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

Cell Cycle
Tsutomu ShimuraNaoki Kunugita

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 ...Continue Reading

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Citations

Oct 15, 2018·The Plant Journal : for Cell and Molecular Biology·José-Antonio Pedroza-GarcíaJavier Plasencia
Mar 7, 2019·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Tsutomu ShimuraNaoki Kunugita
Aug 5, 2020·Experimental Lung Research·Ying LiuYongli Bao
Nov 24, 2020·Cell Cycle·Tsutomu ShimuraAkira Ushiyama
Jul 26, 2018·Molecular Cancer Research : MCR·Tsutomu ShimuraNaoki Kunugita
Nov 7, 2021·The Plant Journal : for Cell and Molecular Biology·José Antonio Pedroza-GarciaLieven De Veylder
Jan 4, 2022·Journal of Radiation Research·Tsutomu ShimuraAkira Ushiyama

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Methods Mentioned

BETA
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X-ray

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