A long-lived pool of PINK1 imparts a molecular memory of depolarisation-induced activity.
Pollock, L.; Georgiou, I. C.; Rusilowicz-Jones, E. V.; Clague, M. J.; Urbe, S.
Show abstract
The Parkinsons disease linked kinase, PINK1, is a short lived protein that undergoes cleavage upon mitochondrial import leading to its release to the cytosol and proteasomal degradation. Under mitochondria depolarising conditions, it accumulates on mitochondria where it becomes activated, phosphorylating both ubiquitin and the ubiquitin E3 ligase Parkin, at Ser65. Here we have used a ubiquitylation inhibitor TAK-243 to accumulate cleaved PINK1 (cPINK1) in a cell line that lacks Parkin. We show that cPINK1 phosphorylates free ubiquitin and can be released to the cytosol in an active form. We show that in RPE1 cells under mitochondria depolarising conditions (i) the majority of PINK1 cleavage proceeds unimpeded and (ii) accrued PINK1 cannot be accounted for by protein stabilisation alone. Accordingly, we suggest that translation of PINK1 mRNA must be mobilised under mitochondrial depolarisation. We have further discovered a pre-conditioning phenomenon, whereby an initial depolarising treatment leaves a residual pool of active PINK1, which remains competent for seeding the activation of nascent cPINK1, despite a 16 hour recuperation period.
Matching journals
The top 9 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- The actin binding protein profilin 1 is critical for mitochondria function 94%
- Parkin coordinates mitochondrial lipid remodeling to execute mitophagy 93%
- Loss of the lysosomal protein CLN3 modifies the lipid content of the nuclear envelope leading to DNA damage and activation of YAP1 pro-apoptotic signaling 93%
Similar papers in this journal
Similar papers in this journal
- Pharmacological rescue of impaired mitophagy in Parkinson's disease-related LRRK2 G2019S knock-in mice 93%
- Biochemical and neurophysiological effects of deficiency of the mitochondrial import protein TIMM50 93%
- Elevated Ubiquitin Phosphorylation by PINK1 Contributes to Proteasomal Impairment and Promotes Neurodegeneration 92%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.