Autophagy regulatory pathway

Autophagy is a fundamental eukaryotic cytoprotective process involving the lysosomal degradation and recycling of intracellular components, such as damaged organelles and misfolded proteins [PubMed: 20649474]. The regulatory pathways governing autophagy are complex, primarily centered around the Mechanistic Target of Rapamycin Complex 1 (mTORC1), which inhibits autophagy under nutrient-rich conditions, and the AMP-activated protein kinase (AMPK), which activates it during energy stress [PubMed: 21407206]. Key molecular players include the ULK1 initiation complex, the Class III Phosphoinositide 3-kinase (PI3K) complex, and a series of Autophagy-related (ATG) proteins that facilitate the formation of the double-membrane autophagosome [PubMed: 28521368]. In disease, autophagy plays a dual role; it acts as a tumor suppressor in early stages of cancer but can promote survival in established tumors, and its impairment is a hallmark of neurodegenerative diseases like Alzheimer's and Parkinson's [PubMed: 21407206]. Pharmacological modulation of these pathways includes the use of mTOR inhibitors like Rapamycin to induce autophagy or lysosomotropic agents like Hydroxychloroquine to inhibit the final stages of degradation [Nature Reviews Drug Discovery, 2017]. Given its ubiquitous role in cellular homeostasis, targeting autophagy regulatory pathways presents significant challenges regarding tissue specificity and the potential for pleiotropic side effects [PubMed: 28521368].

Other names

MacroautophagyAutophagic signalingATG-dependent pathwayCellular self-eating

mTORC1 inhibition, ULK1 inhibition, VPS34 inhibition, ATG protein modulation, and lysosomal acidification inhibition [PubMed: 28521368]