(a) activation of a signaling pathway initiates a nucleation event in the cytoplasm. a crescent of autophagosomal membrane grows by fusion of vesicles of unknown origin and eventually fuses to form a double-membrane-enclosed autophagosome, which sequesters a portion of the cytoplasm. The autophagosome then fuses with lysosomes containing acid hydrolases that digest its content. during the formation of the autophagosome membrane, a ubiquitinlike protein becomes activated by covalent attachment of a phosphatidylethanolamine lipid anchor. These proteins then mediate vesicle tethering and fusion, leading to the formation of a crescent-shaped membrane structure that assembles around its target (not shown). (b) an electron micrograph of an autophagosome containing a mitochondrion and a peroxisome.  (b, courtesy of daniel s. friend, from d.w. fawcett, a Textbook of histology, 12th ed. new york: chapman and hall, 1994. with permission from kluwer.)
The selective autophagy of worn out or damaged mitochondria is called mitophagy. As discussed in Chapters 12 and 14, when mitochondria function normally, the inner mitochondrial membrane is energized by an electrochemical H+ gradient that drives ATP synthesis and the import of mitochondrial precursor proteins and metabolites. Damaged mitochondria cannot maintain the gradient, so protein import is blocked. As a consequence, a protein kinase called Pink1, which is normally imported into mitochondria, is instead retained on the mitochondrial surface where it recruits the ubiquitin ligase Parkin from the cytosol. Parkin ubiquitylates mitochondrial outer membrane proteins, which mark the organelle for selective destruction in autophagosomes. Mutations in Pink1 or Parkin cause a form of early-onset Parkinson’s disease, a degenerative disorder of the central nervous system. It is not known why the neurons that die prematurely in this disease are particularly reliant on mitophagy.
a Mannose 6-phosphate receptor sorts lysosomal hydrolases in the Trans golgi network
We now consider the pathway that delivers lysosomal hydrolases from the TGN to lysosomes. The enzymes are first delivered to endosomes in transport vesicles that bud from the TGN, before they move on to endolysosomes and lysosomes (see Figure 13–39). The vesicles that leave the TGN incorporate the lysosomal proteins and exclude the many other proteins being packaged into different transport vesicles for delivery elsewhere.
How are lysosomal hydrolases recognized and selected in the TGN with the required accuracy? In animal cells they carry a unique marker in the form of mannose 6-phosphate (M6P) groups, which are added exclusively to the N-linked oligosaccharides of these soluble lysosomal enzymes as they pass through the lumen of the cis Golgi network (Figure 13–44). Transmembrane M6P receptor proteins, which are present in the TGN, recognize the M6P groups and bind to the lysosomal hydrolases on the lumenal side of the membrane and to adaptor proteins in assembling clathrin coats on the cytosolic side. In this way, the receptors help package the hydrolases into clathrin-coated vesicles that bud from the TGN and deliver their contents to early endosomes.