Mechanistic insights into fasting-induced autophagy in the aging heart

Figure 1 Molecular mechanisms of various stages of autophagy. Autophagy is activated in response to various cellular stresses and is triggered by a decrease in rapamycin complex 1 (mTORC1) activity due to the activation of AMP-activated protein kinase (AMPK) or p53 signaling. mTORC1 suppresses the activity of Unc-51-like autophagy activating kinase 1 (ULK1) complex. Therefore, inhibition of mTORC1 causes the initialization of the ULK1-mediated formation of the isolation (autophagosomal) membrane (IM) in association with the class III phosphatidylinositide 3-kinase complex. The IM expands into an autophagosome (AP) with a double-layer membrane, which can engulf any cellular component, including proteins, damaged organelles, and lipid droplets. The AP merges with the lysosome (via LAMP-1, 2), forming autophagolysosome or autolysosome (AL), and resulting in the degradation of the cargo by cathepsins and the autophagic lysosome reformation. The nucleation, elongation and maturation of the IM are dependent on two ubiquitin-like conjugation systems (ATG12 and ATG8), which involve multiple autophagy proteins, including Beclin1, ATG5, ATG16 and MT-associated protein 1 LC3. The AL provides an acidic milieu for hydrolytic enzymes to digest the engulfed components. Nuclear localization of transcription factor EB is critical to the formation of lysosomes and to the enhanced expression of autophagy proteins. Importantly, autophagy could be selective of mitochondria (mitophagy) or ER (ER-phagy). However, the detailed mechanisms of this selected autophagy are beyond the scope of this study[28]. AMPK: AMP-activated protein kinase; PI3KC3: Phosphatidylinositide 3-kinase complex; APL: Autophagolysosome; AL: Autolysosome; ALR: Autophagic lysosome reformation; IM: Isolation (autophagosomal) membrane; TFEB: Transcription factor EB; mTORC1: Rapamycin complex 1. Citation: Al-Bari MAA, Ito Y, Ahmed S, Radwan N, Ahmed HS, Eid N. Targeting Autophagy with Natural Products as a Potential Therapeutic Approach for Cancer. Int J Mol Sci 2021; 22: 9807. Copyright ©The Author(s) 2021. Published by MDPI.