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.

Autophagosome dynamics in neurodegeneration at a glance

“…As many of these studies were performed in nonneuronal cells, it will be important to establish which of these steps also occur in neurons and might be defective during neurodegeneration. Robust basal mitophagy occurs in neurons (Maday et al, 2012), but it is unclear whether this constitutive process occurs through PINK1-and parkin-dependent or independent pathways (Allen et al, 2013;Bingol et al, 2014;Grenier et al, 2013;Strappazzon et al, 2014;Webster et al, 2013). By contrast, locally induced mitophagy in the axon has been shown to be dependent on both PINK1 and parkin (Ashrafi et al, 2014(Ashrafi et al, ).…”

“…Three different deubiquitylating enzymes (DUBs) were also recently found to regulate mitophagy, with USP30 and USP15 opposing mitophagy by deubiquitylating parkin substrates (Bingol et al, 2014;Cornelissen et al, 2014), and USP8 promoting mitophagy by deubiquitylating parkin itself (Durcan et al, 2014). Another E3 ubiquitin ligase, Gp78 (also known as AMFR), also ubiquitylates mitofusin1 and mitofusin2 to induce mitophagy .…”

Mitophagy and the therapeutic clearance of damaged mitochondria for neuroprotection

“…In conditions such as ALS and Huntington disease where the PINK1/Parkin machinery remains intact novel deubiquitinases inhibitors may be beneficial, tipping the balance and promoting mitochondrial quality control (Bingol et al, 2014). Similarly in PD in which the PINK1/parkin pathway is impaired, molecules that enhance the expression or activity of BNIP3/Nix and FUNDC1 have the potential to promote therapeutic levels of mitophagy.…”

“…For example, the ubiquitin ligase Mul1 also induces mitophagy by ubiquitinating mitofusin 2, required for mitochondrial fusion, which is consequently degraded increasing the rate of mitochondrial fission and mitophagy (Lokireddy et al, 2012). Conversely, negative regulation is achieved via deubiquitinases such as USP30 (Bingol et al, 2014) and the 18 kDa TSPO, which is upregulated during cellular stressaccumulates on mitochondria preventing autophagic clearance by limiting ubiquitination of OMM proteins (Gatliff et al, 2014). …”

Investigation into experimental toxicological properties of plant protection products having a potential link to Parkinson's disease and childhood leukaemia†

“…The polarity and correct function of different types of cells depend on an efficient transport of mitochondria to areas of high energy consumption (Sheng, 2014). Therefore, the correct distribution of mitochondria to various parts of a cell is essential to preserve cell function Schwarz, 2013).…”