Ubiquitin-specific-processing protease 30 (USP30) (USP30)

Ubiquitin-specific-processing protease 30 (USP30) is a cysteine deubiquitinating enzyme (DUB) localized to the outer mitochondrial membrane (UniProt: Q70CQ3). It serves as a key negative regulator of mitophagy, the process by which damaged mitochondria are selectively degraded via the autophagosome-lysosome pathway (Bingol et al., Nature 2014). USP30 antagonizes the E3 ubiquitin ligase Parkin by removing ubiquitin chains from mitochondrial substrates, such as TOMM20, thereby halting the signal for mitochondrial clearance (PubMed: 24896184). In the context of neurodegenerative disorders like Parkinson's disease, where mitochondrial dysfunction is prevalent, USP30 inhibition is being explored as a therapeutic strategy to restore healthy mitochondrial populations (Mission Therapeutics, 2024). Beyond neurology, USP30 is also implicated in fibrotic diseases and certain cancers, making it a versatile target for small-molecule drug development (PubMed: 33108773). Several inhibitors, such as MTX-458, are currently in clinical and preclinical development to treat these conditions by enhancing mitochondrial turnover (ClinicalTrials.gov: NCT05687266). Therapeutic challenges include ensuring selectivity over other DUBs and avoiding excessive mitophagy in healthy tissues.

Other names

Ubiquitin carboxyl-terminal hydrolase 30Deubiquitinating enzyme 30USP30

Inhibition of USP30 enzyme activity to promote the ubiquitination of mitochondrial outer membrane proteins, thereby enhancing PINK1/Parkin-dependent mitophagy and the clearance of damaged mitochondria.