Cellular Senescence in Age-Related Macular Degeneration: Can Autophagy and DNA Damage Response Play a Role?

Figure 4

Autophagy dependent on mTOR. In normal nutrient conditions, the mTOR complex 1 (mTORC1) inhibits the ULK1 complex, consisting of ULK1, Atg13, Atg101, and FIP200, which can activate autophagy in stress conditions, including starvation and hypoxia or when the inhibitory effect of mTORC1 is abolished by growth factors, insulin, amino acids, or other agents. The material to be degraded (cargo) is then enclosed by a nucleating phagophore, which requires a translocation of ULK1 to endoplasmic reticulum (ER). ER membrane is used to form the phagophore, but other sources are also possible. The phagophore membrane is elongated, which leads to the formation of autophagosome, a vesicle with the enclosed cargo. This process is assisted by LC3 lipidated by phosphatidylethanolamine (PE) and many individual proteins, including Beclin 1, Vps34, and autophagy-related proteins (Atgs). The p62 protein functions as a selective autophagy receptor for degradation of ubiqutinated substrates, but it is itself a specific substrate for autophagy after its phosphorylation and can be selectively incorporated into the autophagosome and degraded. Fusion of autophagosome with lysosome creates autolysosome in which the cargo is degraded by lysosomal enzymes. Autophagy can be also activated by mTOR-independent pathways.