Models for mitophagy in yeast and mammalian cells. (A) Atg32-mediated mitophagy in S. cerevisiae. Under respiratory conditions, the mitophagy receptor Atg32 is induced in response to oxidative stress, targeted, and anchored to the mitochondrial surface. Atg32 recruits Atg8 and Atg11 to mitochondria via distinct domains. CK2 phosphorylates Atg32 to stabilize the interaction between Atg32 and Atg11. This tertiary complex and core Atg proteins cooperatively generate isolation membranes to sequester mitochondria. The protein kinases Slt2 and Hog1 are also critical for mitophagy in yeast, although their targets remain unknown. (B) FUNDC1-mediated mitophagy in mammals. Under normoxic conditions, the mitochondrial outer membrane protein FUNDC1 is phosphorylated by Src and CK2, thereby preventing LC3 binding. Upon hypoxia, the expression of Src is strongly suppressed, and the protein phosphatase PGAM5 dephosphorylates FUNDC1 and promotes LC3 binding. In addition, ULK1, a mammalian Atg1 kinase homologue, interacts with FUNDC1 and phosphorylates the mitophagy receptor. This posttranslational modification also stabilizes the interaction between FUNDC1 and LC3. (C) PINK1/Parkin-mediated mitophagy in mammals. When targeted to healthy mitochondria, PINK1 is partially translocated across the mitochondrial membranes, proteolytically processed, released back to the cytosol, and rapidly degraded. In cells containing damaged mitochondria, PINK1 is stalled in the outer membrane and associated with the TOM complex. Two molecules of PINK1 undergo self-activation via autophosphorylation. Active PINK1 then phosphorylates Parkin and stabilizes the E3 ligase on the surface of mitochondria. Mitochondria-associated Parkin promotes ubiquitination of multiple substrates, ultimately leading to LC3 and p62/NBR1 recruitment and core Atg protein assembly. Ubiquitin chains and these proteins are bridged by an unknown factor (X).