Dual role of USP 30 in controlling basal pexophagy and mitophagy

Abstract

USP30 is an integral protein of the outer mitochondrial membrane that counteracts PINK1 and Parkin‐dependent mitophagy following acute mitochondrial depolarisation. Here, we use two distinct mitophagy reporter systems to reveal tonic suppression by USP30, of a PINK1‐dependent component of basal mitophagy in cells lacking detectable Parkin. We propose that USP30 acts upstream of PINK1 through modulation of PINK1‐substrate availability and thereby determines the potential for mitophagy initiation. We further show that a fraction of endogenous USP30 is independently targeted to peroxisomes where it regulates basal pexophagy in a PINK1‐ and Parkin‐independent manner. Thus, we reveal a critical role of USP30 in the clearance of the two major sources of ROS in mammalian cells and in the regulation of both a PINK1‐dependent and a PINK1‐independent selective autophagy pathway.

A novel USP30 inhibitor recapitulates genetic loss of USP30 and sets the trigger for PINK1-PARKIN amplification of mitochondrial ubiquitylation

“…We see enhanced pUb accumulation in the absence of USP30 activity, despite the published observations that pUb modified chains provide a poor substrate for USP30 (9,41). How then might USP30 suppress mitophagy, as previously reported in several studies (20,(22)(23)(24)? We have previously shown that USP30 depletion enhances PINK1-dependent basal mitophagy even in the absence of Parkin (20).…”

“…USP30 is one of only two DUBs that possess a transmembrane domain. Its localisation is restricted to the outer mitochondrial membrane and to peroxisomes (18)(19)(20)(21). USP30 can limit the Parkin-dependent ubiquitylation of selected substrates and depolarisation-induced mitophagy in cell systems that have been engineered to over-express Parkin (22)(23)(24)(25).…”

“…USP30 can limit the Parkin-dependent ubiquitylation of selected substrates and depolarisation-induced mitophagy in cell systems that have been engineered to over-express Parkin (22)(23)(24)(25). We have recently shown that it can also suppress a PINK1-dependent component of basal mitophagy, even in cells that do not express Parkin (20). Thus USP30 may represent an actionable drug target relevant to PD progression and other pathologies to which defective mitophagy can contribute (26)(27)(28).…”

Peroxisomal fission is modulated by the mitochondrial Rho‐GTPases, Miro1 and Miro2

“…Interestingly, Cichocki et al [63] also show that the loss of Pex19 impinges upon mitochondrial targeting. Consequently, the ability to control the extent of the mitochondrial and peroxisomal localisation of Miro may be an important regulatory axis; an axis that likely includes members of an ever-growing list of proteins targeted to both organelles including USP30, Fis1, Mff, MUL1/MAPL, OMP25, BCL-XL, BCL-2, MAVS and GDAP1 [8,10,[21][22][23][24][25]. With this in mind, we propose the following model: the Miro transmembrane domain is required for Pex19 binding and peroxisomal localisation of Miro.…”

“…These include Fis1, Mff, Drp1, GDAP1, USP30, MUL1/MAPL, OMP25, MAVS, BCL-XL, BCL-2 and more recently Miro1/2 [6,10,[21][22][23][24][25][26]. These include Fis1, Mff, Drp1, GDAP1, USP30, MUL1/MAPL, OMP25, MAVS, BCL-XL, BCL-2 and more recently Miro1/2 [6,10,[21][22][23][24][25][26].…”