Autophagy

Autophagy is a conserved cellular process that degrades cytoplasmic components inside lysosomes, enabling turnover of macromolecules and adaptation to stress. It plays a central role in maintaining cellular homeostasis, remodeling organelles, and providing nutrients during scarcity.

There are three main forms of autophagy: macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA). Macroautophagy involves sequestration of cytoplasm or organelles within a double-membrane autophagosome, which then fuses with lysosomes to form an autolysosome where contents are degraded and recycled. Microautophagy describes direct lysosomal engulfment of cytosol through membrane invagination. CMA involves selective translocation of specific soluble proteins across the lysosome membrane, mediated by cytosolic chaperones (notably HSC70) and the receptor LAMP-2A.

Formation and function are regulated by nutrient and energy signals. The ULK1 complex is inhibited by mTOR under nutrient sufficiency and activated via AMPK during energy stress. Beclin-1 and the class III PI3K complexes coordinate phagophore nucleation, while ATG genes drive membrane elongation through the LC3/Atg8 conjugation system. Autophagy targets include damaged organelles, misfolded proteins, and invading pathogens, contributing to cellular quality control and amino acid release during starvation.

Dysregulation of autophagy is linked to ageing and disease, including neurodegenerative disorders, cancer, and infectious diseases. Researchers study autophagy using markers such as LC3-II and p62/SQSTM1, and by assessing autophagic flux rather than static levels.

Autophagy remains a focus of therapeutic research, with approaches aimed at modulating its activity to address various conditions.