ATM at the crossroads of reactive oxygen species and autophagy

Abstract

Reactive oxygen species (ROS) are generally small, short-lived and highly reactive molecules, initially thought to be a pathological role in the cell. A growing amount of evidence in recent years argues for ROS functioning as a signaling intermediate to facilitate cellular adaptation in response to pathophysiological stress through the regulation of autophagy. Autophagy is an essential cellular process that plays a crucial role in recycling cellular components and damaged organelles to eliminate sources of ROS in response to various stress conditions. A large number of studies have shown that DNA damage response (DDR) transducer ataxia-telangiectasia mutated (ATM) protein can also be activated by ROS, and its downstream signaling pathway is involved in autophagy regulation. This review aims at providing novel insight into the regulatory mechanism of ATM activated by ROS and its molecular basis for inducing autophagy, and revealing a new function that ATM can not only maintain genome homeostasis in the nucleus, but also as a ROS sensor trigger autophagy to maintain cellular homeostasis in the cytoplasm.

Keywords: ATM; DNA damage response; ROS; autophagy; oxidative stress.

Figure 1

The role of ROS in cell homeostasis and fate determination. The level of ROS determines its function and cell fate. High quantities of ROS irreversibly changes organelles and intracellular substances and make large-scale damange and lower level of ROS, as a redox sensitive second message, maintain cellular homeostasis. A growing amount of evidence in recent years argues for ROS functioning as a signaling intermediate to facilitate cellular adaptation in response to pathophysiological stress, such as regulation of autophagy. Therefore, ROS is not absolutely harmful, and treatment must consider the important role of ROS in physiologic and adaptive response.

Figure 2

Schematic overview of the ATM signalling pathway in response to DNA damage and ROS. ATM can not only maintain genomic homeostasis in the nucleus when double-strand DNA breaks , but ATM can also act as a ROS sensor to trigger autophagy to maintain cell homeostasis in the cytoplasm.

Figure 3

Schematic of ATM signaling pathway upon oxidative stress induced autophagy. Under metabolic stress conditions, mitochondria and peroxisomes can cause an increase in ROS production. ATM can act as a sensor of ROS to promote the formation of autophagosome membranes through ATM/CHK2/Beclin 1 and ATM/LKB1/AMPK/TSC2/mTOR pathways, promote mitophagy through ATM/CHK2/p53/ADH5 pathways, and enhance pexophagy through ATM/PEX5/p62 pathway.