17.20: Autophagy

Autophagy is a self-digesting process by which a cell protects itself from threats both within and outside the cell, ranging from abnormal proteins to invading bacteria. In this process, obsolete components of the cell and invading microbes are degraded by hydrolytic enzymes active in an acidic environment of the lysosomal lumen.

An autophagic pathway consists of a series of signaling events activated in response to diverse stress and physiological conditions such as food deprivation, hyperthermia, hypoxia, and aging. The component to be digested is sequestered, transported to lysosomes, and degraded there. The process often results in lysosomal remnants such as lipofuscin granules and residual bodies.

Studies indicate that a marked increase in autophagy maintains survival during starvation. Mammalian liver cell mitochondria are estimated to undergo autophagy every 10 minutes.

Defective autophagy, occurring during lysosomal storage diseases or certain neurodegenerative diseases, may prevent the degradation of invading microbes, unwanted or abnormal proteins resulting in infections, neurodegenerative disorders, and even cancers. Experimentally blocking autophagy in a particular portion of the brain shows an extensive loss of nerve cells, revealing the role of the process in protecting the cells.

Under stress conditions, such as starvation, deficiency, or infection, cells dispose of obsolete or worn-out organelles through a "self-eating" process called autophagy.

Autophagy occurs when other disposal mechanisms cannot degrade large substances such as whole organelles, macromolecules, and protein aggregates.

Autophagy begins when membrane vesicles of unknown origin fuse to form a crescent-shaped structure that grows and surrounds cytoplasmic cargo to create a double membraned autophagosome.

The outer membrane of the autophagosome contains transmembrane protein markers, such as ATG9, that target it to the lysosome.

SNARE proteins on the outer membrane of the autophagosome mediate membrane fusion with the lysosome to form an autolysosome.

Lysosomal lipases and proteases digest the inner membrane of the autophagosome and its contents. Amino acid permeases on the outer membrane allow the transport of free amino acids back to the cytosol, where they are used to synthesize new proteins.

After the degradation is complete, only the residual body remains, which can be eliminated by exocytosis or retained in the cytosol indefinitely as lipofuscin granule.