Cellular self-eating — bulk degradation of cytoplasmic content via autophagosome → lysosome fusion. Regulated by mTORC1 (active mTORC1 INHIBITS autophagy; nutrient deprivation / rapamycin / metformin via AMPK activates it). Initiation: ULK1 complex. Nucleation: PI3K complex (Beclin-1 / VPS34). Elongation: ATG12-ATG5 conjugation + LC3 (MAP1LC3B) lipidation to PE on autophagosome membrane. Cargo capture (selective autophagy uses adaptors: p62/SQSTM1 for ubiquitinated cargo; NIX for mitochondria = mitophagy; nuclear/ER-phagy variants). Fusion with lysosome → autolysosome → cargo degraded by lysosomal hydrolases. Chloroquine + hydroxychloroquine inhibit autophagosome-lysosome fusion (basis for some cancer trial uses + part of antimalarial mechanism).
Organ Systems
endocrine
musculoskeletal
nervous
Pathway Steps
nutrient-stress-or-rapamycin → ulk1-activation — via mTORC1 inhibition releases ULK1 (also AMPK directly activates ULK1). Macroautophagy is triggered by nutrient stress: when nutrients/growth factors are scarce, mTORC1 (its main inhibitor) switches off and AMPK switches on, jointly activating the ULK1 kinase complex. Rapamycin mimics starvation by inhibiting mTORC1 — the classic pharmacologic autophagy inducer.
ulk1-activation → phagophore-nucleation — via PI3K complex (Beclin-1 / VPS34). Active ULK1 nucleates the phagophore by activating the class-III PI3K (VPS34/Beclin-1) complex, generating PI3P on a nascent membrane to recruit the downstream machinery. This nucleation step commits a patch of membrane to becoming an autophagosome and is where many autophagy regulators act.
phagophore-nucleation → autophagosome — via ATG12-ATG5 + LC3 lipidation; cargo capture via p62/SQSTM1. The phagophore elongates and closes around cargo, driven by two ubiquitin-like conjugation systems (ATG12-ATG5 and the LC3 lipidation that yields membrane-bound LC3-II). LC3-II marks autophagosomes, and cargo receptors like p62/SQSTM1 link ubiquitinated cargo to LC3 for selective autophagy.
autophagosome → lysosomal-degradation — via autophagosome-lysosome fusion (HOPS complex) → autolysosome — CHLOROQUINE-BLOCKED. The completed autophagosome fuses with a lysosome, whose acid hydrolases degrade the engulfed contents; the breakdown products are recycled to the cytosol. This step recycles nutrients during starvation and clears damaged organelles and aggregates — its failure contributes to neurodegeneration and aging.
Known Modulators
rapamycin (activator) — mTORC1 inhibition → autophagy ON