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 |