A substrate-interacting region of Parkin directs ubiquitination of the mitochondrial GTPase Miro1
Open accessPublished version of a preprint
Abstract
Mutations in the E3 ubiquitin ligase Parkin gene have been linked to early onset Parkinson’s disease. Besides many other roles, Parkin is involved in clearance of damaged mitochondria via mitophagy—a process of particular importance in dopaminergic neurons. Upon mitochondrial damage, Parkin accumulates at the outer mitochondrial membrane and is activated, leading to ubiquitination of many mitochondrial substrates and recruitment of mitophagy effectors. While the activation mechanisms of autoinhibited Parkin have been extensively studied, it remains unknown how Parkin recognizes its substrates for ubiquitination. Here, we characterize a conserved region in the flexible linker between the Ubl and RING0 domains of Parkin, which is indispensable for Parkin interaction with the mitochondrial GTPase Miro1. Our results may explain fast kinetics of Miro1 ubiquitination by Parkin in recombinant assays and provide a biochemical explanation for Miro1-dependent Parkin recruitment to the mitochondrial membrane observed in cells. Our findings are important for understanding mitochondrial homeostasis and may inspire new therapeutic avenues for Parkinson’s disease.
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- Authors
- Koszela, J., Rintala-Dempsey, A., Salzano, G., Pimenta, V., Kamarainen, O., Gabrielsen, M., Parui, A. L., Shaw, G. S., & Walden, H.
- Affiliations
- University of Glasgow (GB)
- The University of Western Ontario 2 Department of Biochemistry, , London,
- Human Technopole (IT)
- Western University (CA)
- School of Molecular Biosciences, University of Glasgow 1 , Glasgow,
- Corresponding author
- Walden, Helen
- ORCID
- Venue
- Journal of Cell Biology
- Publisher
- Rockefeller University Press
- Published
- 2025-06-27
- Volume
- 224
- Issue
- 8
- ISSN
- 0021-9525 (ISSN-L)
- 1540-8140
- PMC
- PMC11185606
- OpenAlex
- W4411712603
- Cited by
- 13
- References
- 6
- Citations by year
- 2026: 5 · 2025: 6 · 2024: 2
- FWCI
- 6.70
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- The Journal of Cell Biology (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc)
- PubMed (publishedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion, cc-by-sa)
- PubMed Central (submittedVersion, cc-by-nc)
- PubMed Central (submittedVersion)
- Funders
- Wellcome Trust (209347/Z/17/Z)
- Canadian Institutes of Health Research (PJT 166019)
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- Parkin, Miro1, ubiquitination, mitophagy, Parkinson's disease, substrate recognition, E3 ubiquitin ligase, mitochondrial GTPase, UBL domain, mitochondrial membrane, mitochondrial homeostasis, dopaminergic neurons
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