Fig. 3.

PINK1 is constitutively degraded by the inner mitochondrial membrane protease PARL and maintained at low levels on healthy mitochondria. When a mitochondrion becomes damaged to the point of depolarizing the membrane potential across the inner membrane, PINK1 import to the inner membrane is prevented, thereby sequestering it on the outer mitochondrial membrane and away from PARL. PINK1 accumulates there and recruits the E3 ligase Parkin from the cytosol via PINK1 kinase activity. Parkin conjugates ubiquitin (Ub) to a variety of proteins on the outer mitochondrial membrane and mediates the proteosomal elimination of mitofusins 1 and 2. Lastly, Parkin induces autophagic elimination of the dysfunctional mitochondria. This pathway may constitute a quality-control mechanism to eliminate damaged mitochondria. UPS, ubiquitin proteasome system.