ATM loss disrupts the autophagy-lysosomal pathway

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

“…Lysosomal dynein accumulates in ATM -/mouse brains indicating that ATM inhibits axonal transport through dynein motor proteins. Similarly, the study found that the loss of ATM resulted in the impaired glucose uptake due to the inhibition of the translocation of the SLC2A4/GLUT4 (solute carrier family 4 (facilitated glucose transporter) 4) to the plasma membrane, and increased trafficking to lysosomes instead [80]. This observation further supports previous reports that decreased ATM activity is associated with metabolic syndrome [81] and insulin resistance [82].…”

“…This broad overview describes the apical protein, ATM protein kinase, at the nexus of oxidative stress-induced autophagy [14,18] as well as nitrosative stress-induced autophagy [72,116], mitophagy [113,114], and pexophagy [17,132] mainly in the context of nondividing cells such as cardiomyocytes and neurons. Site-specific mutations that renders ATM insensitive to oxidative stress increase protein aggregation [95], whilst loss of function increases perinuclear lysosomal accumulation [80] as well as mitochondrial oxidative stress [25] and dysfunction [24,25,120]. Cytoplasmic ATM thus plays a central role in redox homeostasis and ROS-mediated autophagy.…”

“…Both redox balance and ROS formation can be regulated by changes in the autophagy rate and consequently either directly regulate mitochondrial homeostasis or indirectly regulate mitochondrial function [79]. Key to effective autophagy, which is also responsible for the degradation of ATM [80], is the fusion of the autophagosome to lysosomes, in order to form an autolysosome where the targeted content is degraded. Recent observations in ATM -/neurons showed upregulated autophagic flux of lysosomes with a more acidic pH and led to the finding that the ATPase, H + transporting lysosomal V1 subunit A 4…”

“…Oxidative Medicine and Cellular Longevity (ATP6V1A proton pump) is a target of ATM [80]. The absence of ATM results in the peri-nuclear accumulation of lysosomes which suggests that this could be due to a physical interaction between ATM and the retrograde transport motor protein, dynein.…”

Crosstalk between Different DNA Repair Pathways Contributes to Neurodegenerative Diseases

“…ATM activation can cause autophagy induction through 5′ AMP-activated protein kinase (AMPK) in response to ROS [ 162 , 163 ]. While Atm −/− neurons show abnormal autophagy, ATM itself is processed through autophagic degradation [ 164 ]. Parp1 knockout mice subjected to acute starvation displayed deficient liver autophagy, implying a physiological role for PARP1 in starvation-induced autophagy [ 165 ].…”