Department of Environmental Health, National Institute of Public Health 2-3-6 Minami, Wako 351-0197, Saitama, Japan.
Genes (Basel). 2021 Jun 30;12(7):1015. doi: 10.3390/genes12071015.
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.
毛细血管扩张共济失调症（AT）的特征是对电离辐射极度敏感。在 AT 中突变的基因，共济失调毛细血管扩张突变基因（ATM），具有丝氨酸/苏氨酸蛋白激酶活性，并介导涉及 DNA 双链断裂处理的多个信号转导途径的激活。作为线粒体氧化磷酸化（OXPHOS）副产物产生的活性氧（ROS）已被提议为细胞内 ROS 的来源。线粒体由于是 ROS 产生的部位，因此特别容易受到 ROS 的影响。ROS 诱导的线粒体突变导致线粒体呼吸受损，并进一步增加 ROS 产生的可能性，从而建立 ROS 产生和线粒体损伤的恶性循环。AT 患者和 ATM 缺陷小鼠表现出内在的线粒体功能障碍，并表现出 ROS 水平的持续升高。ATM 在维持细胞氧化还原稳态中起着关键作用。然而，ATM 介导的线粒体抗氧化剂的确切机制尚不清楚。本综述论文的目的是介绍我们围绕 ATM 在维持人类成纤维细胞细胞内氧化还原控制中的作用的当前研究。ATM 介导的信号转导在线粒体辐射反应中很重要。线粒体氧化还原控制的扰动会升高 ROS，ROS 通过多种机制在癌症的发展中起着关键介质的作用，包括 ROS 介导的基因组不稳定性、肿瘤微环境形成和慢性炎症。
