Fig. 2
Mitochondrial function of Parkinson’s disease-related proteins. A. VPS35 mediates degradation of mitochondrial E3 ubiquitin ligase 1 (MUL1), which ubiquitinates mitofusins (MFNs), acting as a pro-fusion factor. Conversely, PINK1 inhibits protein kinase A (PKA) mediated release of dynamin-related protein 1 (DRP1) from mitochondria, promoting mitochondrial fission. Additionally, LRRK2 acts on several fission and fusion effectors, such as MFNs, optic atrophy 1 (OPA1) and DRP1, to variably alter the balance of mitochondrial dynamics. B. Parkin interacting substrate (PARIS) inhibits mitochondrial biogenesis by suppressing expression of the master regulator peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC1α). Under steady-state conditions, PINK1 and Parkin mediate the degradation of PARIS by phosphorylation and ubiquitination respectively, followed by proteasomal degradation, which maintains PGC1α levels and mitochondrial biogenesis. Under mitochondrial stress, CHCHD2 translocates to the nucleus and upregulates expression of mitochondrial complex IV subunit 4 isoform (COX4I2). C. Miro facilitates mitochondrial transportation with another adaptor protein Milton and the motor protein Kinesin-1. PINK1 and Parkin promote mitophagy of dysfunctional mitochondria by inducing proteasomal degradation of Miro and thereby halting mitochondrial transport. Similarly, LRRK2 has been shown to facilitate removal of Miro. D. Parkin, activated by PINK1, ubiquitinates outer mitochondrial membrane proteins, such as MFNs, to which the autophagosomal protein microtubule-associated protein light chain 3 (LC3) binds with p62, a polyubiquitin-binding protein, leading to engulfment of dysfunctional mitochondria by autophagosomes. Degradation of mitochondria occurs upon fusion with lysosomes. ATP13A2 ensures mitophagy by maintaining functional lysosomes