Mitochondria are integral to cellular energy metabolism and ATP production and are involved in regulating many cellular processes. Mitochondria produce reactive oxygen species (ROS), which not only can damage cellular components but also participate in signal transduction. The kinase ATM, which is mutated in the neurodegenerative, autosomal recessive disease ataxia-telangiectasia (A-T), is a key player in the nuclear DNA damage response. However, ATM also performs a redox-sensing function mediated through formation of ROS-dependent disulfide-linked dimers. We found that mitochondria-derived hydrogen peroxide promoted ATM dimerization. In HeLa cells, ATM dimers were localized to the nucleus and inhibited by the redox regulatory protein thioredoxin 1 (TRX1), suggesting the existence of a ROS-mediated, stress-signaling relay from mitochondria to the nucleus. ATM dimer formation did not affect its association with chromatin in the absence or presence of nuclear DNA damage, consistent with the separation of its redox and DNA damage signaling functions. Comparative analysis of U2OS cells expressing either wild-type ATM or the redox sensing–deficient C2991L mutant revealed that one function of ATM redox sensing is to promote glucose flux through the pentose phosphate pathway (PPP) by increasing the abundance and activity of glucose-6-phosphate dehydrogenase (G6PD), thereby increasing cellular antioxidant capacity. The PPP produces the coenzyme NADPH needed for a robust antioxidant response, including the regeneration of TRX1, indicating the existence of a regulatory feedback loop involving ATM and TRX1. We propose that loss of the mitochondrial ROS-sensing function of ATM may cause cellular ROS accumulation and oxidative stress in A-T.

线粒体是细胞能量代谢和ATP产生所不可或缺的，并且参与调节许多细胞过程。线粒体产生活性氧（ROS），不仅可以破坏细胞成分，而且可以参与信号转导。在神经退行性常染色体隐性疾病共济失调毛细血管扩张症（AT）中发生突变的ATM激酶是核DNA损伤反应的关键因素。然而，ATM还执行通过形成ROS依赖的二硫键连接的二聚体介导的氧化还原传感功能。我们发现，线粒体来源的过氧化氢促进了ATM二聚化。在HeLa细胞中，ATM二聚体位于细胞核内，并被氧化还原调节蛋白thioredoxin 1（TRX1）抑制，表明存在ROS介导的，从线粒体到细胞核的应力信号传递。在不存在或存在核DNA损伤的情况下，ATM二聚体的形成并不影响其与染色质的缔合，这与其氧化还原和DNA损伤信号传导功能的分离是一致的。对表达野生型ATM或氧化还原感应缺陷的C2991L突变体的U2OS细胞的比较分析显示，ATM氧化还原感应的功能之一是通过增加葡萄糖6的丰度和活性来促进通过戊糖磷酸途径（PPP）的葡萄糖通量。 -磷酸脱氢酶（G6PD），从而增加细胞的抗氧化能力。PPP产生强大的抗氧化剂反应（包括TRX1的再生）所需的辅酶NADPH，表明存在涉及ATM和TRX1的调节反馈回路。