The Physiological Role of Mitophagy: New Insights into Phosphorylation Events

Figure 2

Parkin/PINK1 and mitophagy in higher eukaryotes. PINK1 is constitutively targeted and imported into the inner membrane via the mitochondrial import machinery, the TOM and TIM complexes, and degraded by presenilin-associated rhomboid-like protein (PARL). When the mitochondrial membrane potential is depolarized, PINK1 cannot translocate across the mitochondrial outer membrane and instead accumulates on it. PINK1 on the outer membrane causes the translocation of Parkin to mitochondria which triggers the ubiquitination of mitofusin 1 (Mfn1), mitofusin 2 (Mfn2), and voltage-dependent anion channel 1 (VDAC) in mammals, and mitochondrial assembly regulatory factor (MARF) in flies. The ubiquitinated proteins on mitochondria are captured by p62, a substrate of autophagy that can bind ubiquitinated proteins, resulting in the sequestration of mitochondria into autophagosomes. OM: outer membrane; IM: inner membrane.