ATM-Mediated Mitochondrial Radiation Responses of Human Fibroblasts.

Tsutomu Shimura

doi:10.3390/genes12071015

Abstract

Ataxia telangiectasia (AT) is characterized by extreme sensitivity to ionizing radiation. The gene mutated in AT, Ataxia Telangiectasia Mutated (ATM), has serine/threonine protein kinase activity and mediates the activation of multiple signal transduction pathways involved in the processing of DNA double-strand breaks. Reactive oxygen species (ROS) created as a byproduct of the mitochondria’s oxidative phosphorylation (OXPHOS) has been proposed to be the source of intracellular ROS. Mitochondria are uniquely vulnerable to ROS because they are the sites of ROS generation. ROS-induced mitochondrial mutations lead to impaired mitochondrial respiration and further increase the likelihood of ROS generation, establishing a vicious cycle of further ROS production and mitochondrial damage. AT patients and ATM-deficient mice display intrinsic mitochondrial dysfunction and exhibit constitutive elevations in ROS levels. ATM plays a critical role in maintaining cellular redox homeostasis. However, the precise mechanism of ATM-mediated mitochondrial antioxidants remains unclear. The aim of this review paper is to introduce our current research surrounding the role of ATM on maintaining cellular redox control in human fibroblasts. ATM-mediated signal transduction is important in the mitochondrial radiation response. Perturbation of mitochondrial redox control elevates ROS which are key mediators in the development of cancer by many mechanisms, including ROS-mediated genomic instability, tumor microenvironment formation, and chronic inflammation.

Highlights

Ataxia telangiectasia (AT) is a rare autosomal recessive disorder characterized by progressive impairments in muscular coordination, immunodeficiency, radiosensitivity, and a predisposition to cancer
Radiation-induced mitochondrial reactive oxygen species (ROS) are associated with the induction of mitophagy, which can be detected by the formation of Parkin and activation of the antioxidative response of nuclear factor erythroid 2-related factor 2 (Nrf2) in human fibroblasts [32,35]
We recently revealed that radiation affects malignant cancer cells and can cause molecular alterations in stromal fibroblasts

Summary

Introduction

Ataxia telangiectasia (AT) is a rare autosomal recessive disorder characterized by progressive impairments in muscular coordination, immunodeficiency, radiosensitivity, and a predisposition to cancer. The trimeric MRE11–RAD50–NBS1 (MRN) complex is involved in DSB recognition, pre-repair mechanisms, and keeping sister chromatids or broken ends in close proximity to one another [1] This complex recruits ATM to the DSB site [2], which, in turn, initiates DNA repair and checkpoint responses by activating an extensive signaling network [3,4,5,6]. Mitochondrial DNA (mtDNA) is located near the site of ROS production (Lambert and Brand, 2009) and is especially vulnerable to ROS-induced damage [17] This makes genes encoded by mtDNA especially sensitive to oxidative-stress-induced mutations (Wallace, 2010). Disruption of cellular redox homeostasis leads to ROS-mediated oxidative stress which causes detrimental health effects, including cancer, neurodegenerative diseases, and cardiac diseases [26,27,28,29,30]

Radiation-Induced Oxidative Stress

Mitochondrial Radiation Responses

The Role of Oxidative Stress in Cancer

Conclusions