Figure 7. Working model depicting USP30 action upstream of PINK1.

Under depolarising conditions, PINK1 becomes activated but remains associated with TOM complex components. TOM complex associated ubiquitylation provides the nucleating substrate for PINK1-dependent phosphorylation of ubiquitin on Ser65. This leads to recruitment and activation of the E3 ligase Parkin, which can then amplify the signal. By opposing TOM complex ubiquitylation, USP30 suppresses the trigger for mitophagy.