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ATM-Mediated Mitochondrial Radiation Responses of Human Fibroblasts
1Department of Environmental Health, National Institute of Public Health 2-3-6 Minami, Wako 351-0197, Saitama, Japan.
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.
Insights
Ataxia telangiectasia (AT) involves extreme radiation sensitivity due to ATM gene mutations. This research explores how ATM maintains cellular redox control, focusing on mitochondria and reactive oxygen species (ROS) to understand cancer development.
Area of Science:
- Molecular Biology
- Genetics
- Cell Biology
Background:
- Ataxia telangiectasia (AT) is a genetic disorder characterized by extreme sensitivity to ionizing radiation.
- The ATM gene, mutated in AT, encodes a protein kinase crucial for DNA double-strand break repair and signal transduction.
- Mitochondria are implicated as a primary source of reactive oxygen species (ROS), contributing to cellular damage and disease.
Purpose of the Study:
- To review current research on the role of ATM in maintaining cellular redox control, particularly within human fibroblasts.
- To elucidate the mechanisms by which ATM influences mitochondrial antioxidant functions.
- To understand the link between ATM, ROS, and cancer development.
Main Methods:
- Review of existing literature on ATM, DNA repair, mitochondrial function, and ROS.
- Analysis of studies investigating ATM-deficient cells and mice.
- Focus on signal transduction pathways involved in redox homeostasis.
Main Results:
- ATM plays a critical role in maintaining cellular redox homeostasis and mitochondrial function.
- ATM-deficient cells and mice exhibit elevated ROS levels and mitochondrial dysfunction.
- ATM-mediated signaling is vital for the mitochondrial response to radiation.
Conclusions:
- ATM is essential for cellular redox control and protecting mitochondria from ROS-induced damage.
- Dysregulation of ATM and mitochondrial redox balance contributes to cancer development through mechanisms like genomic instability and inflammation.
- Further research into ATM-mediated antioxidant pathways is needed to understand its full role in health and disease.
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