Table 2 Molecular and functional pathways involved in oxidative regulation of autophagy
Components involved in autophagy | Basal function | Effects after oxidative regulation | Ref. |
|---|---|---|---|
Initiation | |||
 AMPK | AMPK, a key factor regulating autophagy, is a major sensor of intracellular energy stress and is able to sense and respond to energy changes and is essential for energy homeostasis | ROS↑ AMPK↑ activating Ulk1 through phosphorylation of Ser 317 and Ser 777 ↑ autophagy↑ | [94] |
 mTOR | mTOR is a negative regulator of autophagy. It impedes ULK1 complex formation by phosphorylating ULK1 and Atg13 proteins in components of the ULK1 | 1)ROS↑ AMPK↑ Phosphorylation of TSC2 and RAPTOR↑ mTORC1 inhibition↑ autophagy↑ 2)ROS↑ oxidization of PTEN↑ PI3K/AKT↑TSC1 / 2↓ mTORC1 inhibition↑ autophagy↑ | |
 Beclin1 | BCL-2 or PI3k class III play critical roles in the regulation of autophagy and cell death through binding interactions with Beclin1 | 1)ROS↑ JNK↑ Bcl2 phosphorylation↑ BECN1 release from the inhibitory BCL2-BECN1 complex autophagy↑ 2) ROS↑ stability of HIF↑ BNip3↑ BNip3 regulate autophagy by competing with Beclin-1 for binding to Bcl2, thereby releasing Beclin-1 to induce autophagy | |
Expansion | |||
 Atg5-Atg12-Atg16 complex | The Atg5-Atg12-Atg16 complex acts as an ubiquitin-like conjugation system and contributes to elongation and autophagosome maturation of isolated membranes | ROS↑ Atg5 Atg12↑ autophagy↑ | |
 LC3/LC3-I/LC3-II | LC3-I is produced after LC3 is cleaved by Atg4 LC3-I binds to phosphatidylethanolamine (PE) to form a lipidated form of LC3-II through an ubiquitin-like reaction that requires the participation of Atg7 and Atg3 | Mild level of ROS induce ATG3 and ATG7 oxidation, contributing to inhibition of LC3 lipidation. High level of ROS lead to ATG4 oxidation and inhibit its LC3 decoupling function, thereby allowing phagophore expansion. ATG3 and ATG7 may be more sensitive than ATG4. | |
 SQSTM1 | SQSTM1 achieves autophagic cargo recognition by interacting with LC3, involved in autophagic cargo assembly and autophagosome-lysosome fusion. The antioxidant effect of SQSTM1 is mainly achieved through its activation of NRF2 and NFKB1 | Mild ROS increases, SQSTM1 first uses autophagy to recognize LC3 Severe ROS increases, autophagy antioxidant defenses all fail to limit ROS, and SQSTM1 activates NFE2L2 or NFKB1 antioxidant gene transcription | [104] |
Fusion | |||
 SNARE System  (STX17,SNAP29,VAMP8/7) | It is involved in autophagosome-lysosome fusion as well as other autophagic processes, including autophagosome formation and mitophagy | ?ROS↑ SNAR depletion leads to accumulation of autophagosomes without degradation | |
 TRPML1 | It mediates lysosomal enzyme calcium release and activation triggers calcineurin-dependent TFEB nuclear translocation, autophagy induction and lysosomal biogenesis | TRPML1 is specifically required for ROS-induced autophagy, with oxidants specifically activating lysosomal TRPML1 channels and calcium release | [107] |
Degradation | |||
 Lysosomal protease | Autophagosomes combine with lysosomes to form autolysosomes, and the contents in autolysosomes decrease in the action of enzymes. | Lysosomal protease cathepsin has different sensitivity to ROS, with increased ROS and decreased hydrolytic activity of the enzyme | [107] |