Reactive oxygen species trigger Parkin/PINK1 pathway–dependent mitophagy by inducing mitochondrial recruitment of Parkin

Abstract

Defective mitophagy linked to dysfunction in the proteins Parkin and PTEN-induced putative kinase 1 (PINK1) is implicated in the pathogenesis of Parkinson's disease. Although the mechanism by which Parkin mediates mitophagy in a PINK1-dependent manner is becoming clearer, the triggers for this mitophagy pathway remain elusive. Reactive oxygen species (ROS) have been suggested as such triggers, but this proposal remains controversial because ROS scavengers fail to retard mitophagy. Here we demonstrate that the role of ROS in mitophagy has been underappreciated as a result of the inefficiency of ROS scavengers to control ROS bursts after high-dose treatment with carbonyl cyanide -chlorophenylhydrazone. Supporting this, combinatorial treatment with-acetyl-l-cysteine and catalase substantially inhibited the ROS upsurge and PINK1-dependent Parkin translocation to mitochondria in response to carbonyl cyanide -chlorophenylhydrazone treatment. In addition to the chemical mitophagy inducer, overexpression of voltage-dependent anion channel 1 (VDAC1) induced Parkin translocation to mitochondria, presumably by stimulating ROS generation. Similarly, combined-acetyl-l-cysteine and catalase treatment also suppressed VDAC1-induced redistribution of Parkin. Alongside these observations, we also found that the elevated protein level of PINK1 was not necessary for Parkin translocation to mitochondria. Thus, our data suggest that ROS may act as a trigger for the induction of Parkin/PINK1-dependent mitophagy. In addition, our study casts doubt on the importance of protein quantity of PINK1 in the recruitment of Parkin to mitochondria.

Stanniocalcin-1 Alleviates Contrast-Induced Acute Kidney Injury by Regulating Mitochondrial Quality Control via the Nrf2 Pathway

“…Our results indicated that rhSTC1 treatment decreased the expression of Drp1 and the translocation of Drp1 to mitochondria. Fourth, other researchers found that ROS as a trigger for the generation of PINK1-Parkin mediated mitophagy and the inhibition of ROS generation significantly decreased the expression of Parkin and its translocation to mitochondria [34]. This was also consistent with our results that rhSTC1 treatment decreased ROS generation and then probably decreased mitophagy and mitophagy-related proteins.…”

Poly (ADP‐ribose) polymerase inhibition protects against myocardial ischaemia/reperfusion injury via suppressing mitophagy

“…Excessive ROS trigger the opening of the MPTP and activate PINK1/Parkin‐mediated mitophagy . To investigate whether ROS play a role in PARP‐mediated changes in ΔΨm, we measured ROS production in H/R‐treated H9C2 cells.…”

“…At the beginning of myocardial reperfusion, a large amount of ROS is produced from a variety of sources including extracellular and intracellular actions . ROS activate PINKI/Parkin‐mediated mitophagy by promoting the opening of the MPTP and disrupting ΔΨm . ROS also function as a direct signal to induce mitophagy .…”

“…Consistent with previous studies, 23,24 we also found that PARP inhi- ΔΨm. 18 ROS also function as a direct signal to induce mitophagy. 30 ROS modulate MPTP opening by oxidizing Cys56 and, Cys160 of adenine nucleotide translocator (ANT) and Cys203 of cyclophilin D (CypD), increasing mitochondrial Ca2+ and translocating Bid to jBid.…”

“…Excessive ROS trigger the opening of the MPTP and activate PINK1/ Parkin-mediated mitophagy. 18 To investigate whether ROS play a role in PARP-mediated changes in ΔΨm, we measured ROS production in H/R-treated H9C2 cells. The production of ROS was significantly increased in H/R-treated H9C2 cells compared with that in control cells, and PARP inhibition partially prevented the increase in ROS production after H/R ( Figure 5A).…”