Autophagy plays an essential role during starvation, cellular differentiation, cell death, and cell aging. In the last few years, applying genetic-screening tests originally developed for yeasts, researchers uncovered several autophagy-related genes (Atg genes) in mammalian cell genome. The presence of adequate nutrients and growth factors stimulates enzymatic activity of a serine/threonine kinase known as mammalian target of rapamycin (mTOR). High mTOR activity exerts an inhibitory effect on autophagy. The opposite is found in nutrient starvation, hypoxia, and high temperature, where lack of mTOR activity causes activation of Atg genes. This results in formation of an Atg1 proteinkinase autophagy–regulatory complex that initiates process of autophagy. Generally, autophagy can be divided into three well-characterized pathways:  Macroautophagy, or simply autophagy, is a nonspecific process in which a portion of the cytoplasm or an entire organelle is first surrounded by a double or multilamellar intracellular membrane of endoplasmic reticulum, called isolation membrane, to form a vacuole called an autophagosome. This process is aided by proteins encoded by several Atg genes. At first, the complex containing Atg12–Atg5–Atg16L proteins attaches to a part of endoplastic reticulum and localizes the isolation membrane. Subsequently, Atg8 is recruited and bound to the membrane. Together they change the shape of the isolation membrane, which bends to enclose and seal an organelle destined for digestion within the lumen of the autophagosome. Once the autophagosome is completed, the Atg12–Atg5–Atg16L complex and Atg8 dissociate from this structure. After targeted delivery of lysosomal enzymes autophagosome matures into a lysosome. The isolation membrane disintegrates within the hydrolytic compartment of a lysosome. Macroautophagy occurs in the liver during the first stages of starvation (Fig. 2.23).
 Microautophagy is also a nonspecific process in which cytoplasmic proteins are degraded in a slow, continuous process under normal physiologic conditions. In microautophagy, small cytoplasmic soluble proteins are internalized into the lysosomes by invagination of the lysosomal membrane.
 Chaperone-mediated autophagy is the only selective process of protein degradation and requires assistance from specific cytosolic chaperones such as heat-shock chaperone protein called hsc73. This process is  activated during nutrient deprivation and requires the presence of targeting signals on the degraded proteins and a specific receptor on
FIGURE 2.22 • Three autophagic pathways for degradation of cytoplasmic constituents. In macroautophagy, a portion of the cytoplasm or an entire organelle is surrounded by an intracellular membrane of the endoplasmic reticulum to form a double-membraned autophagosome vacuole. After fusion with a lysosome, the inner membrane and the contents of the vacuole are degraded. In microautophagy, cytoplasmic proteins are internalized into lysosomes by invagination of the lysosomal membrane. Chaperone-mediated autophagy to lysosomes is the most selective process for degradation of specifc cytoplasmic proteins. It requires assistance of proteins called chaperones. The chaperone protein—that is, hsc73—binds to the protein and helps transport it into the lysosomal lumen, where it is fnally degraded.