Objective: To investigate the role of chronic oxidative phosphorylation (OXPHOS) stress in mitophagy and the therapeutic potential of PINK1 activation in the UQCRC1 models of Parkinson’s disease (PD).

Background: OXPHOS stress is one of the crucial mechanisms in PD pathogenesis. UQCRC1 is a recently identified familial PD gene, encoding a core subunit of the respiratory chain complex III. Mutations in UQCRC1 lead to respiratory chain defects and OXPHOS stress. Whether UQCRC1 has any role in idiopathic PD is not yet known and the associated disease mechanisms are not fully understood. Mitophagy is essential for neuronal integrity and its defects also contribute to PD. We wonder in the UQCRC1 models of PD whether the OXPHOS stress also impairs mitophagy.

Method: We collected datasets of human postmortem substantia nigra from Gene Expression Omnibus (GEO) and performed meta-analysis to compare the UQCRC1 mRNA expression levels between PD patients and non-disease control. We then used fly and cell models depleted with UQCRC1 to investigate how mitophagy is influenced. Finally we tested the PINK1 activators in the UQCRC1 models of PD to evaluate their therapeutic potential.

Results: We collected 19 datasets, consisting of 150 cases of controls and 185 cases of PD or incidental Lewy body disease (iLBD). We found that UQCRC1 expression level was widely reduced in idiopathic PD. By using fluorescent reporters, we showed that the deficiency of UQCRC1 led to impaired mitophagy in both SH-SY5Y cells and fly models. The mRNA expression level of UQCRC1 was correlated with the level of PINK1 rather than PRKN in the postmortem brains. In the fly model with neuronal knockdown of uqcrc1, overexpression of Pink1 alleviated its locomotion defect. When PINK1 activators, kinetin and MTK458, were administered to our UQCRC1 models of PD, we found they can rescue the locomotion defects in flies and the neurite length in SH-SY5Y cell models.

Conclusion: We discovered that UQCRC1 is deficient in idiopathic PD. Deficiency of UQCRC1 undermined the PINK1-mdeiated mitophagy. Treatment of PINK1 activators alleviated the defects in the UQCRC1 models of PD, suggesting their potential in PD treatment.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/pink1-activation-improves-outcomes-in-the-uqcrc1-models-of-parkinsons-disease/