USP30

Ubiquitin-specific peptidase 30 (USP30), also known as DUB30, is a mitochondrial outer membrane-localized deubiquitinating enzyme (DUB). It catalyzes the removal of ubiquitin moieties from substrates like mitofusins (Mfn1/2) and TOM20, regulating mitochondrial dynamics and mitophagy. USP30 counteracts the Parkin-PINK1 pathway—critical for clearing damaged mitochondria—by reversing Parkin-mediated ubiquitination of mitochondrial targets.
Dysregulated USP30 activity is linked to Parkinson’s disease (PD), where impaired mitophagy leads to accumulation of dysfunctional mitochondria, a key PD hallmark. Preclinical USP30 inhibitors enhance mitophagy in cellular and animal models, restoring mitochondrial quality control and showing promise as potential therapeutics for PD.