Figure 1

We propose a two-step mitophagy model in mammalian cells: the induction of canonic Atg-dependent macroautophagy and mitochondrial priming. The induction of canonic autophagy requires Atg proteins and furthermore involves mTOR suppression mediated by mitochon-drial damage-generated ROS production and ATP depletion-mediated AMPK activation. Priming of mitochondria is mediated by multiple mechanisms that could be Parkin dependent or Parkin independent. In the presence of Parkin, one common mechanism is that mitochondrial depolarization (e.g., following CCCP treatment) results in impaired PARL-mediated Pink1 cleavage, leading to Pink1 stabilization and Parkin recruitment to the mitochondria. Mitochondria-localized Parkin promotes ubiquitination of outer membrane proteins, which may either be degraded through the proteasome or serve as binding partners for p62. p62 may in turn act as an adaptor molecule through direct interaction with LC3 to recruit autophagosomal membranes to the mitochondria. Parkin can also interact with Ambra1, which in turn activates the PI3K complex around mitochondria to facilitate selective mitophagy. For the Parkin-independent mechanism, damaged mitochondria (particularly under hypoxia conditions) may increase FUNDC1 and Nix expression, which may in turn recruit autophagosomes to mitochondria by direct interaction with LC3 through their LIR domains. Upon mitochondrial depolarization, Smurf1 also _targets mitochondria to promote mitophagy, most likely through the ubiquitination of mitochondrial proteins. Hsp90-Cdc37 stabilizes and activates Ulk1, which further phosphorylates Atg13. Phosphorylated Atg13 is recruited to damaged mitochondria to promote mitophagy. Atg-independent mitophagy is less understood, but 15-lipoxygenase has been shown to promote mitochondrial degradation. Direct lysosomal invagination or interaction with damaged mitochon-dria (microautophagy) could also play a role.