Under normal conditions, PINK1 is imported into the mitochondria, where it is cleaved and degraded faster that it is synthesized, which results in low levels of the protein. In damaged mitochondria, this degradation process is halted, which results in the accumulation of PINK1 on the mitochondrial outer membrane (MOM), where it is activated and phosphorylates mitochondrially tethered ubiquitin to signal recruitment of Parkin. In turn, activated Parkin ubiquitylates various proteins on the MOM to mark mitochondria for targeted degradation.
In two parallel studies, Gan et al. (https://doi.org/10.1038/s41586-021-04340-2) and Rasool et al. https://doi.org/10.1016/j.molcel.2021.11.012), writing in Nature and Molecular Cell, respectively, report molecular details on the activation of PINK1 — the first step in the mitophagy-activation cascade. Whereas Gan et al. looked at PINK1 from the body louse Pediculus humanus corporis (PhPINK1), Rasool et al. studied PINK1 from the beetle Tribolium castaneum (TcPINK1).These insect orthologs have the advantage of being active in vitro after recombinant expression and purification and are therefore used as models to elucidate the molecular details of this system. The crystal structures of their respective cytosolic domains revealed an additional previously unresolved N-terminal helix (shown in teal) that is needed for docking PINK1 on the translocase of the outer mitochondrial membrane (TOM) complex, its binding counterpart on the MOM. Not surprisingly, this helix represents a hotspot for Parkinson’s disease–associated mutations, and its structural integrity is critical for mitophagy.
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