Objective: This study investigates the role of Parkin deficiency in mitochondrial dysfunction and its contribution to mitochondrial DNA (mtDNA) release in Parkinson’s disease (PD). We examined potential triggers of mtDNA release in a Parkin knockout (KO) and wild-type (WT) SH-SY5Y neuroblastoma cell line.

Background: Mitochondrial dysfunction is a key driver of energy depletion and subsequent degeneration of dopaminergic neurons in the substantia nigra, leading to the motor and non-motor symptoms of PD. While less than 10% of PD cases have a monogenic origin, mutations in PRKN, encoding the E3 ubiquitin ligase Parkin, are the most common cause of autosomal recessive juvenile parkinsonism (AR-JP) [1,2]. Our previous research suggests that Parkin plays a critical role in mitochondrial quality control and that mtDNA dysregulation may contribute to neuroinflammation in PD models [3]. We hypothesize that oxidative stress exacerbates mitochondrial dysfunction in Parkin-deficient cells, promoting mtDNA release and driving inflammation.

Method: To investigate the molecular mechanisms underlying mtDNA release, we exposed WT and PRKN KO SH-SY5Y cells to hydrogen peroxide (H₂O₂), a known inducer of oxidative stress. We also examined the effects of Quercetin, a widely available antioxidant with potential therapeutic properties, on mitochondrial function and mtDNA release. High-content confocal imaging and digital PCR were used to assess mitochondrial integrity, ROS levels, and mtDNA release.

Results: H₂O₂ treatment increased mitochondrial ROS levels in both genotypes. In PRKN-KO cells, oxidative stress further reduced mitochondrial membrane potential, increased mitochondrial mass, and led to enhanced mtDNA release into the cytosol. Treatment with Quercetin reduced ROS levels, decreased mitochondrial fragmentation, restored mitochondrial membrane potential, and improved mitophagy in PRKN-KO cells. Notably, Quercetin treatment also mitigated oxidative stress-induced mtDNA release.

Conclusion: Our findings highlight oxidative stress as a key driver of mtDNA release in Parkin-deficient cell models. Furthermore, we demonstrate the potential of Quercetin to counteract mitochondrial dysfunction and mtDNA release, positioning it as a promising candidate at the intersection of neurodegeneration and neuroinflammation.

References: [1] Klein et al. 2012, Cold Spring Harb Perspect Med. 2012 Jan;2(1):a008888. Doi: 10.1101/cshperspect.a008888.PMID: 22315721
[2] Kitada et al., 1998, Nature. 1998 Apr 9;392(6676):605-8. doi: 10.1038/33416.
[3] Wasner et al., 2022, Mov Disord. 2022 Jul;37(7):1405-1415. doi: 10.1002/mds.29025. Epub 2022 Apr 23.PMID: 35460111

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MDS Abstracts - https://www.mdsabstracts.org/abstract/quercetin-reduces-mtdna-release-in-prkn-deficient-and-oxidatively-stressed-sh-sy5y-cells/