Ubiquitin-specific peptidase 30 (USP30)

Ubiquitin-specific peptidase 30 (USP30) is a deubiquitinating enzyme (DUB) tethered to the mitochondrial outer membrane, where it acts as a primary negative regulator of mitophagy by counteracting the E3 ligase Parkin [1, 6]. By specifically cleaving Lys-6 and Lys-11 linked polyubiquitin chains from damaged mitochondria, USP30 prevents their recognition and subsequent degradation by the autophagic machinery, thereby maintaining mitochondrial density [1, 5, 12]. Dysregulation of USP30 is implicated in the pathogenesis of neurodegenerative disorders, particularly Parkinson's disease, as well as renal failure, pulmonary fibrosis, and certain cancers [2, 11, 14, 15]. Therapeutic strategies focus on small-molecule USP30 inhibitors to enhance the clearance of dysfunctional mitochondria (mitophagy), which is crucial for the survival of high-energy-demand cells such as dopaminergic neurons and renal proximal tubule epithelial cells [4, 12, 16]. Several clinical-stage candidates, including MTX325 for Parkinson's and MTX652 for acute kidney injury, are currently under investigation to evaluate their potential in restoring mitochondrial homeostasis and slowing disease progression [12, 16, 19]. Beyond mitophagy, USP30 also regulates pexophagy and apoptotic pathways, making it a versatile but complex target within the ubiquitin-proteasome system [1, 13, 17].

Other names

Ubiquitin carboxyl-terminal hydrolase 30Deubiquitinating enzyme 30Ubiquitin thioesterase 30Ubiquitin-specific-processing protease 30UBP30

Inhibition of USP30 deubiquitinase activity to prevent the removal of ubiquitin markers from damaged mitochondria, thereby promoting PINK1/Parkin-mediated mitophagy and the clearance of dysfunctional organelles [1, 14, 16].