Fig. 1.
Involvement of PINK1 and Parkin in mitochondrial processes. The most investigated function of PTEN-induced putative kinase 1 (PINK1) and Parkin is the initiation of mitophagy. A loss in membrane potential triggers the PINK1-mediated recruitment of the E3 ubiquitin ligase Parkin to mitochondria. At the outer mitochondrial membrane, Parkin ubiquitinates proteins thereby tagging dysfunctional mitochondria for lysosomal degradation. This process can be inhibited by mutant LRRK2. In addition, both PINK1 and Parkin, in conjunction with Snx9, are involved in the formation of mitochondria-derived vesicles (MDVs), which can transport cargo such as mitochondrial damage-associated molecular patterns (mitoDAMPs). After engulfment of MDVs by endosomes, mitochondrial antigens are transported to the plasma membrane, where they are presented on histocompatibility complex class I (MHC I) molecules. MitoDAMPs can also be released from mitochondria trough the mitochondrial permeability transition pore (MPTP), which is formed under the control of Parkin –an interaction partner of the pro-apoptotic protein BCL2-antagonist/killer (BAK). In a PINK1- or Parkin-deficient environment, mitoDAMPs accumulate extracellularly and trigger cyclic GMP-AMP synthase/stimulator of interferon genes (cGas/STING) inflammatory signaling. However, the exact release mechanisms of mitoDAMPs and their impact on the interplay of neuronal and glial cells remain to be studied in human-derived PD models. In addition to its role in mitophagy, Parkin can modulate mitochondrial biogenesis by ubiquitination of the Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1-α) inhibitor PARIS or by direct interaction with the mitochondrial transcription factor A (TFAM) at the mtDNA. Moreover, Parkin influences cell cycle progression via its ubiquitination target TANK-binding kinase 1 (TBK1). By controlling the degradation of the microtubule adaptor protein Miro1, which links kinesin heavy chain (KHC) to mitochondria, PINK1 and Parkin regulate mitochondrial arrest as a prerequisite for mitochondrial clearance. Finally, there is also evidence for a direct interaction between PINK1 and respiratory chain complex I. Accordingly, PINK1 influences the activity of complex I by phosphorylation of its subunit NADH:ubiquinone oxidoreductase subunit A10 (NdufA10). The online image library Servier Medical Art (http://smart.servier.com/) was used to create this Figure, which is partially based on our previous review [3].