Koszela, Joanna and Rintala-Dempsey, Anne and Salzano, Giulia and Pimenta, Viveka and Kamarainen, Outi and Gabrielsen, Mads and Parui, Aasna L. and Shaw, Gary S. and Walden, Helen (2024) A substrate-interacting region of Parkin directs ubiquitination of the mitochondrial GTPase Miro1. bioRxiv.

Abstract

Mutations in the gene encoding for the E3 ubiquitin ligase Parkin have been linked to early-onset Parkinson's disease. Besides many other cellular 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 recognises its substrates for ubiquitination, and no substrate interaction site in Parkin has been reported. Here, we identify 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 explain the preferential targeting and ubiquitination of Miro1 by Parkin and provide a biochemical explanation for the presence of Parkin at the mitochondrial membrane prior to activation induced by mitochondrial damage. Our findings are important for understanding mitochondrial homeostasis and may inspire new therapeutic avenues for Parkinson's disease.

People
Koszela, Joanna
Author

Koszela, Joanna and Rintala-Dempsey, Anne and Salzano, Giulia and Pimenta, Viveka and Kamarainen, Outi and Gabrielsen, Mads and Parui, Aasna L. and Shaw, Gary S. and Walden, Helen (2024) A substrate-interacting region of Parkin directs ubiquitination of the mitochondrial GTPase Miro1. bioRxiv.

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Rintala-Dempsey, Anne
Author

Koszela, Joanna and Rintala-Dempsey, Anne and Salzano, Giulia and Pimenta, Viveka and Kamarainen, Outi and Gabrielsen, Mads and Parui, Aasna L. and Shaw, Gary S. and Walden, Helen (2024) A substrate-interacting region of Parkin directs ubiquitination of the mitochondrial GTPase Miro1. bioRxiv.

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Salzano, Giulia
Author

Koszela, Joanna and Rintala-Dempsey, Anne and Salzano, Giulia and Pimenta, Viveka and Kamarainen, Outi and Gabrielsen, Mads and Parui, Aasna L. and Shaw, Gary S. and Walden, Helen (2024) A substrate-interacting region of Parkin directs ubiquitination of the mitochondrial GTPase Miro1. bioRxiv.

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Pimenta, Viveka
Author

Koszela, Joanna and Rintala-Dempsey, Anne and Salzano, Giulia and Pimenta, Viveka and Kamarainen, Outi and Gabrielsen, Mads and Parui, Aasna L. and Shaw, Gary S. and Walden, Helen (2024) A substrate-interacting region of Parkin directs ubiquitination of the mitochondrial GTPase Miro1. bioRxiv.

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Kamarainen, Outi
Author

Koszela, Joanna and Rintala-Dempsey, Anne and Salzano, Giulia and Pimenta, Viveka and Kamarainen, Outi and Gabrielsen, Mads and Parui, Aasna L. and Shaw, Gary S. and Walden, Helen (2024) A substrate-interacting region of Parkin directs ubiquitination of the mitochondrial GTPase Miro1. bioRxiv.

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Gabrielsen, Mads
Author

Koszela, Joanna and Rintala-Dempsey, Anne and Salzano, Giulia and Pimenta, Viveka and Kamarainen, Outi and Gabrielsen, Mads and Parui, Aasna L. and Shaw, Gary S. and Walden, Helen (2024) A substrate-interacting region of Parkin directs ubiquitination of the mitochondrial GTPase Miro1. bioRxiv.

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Parui, Aasna L.
Author

Koszela, Joanna and Rintala-Dempsey, Anne and Salzano, Giulia and Pimenta, Viveka and Kamarainen, Outi and Gabrielsen, Mads and Parui, Aasna L. and Shaw, Gary S. and Walden, Helen (2024) A substrate-interacting region of Parkin directs ubiquitination of the mitochondrial GTPase Miro1. bioRxiv.

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Shaw, Gary S.
Author

Koszela, Joanna and Rintala-Dempsey, Anne and Salzano, Giulia and Pimenta, Viveka and Kamarainen, Outi and Gabrielsen, Mads and Parui, Aasna L. and Shaw, Gary S. and Walden, Helen (2024) A substrate-interacting region of Parkin directs ubiquitination of the mitochondrial GTPase Miro1. bioRxiv.

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Walden, Helen
Author

Koszela, Joanna and Rintala-Dempsey, Anne and Salzano, Giulia and Pimenta, Viveka and Kamarainen, Outi and Gabrielsen, Mads and Parui, Aasna L. and Shaw, Gary S. and Walden, Helen (2024) A substrate-interacting region of Parkin directs ubiquitination of the mitochondrial GTPase Miro1. bioRxiv.

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Information
Title:
A substrate-interacting region of Parkin directs ubiquitination of the mitochondrial GTPase Miro1
Creators:
Koszela, Joanna and Rintala-Dempsey, Anne and Salzano, Giulia and Pimenta, Viveka and Kamarainen, Outi and Gabrielsen, Mads and Parui, Aasna L. and Shaw, Gary S. and Walden, Helen
Identification Number:
10.1101/2024.06.03.597144
Date:
3 June 2024
Divisions:
College of Medical Veterinary and Life Sciences > School of Cancer Sciences
College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
Additional Information:
Preprint. This research was supported through grants from the Wellcome Trust (209347/Z/17/Z, HW) and Canadian Institutes of Health Research (PJT 166019, GSS).
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URI:
https://pub.demo35.eprints-hosting.org/id/eprint/240
Item Type:
Article
Depositing User:
Unnamed user with email ejo1f20@soton.ac.uk
SWORD Depositor:
Users 37347 not found.
Date Deposited:
11 Jun 2025 16:36
Revision:
11
Last Modified:
12 Jun 2025 10:33
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