macroautophagy

Macroautophagy, commonly referred to simply as autophagy, is a conserved lysosome-dependent degradation pathway that cells use to recycle cytoplasmic components. During macroautophagy, portions of the cytoplasm, including damaged organelles and protein aggregates, are sequestered by a double-membrane autophagosome, which then fuses with lysosomes where the cargo is degraded and recycled.

Core machinery involves initiation by the ULK1 kinase complex in response to nutrient and energy status (downstream of mTOR), nucleation by a class III PI3K complex containing Beclin-1, Vps34, and Atg14L, and expansion by a conjugation system that covalently links LC3 (ATG8 family) to phosphatidylethanolamine (LC3-II) on the growing autophagosomal membrane. The Atg5–Atg12–Atg16L1 complex facilitates membrane expansion. After maturation, autophagosomes fuse with lysosomes in a process involving Rab7 and SNARE proteins, releasing hydrolytic enzymes that degrade the cargo and restore basic building blocks to the cytosol.

Selective autophagy uses receptors such as p62/SQSTM1, NBR1, NDP52, and optineurin to recognize ubiquitinated cargo and link it to LC3 on autophagosomes, enabling targeted removal of damaged mitochondria (mitophagy), peroxisomes (pexophagy), the endoplasmic reticulum (ER-phagy), and invading pathogens (xenophagy).

Physiological roles include adaptation to nutrient deprivation, maintenance of organelle quality control, development, and immune defense. Dysregulation of macroautophagy has been linked to aging and a range of diseases, notably neurodegenerative disorders, cancer, and infectious diseases. The study of autophagy genes, initially in yeast, led to landmark discoveries by Yoshinori Ohsumi, earning the Nobel Prize in Physiology or Medicine in 2016. Early observations of autophagic processes date to the mid-20th century and were followed by genetic elucidation in the 1990s.