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The mitochondrial deubiquitinase USP30 opposes parkin-mediated mitophagy

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  • Baris Bingol

    (Genentech, Inc., South San Francisco, California 94080, USA)

  • Joy S. Tea

    (Genentech, Inc., South San Francisco, California 94080, USA)

  • Lilian Phu

    (Genentech, Inc., South San Francisco, California 94080, USA)

  • Mike Reichelt

    (Genentech, Inc., South San Francisco, California 94080, USA)

  • Corey E. Bakalarski

    (Genentech, Inc., South San Francisco, California 94080, USA)

  • Qinghua Song

    (Genentech, Inc., South San Francisco, California 94080, USA)

  • Oded Foreman

    (Genentech, Inc., South San Francisco, California 94080, USA)

  • Donald S. Kirkpatrick

    (Genentech, Inc., South San Francisco, California 94080, USA)

  • Morgan Sheng

    (Genentech, Inc., South San Francisco, California 94080, USA)

Abstract

Cells maintain healthy mitochondria by degrading damaged mitochondria through mitophagy; defective mitophagy is linked to Parkinson’s disease. Here we report that USP30, a deubiquitinase localized to mitochondria, antagonizes mitophagy driven by the ubiquitin ligase parkin (also known as PARK2) and protein kinase PINK1, which are encoded by two genes associated with Parkinson’s disease. Parkin ubiquitinates and tags damaged mitochondria for clearance. Overexpression of USP30 removes ubiquitin attached by parkin onto damaged mitochondria and blocks parkin’s ability to drive mitophagy, whereas reducing USP30 activity enhances mitochondrial degradation in neurons. Global ubiquitination site profiling identified multiple mitochondrial substrates oppositely regulated by parkin and USP30. Knockdown of USP30 rescues the defective mitophagy caused by pathogenic mutations in parkin and improves mitochondrial integrity in parkin- or PINK1-deficient flies. Knockdown of USP30 in dopaminergic neurons protects flies against paraquat toxicity in vivo, ameliorating defects in dopamine levels, motor function and organismal survival. Thus USP30 inhibition is potentially beneficial for Parkinson’s disease by promoting mitochondrial clearance and quality control.

Suggested Citation

  • Baris Bingol & Joy S. Tea & Lilian Phu & Mike Reichelt & Corey E. Bakalarski & Qinghua Song & Oded Foreman & Donald S. Kirkpatrick & Morgan Sheng, 2014. "The mitochondrial deubiquitinase USP30 opposes parkin-mediated mitophagy," Nature, Nature, vol. 510(7505), pages 370-375, June.
    • Handle: RePEc:nat:nature:v:510:y:2014:i:7505:d:10.1038_nature13418
    DOI: 10.1038/nature13418
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    Cited by:

    1. Véronique Sauvé & Eric Stefan & Nathalie Croteau & Thomas Goiran & Rayan Fakih & Nupur Bansal & Adelajda Hadzipasic & Jing Fang & Paramasivam Murugan & Shimin Chen & Edward A. Fon & Warren D. Hirst & , 2024. "Activation of parkin by a molecular glue," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    2. Su Jin Ham & Heesuk Yoo & Daihn Woo & Da Hyun Lee & Kyu-Sang Park & Jongkyeong Chung, 2023. "PINK1 and Parkin regulate IP3R-mediated ER calcium release," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    3. Fumika Koyano & Koji Yamano & Tomoyuki Hoshina & Hidetaka Kosako & Yukio Fujiki & Keiji Tanaka & Noriyuki Matsuda, 2024. "AAA+ ATPase chaperone p97/VCPFAF2 governs basal pexophagy," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    4. Thomas M. Goralski & Lindsay Meyerdirk & Libby Breton & Laura Brasseur & Kevin Kurgat & Daniella DeWeerd & Lisa Turner & Katelyn Becker & Marie Adams & Daniel J. Newhouse & Michael X. Henderson, 2024. "Spatial transcriptomics reveals molecular dysfunction associated with cortical Lewy pathology," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    5. Tracy-Shi Zhang Fang & Yu Sun & Andrew C. Pearce & Simona Eleuteri & Mark Kemp & Christopher A. Luckhurst & Rachel Williams & Ross Mills & Sarah Almond & Laura Burzynski & Nóra M. Márkus & Christopher, 2023. "Knockout or inhibition of USP30 protects dopaminergic neurons in a Parkinson’s disease mouse model," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

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