Redox Biology (Sep 2024)
Oxidative stress and the multifaceted roles of ATM in maintaining cellular redox homeostasis
Abstract
The ataxia telangiectasia mutated (ATM) protein kinase is best known as a master regulator of the DNA damage response. However, accumulating evidence has unveiled an equally vital function for ATM in sensing oxidative stress and orchestrating cellular antioxidant defenses to maintain redox homeostasis. ATM can be activated through a non-canonical pathway involving intermolecular disulfide crosslinking of the kinase dimers, distinct from its canonical activation by DNA double-strand breaks. Structural studies have elucidated the conformational changes that allow ATM to switch into an active redox-sensing state upon oxidation. Notably, loss of ATM function results in elevated reactive oxygen species (ROS) levels, altered antioxidant profiles, and mitochondrial dysfunction across multiple cell types and tissues. This oxidative stress arising from ATM deficiency has been implicated as a central driver of the neurodegenerative phenotypes in ataxia-telangiectasia (A-T) patients, potentially through mechanisms involving oxidative DNA damage, PARP hyperactivation, and widespread protein aggregation. Moreover, defective ATM oxidation sensing disrupts transcriptional programs and RNA metabolism, with detrimental impacts on neuronal homeostasis. Significantly, antioxidant therapy can ameliorate cellular and organismal abnormalities in various ATM-deficient models. This review synthesizes recent advances illuminating the multifaceted roles of ATM in preserving redox balance and mitigating oxidative insults, providing a unifying paradigm for understanding the complex pathogenesis of A-T disease.
