RRC ID 33033
著者 Bingol B, Tea JS, Phu L, Reichelt M, Bakalarski CE, Song Q, Foreman O, Kirkpatrick DS, Sheng M.
タイトル The mitochondrial deubiquitinase USP30 opposes parkin-mediated mitophagy.
ジャーナル Nature
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.
巻・号 510(7505)
ページ 370-5
公開日 2014-6-19
DOI 10.1038/nature13418
PII nature13418
PMID 24896179
MeSH Animals Cell Line Cells, Cultured Drosophila melanogaster / genetics Drosophila melanogaster / metabolism Gene Knockdown Techniques HEK293 Cells HeLa Cells Humans Male Mitochondrial Proteins / genetics Mitochondrial Proteins / metabolism* Mitophagy / physiology* Neurons / metabolism Parkinson Disease / physiopathology Protein Kinases / metabolism Rats Thiolester Hydrolases / genetics Thiolester Hydrolases / metabolism* Ubiquitin-Protein Ligases / genetics Ubiquitin-Protein Ligases / metabolism* Ubiquitin-Specific Proteases / genetics Ubiquitin-Specific Proteases / metabolism Ubiquitination
IF 42.779
引用数 348
WOS 分野 BIOCHEMISTRY & MOLECULAR BIOLOGY
リソース情報
ショウジョウバエ 3016R-2、5486R-3、4603R-2