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.
Highlights
Ataxia Telangiectasia Mutated protein kinase (ATM) derives its name from the severe, recessive autosomal disease AtaxiaTelangiectasia (A-T)
The protein resides predominantly in the nucleus of dividing cells [12], where it acts as a transducer in the DNA damage response pathway (DDR), but ATM is mainly found in the cytoplasm of nondividing neuronal cells where it maintains basal metabolic flux [13]
This study investigated ATM activation under oxidative stress conditions generated with H2O2 and double strand DNA
Summary
Ataxia Telangiectasia Mutated protein kinase (ATM) derives its name from the severe, recessive autosomal disease AtaxiaTelangiectasia (A-T). The protein resides predominantly in the nucleus of dividing cells [12], where it acts as a transducer in the DNA damage response pathway (DDR), but ATM is mainly found in the cytoplasm of nondividing neuronal cells where it maintains basal metabolic flux [13]. Studies showed that ATM can be activated by endogenous ROS including peroxisomal reactive oxygen species (ROS) induced by clofibrate treatment [17] and mitochondrial superoxide induced by low doses of the redox-cycling chemical, menadione [18] Both peroxisomal and mitochondrial ROS activation of ATM increase autophagy through the activation of AMPK that results in mTOR suppression in the cytosol [19]. This review will focus on crosstalk between ROS as an activator of ATM and autophagy as a regulatory mechanism of protein aggregation and oxidative stress in the context of nondividing cells
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