The Emerging Role of Proteolysis in Mitochondrial Quality Control and the Etiology of Parkinson’s Disease
Figure 4
Proposed model for how PARL regulates PINK1 localization under normal conditions and during stress. (a) In a healthy mitochondrion, newly synthesized PINK1 is imported by the TOM/TIM complex. Once it is tethered to the inner mitochondrial membrane (IMM), PINK1 is effectively cleaved by the mitochondrial rhomboid protease PARL, which associates with the TOM/TIM protein-importing machinery. This PARL-dependent cleavage releases PINK1 into the intramembrane space (IMS). The cleaved PINK1 is then retrotranslocated to the cytoplasm, where it undergoes rapid proteasomal degradation. Normal mitochondrial ATP levels facilitate the phosphorylation of the PARL N-terminus. These phosphorylations inhibit the self-regulated proteolysis (β-cleavage) that releases the PARL N-terminal domain. (b) During stress, such as accumulation of ROS and the depolarization of mitochondrial membrane potential, mitochondrial ATP levels drop significantly as a result of an inhibition of the electron transport chain. Reduced ATP levels result in the dephosphorylation of the PARL N-terminus, which leads to β-cleavage. β-cleavage generates a short nuclear-targeted peptide, pβ, which activates the expression of several genes involved in cell metabolism and mitochondrial biogenesis. Another product of β-cleavage, the N-terminal cleaved PARL, then undergoes another cleavage at the loop connecting its first and second transmembrane domains. This cleavage, known as γ-cleavage, separates the first transmembrane domain from the rest of the protein and leaves a catalytically dead PARL. Disruption of membrane potential also inhibits the import of PINK1; instead of being imported to the IMM, PINK1 stalls at the import machinery. Because of its association with the TOM/TIM complex, the catalytically dead PARL stabilizes PINK1 on the OMM to recruit Parkin. Parkin triggers the recruitment of autophagosomes, which eliminates the damaged mitochondria through a process called mitophagy. Through other mechanisms, PINK1 may be anchored on the OMM but with a lower efficiency. (c) When β-cleavage is inhibited, PARL retains its uncleaved form even when the mitochondrial ATP levels are low. Therefore, during stress, PARL with impaired β-cleavage can no longer facilitate the OMM-anchoring of PINK1. Although PINK1 may be anchored to the OMM by other mechanisms, due to their low anchoring efficiency, there will be less OMM anchored PINK1. As a result, Parkin recruitment to damaged mitochondria as well as subsequent mitophagy will be impaired. As a mitochondrial quality control system, failure of proper mitophagy would lead to an accumulation of damaged mitochondria and eventually trigger the cell death pathway, which is one of the contributors to neurodegeneration in PD.
