title: The mitochondrial deubiquitinase USP30 opposes parkin-mediated mitophagy.
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.
authors.affiliation: 1] Department of Neuroscience, Genentech, Inc., South San Francisco, California 94080, USA [2].
authors.forename: Baris
authors.initials: B
authors.lastname: Bingol
authors.affiliation: 1] Department of Neuroscience, Genentech, Inc., South San Francisco, California 94080, USA [2].
authors.forename: Joy S
authors.initials: JS
authors.lastname: Tea
authors.affiliation: Department of Protein Chemistry, Genentech, Inc., South San Francisco, California 94080, USA.
authors.forename: Lilian
authors.initials: L
authors.lastname: Phu
authors.affiliation: Department of Pathology, Genentech, Inc., South San Francisco, California 94080, USA.
authors.forename: Mike
authors.initials: M
authors.lastname: Reichelt
authors.affiliation: Department of Bioinformatics & Computational Biology, Genentech, Inc., South San Francisco, California 94080, USA.
authors.forename: Corey E
authors.initials: CE
authors.lastname: Bakalarski
authors.affiliation: Department of Non-Clinical Biostatistics, Genentech, Inc., South San Francisco, California 94080, USA.
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Song
authors.affiliation: Department of Pathology, Genentech, Inc., South San Francisco, California 94080, USA.
authors.forename: Oded
authors.initials: O
authors.lastname: Foreman
authors.affiliation: Department of Protein Chemistry, Genentech, Inc., South San Francisco, California 94080, USA.
authors.forename: Donald S
authors.initials: DS
authors.lastname: Kirkpatrick
authors.affiliation: Department of Neuroscience, Genentech, Inc., South San Francisco, California 94080, USA.
authors.forename: Morgan
authors.initials: M
authors.lastname: Sheng
mesh_terms: D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008297:Male; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D063306:Mitophagy / Q000502:physiology*; D009474:Neurons / Q000378:metabolism; D010300:Parkinson Disease / Q000503:physiopathology; D011494:Protein Kinases / Q000378:metabolism; D051381:Rats; D013869:Thiolester Hydrolases / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D064570:Ubiquitin-Specific Proteases / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination; D000099202:PTEN-Induced Putative Kinase
chemical_list: D024101:Mitochondrial Proteins; D011494:Protein Kinases; D013869:Thiolester Hydrolases; D044767:Ubiquitin-Protein Ligases; D064570:Ubiquitin-Specific Proteases; D000099202:PTEN-Induced Putative Kinase; C532819:Usp30 protein, human; C111567:parkin protein