Abstract
Ubiquitylation of outer mitochondrial membrane (OMM) proteins is closely related to the onset of familial Parkinson's disease. Typically, a reduction in the mitochondrial membrane potential results in Parkin‐mediated ubiquitylation of OMM proteins, which are then targeted for proteasomal and mitophagic degradation. The role of ubiquitylation of OMM proteins with non‐degradative fates, however, remains poorly understood. In this study, we find that the mitochondrial E3 ubiquitin ligase MITOL/March5 translocates from depolarized mitochondria to peroxisomes following mitophagy stimulation. This unusual redistribution is mediated by peroxins (peroxisomal biogenesis factors) Pex3/16 and requires the E3 ligase activity of Parkin, which ubiquitylates K268 in the MITOL C‐terminus, essential for p97/VCP‐dependent mitochondrial extraction of MITOL. These findings imply that ubiquitylation directs peroxisomal translocation of MITOL upon mitophagy stimulation and reveal a novel role for ubiquitin as a sorting signal that allows certain specialized proteins to escape from damaged mitochondria.
Highlights
Peroxisomal membrane protein PMP34 fused with FusionRed at its C-terminus (PMP34FusionRed) co-localized with MITOL-GFP in Parkin-expressing HeLa cells after 3 h of carbonyl cyanide m-chlorophenylhydrazone (CCCP) treatment (Fig 1G), and this co-localization was confirmed by quantitative analysis (Fig 1H)
Following extended CCCP treatment, HeLa cells stably expressing HA-Parkin and 3Flag-MITOL were stained with Pex14 (Appendix Fig S2A), Sec61b (Appendix Fig S2B), and Tom20 (Appendix Fig S2C: because Tom20 was substantially degraded via mitophagy for > 12 h, Tom20-positive cells were selected to be shown)
We show for the first time that MITOL migrates from damaged mitochondria to peroxisomes depending on Parkincatalyzed ubiquitylation
Summary
When the mitochondrial membrane potential is decreased, PINK1 and Parkin, which are causal gene products of inherited Parkinson’s disease, play pivotal roles in the selective degradation of damaged mitochondria via the proteasome and autophagy pathway (the following is called mitophagy). PINK1 accumulates on damaged mitochondria and subsequently phosphorylates Ser of both ubiquitin and ubiquitin-like (Ubl) domain of Parkin [10,11,12,13,14,15]. Ubiquitylation of various mitochondrial proteins by the activated Parkin leads to selective elimination of damaged mitochondria [19,20,21,22,23,24,25,26,27,28,29,30,31]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
