Molecular processes of selective autophagy in yeast. The cytoplasm-to-vacuole targeting (Cvt) pathway: Precursor aminopeptidase I (prApe1) is synthesized in the cytosol, forms dodecamers, and is further assembled into an Ape1 complex composed of multiple dodecamers. The prApe1 complex is recognized and bound by the receptor protein autophagy-related 19 (Atg19), which independently recruits α-mannosidase (Ams1) and forms the prApe1-Atg19-Ams1 complex (the Cvt complex). The adaptor protein Atg11 recognizes and binds Atg19 in the Cvt complex and transports the complex to the phagophore assembly site (PAS). When the Cvt complex reaches the PAS, the complex binds the phagophore membrane through an interaction between Atg19 and the lipid-conjugated Atg8–phosphatidylethanolamine (PE). The phagophore membrane expands around the Cvt complex, excluding bulk cytoplasm and forming the Cvt vesicle. Pexophagy in Pichia pastoris: During peroxisome proliferation in P. pastoris, PpAtg30 is induced and binds the peroxisomal proteins PpPex3 and PpPex14. Following the induction of pexophagy, PpAtg30 is phosphorylated and interacts with PpAtg11 and PpAtg17, allowing recruitment of the peroxisome to the PAS for both macropexophagy and micropexophagy. At the PAS, peroxisomes are sequestered by the phagophore membrane during macropexophagy or by the vacuolar sequestering membrane (VSM) and cup-shaped micropexophagy apparatus (MIPA) during micropexophagy. Mitophagy: When mitophagy is induced, Atg11 binds the mitochondrial resident protein Atg32. The Atg11-Atg32 complex recruits mitochondria to the PAS. When mitochondria reach the PAS, mitochondria are surrounded by the phagophore membrane through an interaction between Atg32 and Atg8–PE. The last step of the mitophagy pathway is controversial. In this figure, we show a macroautophagy-like process; however, some researchers observed a microautophagy-like process.

Schematic models of mitophagy in mammals and in yeast. Mitophagy in mammalian cells: Parkin-related process—When mitochondria are depolarized (e.g., by carbonyl cyanide m-chlorophenylhydrazone [CCCP] or paraquat treatment), PINK1 can stably localize on the mitochondrial outer membrane. PINK1 recruits Parkin to the surface of mitochondria. Subsequently, Parkin ubiquitinates mitochondrial proteins, although the specific substrate required for mitophagy remains unclear. Finally, p62 and/or histone deacetylase 6 (HDAC6) interact with ubiquitinated mitochondrial proteins, and then autophagosomes enwrap the mitochondria by p62/HADC6–LC3 interaction. Nix-related process—During terminal erythroid differentiation, an unknown stimulus triggers mitophagy. Nix interacts with LC3; this interaction contributes to the formation of autophagosomes surrounding mitochondria. It is not known whether Nix requires an adaptor protein corresponding to Atg11 in yeast (beige box). Mitophagy in yeast: Mitochondrial damage caused by mutations of fmc1, mdm38, or mip1 induces mitophagy. Mitophagy is also induced at stationary phase when cells are grown in nonfermentable medium. Appropriate signals are delivered to the mitophagic machinery through, in part, Atg33. At stationary phase, the expression level of Atg32 is dramatically increased, positively affecting the induction of mitophagy. N-acetylcysteine (NAC), a scavenger of free radicals, can suppress the expression of Atg32. Nitrogen starvation or the target of rapamycin kinase inhibitor rapamycin also induces mitophagy. The cellular pool of reduced glutathione (GSH) negatively regulates mitophagy induced by nitrogen starvation or rapamycin. Once mitophagy is induced, mitochondrial Atg32 interacts with Atg11. Atg11 recruits mitochondria to the PAS, where mitophagy-specific uptake occurs. At the PAS, Atg32 interacts with Atg8 on the phagophore membrane and promotes formation of the autophagosome surrounding mitochondria (the mitophagosome). Atg20, Atg24, and most of the core autophagy machinery components form a complex at the PAS and cooperate to complete mitophagosome formation. (To see this illustration in color the reader is referred to the web version of this article at www.liebertonline.com/ars).