The Progress of Mitophagy and Related Pathogenic Mechanisms of the Neurodegenerative Diseases and Tumor

Figure 4

The formation of autophagy and its regulation mechanisms [36]. Autophagy is a multistep process involving induction, nucleation, extension, autophagosome’s formation, and autophagy-lysosome’s formation controlled by a set of ATGs. (1) The process starts with the activation of the ULK serine/threonine kinase complex that includes ATG13 and FIP200. This complex is regulated by mTOR which inhibits autophagy by phosphorylation of ULK1/2. The induction of autophagy is completed with the accumulation of the ULK1/2-ATG13-FIP200 complex, resulting in the phagophore. (2) Autophagosome’s development is dependent on PI3K complex involving the proteins Vps-34, beclin1, and p150. This complex localizes to the phagophore and recruits further ATGs to allow for extension and completion of the autophagosome. ATG14 is the positive regulators binding to beclin1. The Rubicon molecule binds to beclin1 and reduces Vps34 activity and impairs autophagosomes formation as a negative regulator. Bcl-2 binds to the beclin1 BH3 domain also as a negative regulator. (3) Once the autophagosome is created, maturation is completed by fusion with a lysosome to form an autophagolysosome. This process involves LAMP1 and LAMP2, as well as UVRAG and the GTPase Rab7.