Fig. 2

PINK1-mediated phosphorylation of ubiquitin and parkin on damaged mitochondria in facilitation of mitophagy. Mitochondrial damage causes PINK1 localization and activation on the OMM, leading to Ser65-phosphorylation of pre-existing ubiquitin chains conjugated to OMM proteins (1). The phosphorylated ubiquitin recruits parkin, enables Ser65-phosphorylation of parkin by PINK1, and activates parkin (2). The activated parkin ubiquitinates additional OMM proteins (3) and thus provides more substrates for phosphorylation by PINK1 (4), leading to further recruitment and activation of parkin (2). This positive feed-forward cycle results in a rapid increase in the local concentration of Ser65-phosphorylated ubiquitin (5), which serves as a signal for recruiting autophagy receptors, such as OPTN and NDP52, to promote mitophagy (6)