 24 hours after IR in irradiated cells. Additionally, long-term FR increased mitochondrial ROS accompanied with enhanced mitochondrial membrane potential (ΔΨm) and mitochondrial complex IV (cytochrome c oxidase) activity. Mitochondrial ROS released from the respiratory chain complex I caused oxidative damage to mitochondria. Inhibition of ATM kinase or ATM loss eliminated nuclear DNA damage recognition and mitochondrial radiation responses. Consequently, nuclear DNA damage activates ATM which in turn increases ROS level and subsequently induces mitochondrial damage in irradiated cells.

In conclusion, we demonstrated that ATM is essential in the mitochondrial radiation responses in irradiated cells. We further demonstrated that ATM is involved in signal transduction from nucleus to the mitochondria in response to IR.

KEYWORDS:

• Long-term fractionated radiation
• mitochondria
• ATM
• parkin
• ROS

Acknowledgements

Sources of support: This research was supported by a grant from the Japanese Ministry of Education and Science Houga (15K12220, 15K12212), Industrial Disease Clinical Research Grants from the Japanese Ministry of Health, Labour, and Welfare and in part by NIFS Collaborative Research Program (NIFS13KOBA028). This work was performed at the Joint Usage/Research Center (Radiation Biology Center), Kyoto University and the Program of the network-type joint Usage/Research Center for Radiation Disaster Medical Science of Hiroshima University, Nagasaki University and Fukushima Medical University.

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.