PINK1-parkin-dependent mitophagy involves ubiquitination of mitofusins 1 and 2: Implications for Parkinson disease pathogenesis

Abstract

Mitochondrial dysfunction has long been implicated in the pathogenesis of Parkinson disease (PD). Recent research has highlighted that two proteins encoded by genes linked to familial PD, PINK1 and parkin, play a role in the autophagic degradation of dysfunctional mitochondria (mitophagy). We have recently shown that mitochondrial dysfunction in PINK1-deficient human dopaminergic cells correlates with decreased autophagic flux and can be rescued by parkin expression. Further dissection of PINK1-parkin-dependent mitophagy indicates that the ubiquitination of mitofusins 1 and 2 is an early event. Here, we discuss how ubiquitination of the mitofusins might facilitate mitochondria degradation and the potential for activating mitophagy as a treatment for diseases affecting brain and muscle.

Figure 1

Immunofluorescent staining of mitochondria with an antibody against the mitochondrial protein MTCO 1 (white) in dopaminergic SH-SY5Y neuroblastoma cells indicates that the mitochondrial network undergoes fission within two hours of depolarization of mitochondria by the mitochondrial toxin CCCP. Depolarized mitochondria (↓ Ψm) display an increase in PIN K1 protein levels, which recruits parkin to mitochondria. Parkin then ubiquitinates (stars) several mitochondrial proteins including MFN-1 and MFN-2. We postulate that ubiquitination prevents the refusion of depolarized/damaged mitochondria with the mitochondrial network (cross) allowing them to be segregated for degradation by mitophagy. Ubiquitination could prevent refusion by degrading the pro-fusion proteins via the proteasome or autophagy. Alternatively, ubiquitination might inhibit MFN GTP ase activity or sterically block inter-mitochondrial and mitochondria-endoplasmic reticulum tethering by the MFNs.