UQCRC1 deficiency impairs mitophagy via PINK1-dependent mechanisms in Parkinson’s disease

Oxidative phosphorylation (OXPHOS) and mitophagy are functionally interconnected cellular processes, the defects of which are considered key driving forces behind the pathogenesis of Parkinson's disease (PD). UQCRC1, a core subunit of the mitochondrial respiratory chain complex III, is a recently identified familial PD gene whose pathogenic mutations result in OXPHOS stress. Given its importance, however, the role of UQCRC1 in idiopathic PD as well as mitophagy has not been investigated. In this study, we collected 19 datasets comprising postmortem substantia nigra from 150 cases of non-disease controls and 185 cases of PD or incidental Lewy body disease (iLBD), and the meta-analysis of the UQCRC1 mRNA level showed reduced expression in idiopathic PD, suggesting the potential of UQCRC1 as a biomarker. Leveraging the SH-SY5Y cells and fly models, we showed that mitophagy was impaired upon UQCRC1 mutation or depletion. Notably, insufficiency of PINK1 mRNA was associated with UQCRC1 deficiency, and overexpression of Pink1 rescued the locomotion and mitophagy defects in the fly models with neuronal loss of uqcrc1. Treatment with two PINK1 activators, kinetin and MTK458, resulted in similar protective effects in the fly and cell models. Overall, we identified OXPHOS stress led by deficiency of UQCRC1 as an etiology of mitophagy defects in PD and PINK1 as a therapeutic target for UQCRC1-associated PD.