Ataxia Telangiectasia Mutated Protein Kinase: A Potential Master Puppeteer of Oxidative Stress-Induced Metabolic Recycling

Abstract

Ataxia Telangiectasia Mutated protein kinase (ATM) has recently come to the fore as a regulatory protein fulfilling many roles in the fine balancing act of metabolic homeostasis. Best known for its role as a transducer of DNA damage repair, the activity of ATM in the cytosol is enjoying increasing attention, where it plays a central role in general cellular recycling (macroautophagy) as well as the targeted clearance (selective autophagy) of damaged mitochondria and peroxisomes in response to oxidative stress, independently of the DNA damage response. The importance of ATM activation by oxidative stress has also recently been highlighted in the clearance of protein aggregates, where the expression of a functional ATM construct that cannot be activated by oxidative stress resulted in widespread accumulation of protein aggregates. This review will discuss the role of ATM in general autophagy, mitophagy, and pexophagy as well as aggrephagy and crosstalk between oxidative stress as an activator of ATM and its potential role as a master regulator of these processes.

Figure 1

ROS can activate cytosolic ATM. ATM is activated in response to both endogenous and exogenous ROS, as well as NO at Cys²⁹⁹¹, where it forms a disulphide bond. Once activated, it phosphorylates LKB1 at Thr³⁶⁶ which phosphorylates AMPK and drives the inhibition of mTORC1 through TSC2. The inhibition of mTORC1 phosphorylates ULK1 at Ser⁷⁵⁷, whilst AMPK phosphorylates ULK1 at Ser³¹³. This initiates autophagy and the formation of an autophagosome that targets peroxisomes specifically for degradation through the ATM-mediated ubiquitination of PEX5. It is currently unknown whether ATM is involved in either the activation of AMPK or suppression of mTOR in response to ROS to induce mitophagy. ATM mediates PINK/Parkin mitophagy pathway in response to spermidine treatment, which induces ROS and consequently activate ATM, that is then recruited to the permeabilized mitochondrial membrane where it colocalize with PINK and drives the recruitment of Parkin which is ubiquitinated. The ubiquitin chain binds to LC3 (green balls) on the autophagosome, which then engulfs damaged mitochondria for lysosomal degradation (not shown). Hypoxia or mitochondrial uncoupling can also activate ULK1, driving its translocation to the damaged mitochondrion membrane where it phosphorylates FUNDC1, which enhances its binding to LC3, whereas the dephosphorylation of FUNDC1 by PGAM5 also allows FUNDC1 to directly interact with LC3. BNIP and NIX can act as mitochondrial receptors in response to hypoxia when the mitochondrial membrane is not permeabilized and bind to LC3 on the autophagosome. Damaged mitochondria produce less ATP that activates AMPK, which in turn phosphorylates ULK1 and activates the Beclin1-VSP34-VSP15 complex and drives the formation of an autophagosome. Damaged mitochondria can also produce ROS which inhibits mTOR and leads to the activation of autophagy.