Objective: Explore metabolic modulation as a disease-modifying target for inflammation in PRKN-PD

Background: The release of mitochondrial DNA (mtDNA) is a well-documented phenotype in PRKN-linked Parkinson’s disease (PD). This observation is of immense clinical relevance due to the immunogenic properties of extramitochondrial DNA. We previously made a convincing argument for the involvement of a metabolic shift in mtDNA release.

Method: Here, we probe further into the modulation of metabolism via NAD+ levels as a potential treatment strategy for PRKN-PD. We pharmacologically induced various mitochondrial anomalies and explored how Parkin confers protection against mtDNA release in these scenarios. We have employed high-content imaging-based assays for the quantification of cytosolic mtDNA, mitochondrial mass, mitophagy, and ROS signalling

Results: First, we validated our previous finding of a link between mitochondrial metabolism and mtDNA leakage. This analysis revealed a significant increase in mtDNA release in both wild-type and PRKN knockout neuroblastoma lines after depleting NAD+ levels with cobalt chloride treatment. Conversely, we saw a significant rescue of the release phenotype, when NAD+ increasing drug fumarate was used. While the release phenotype was independent of the genotype, the effect size was larger in Parkin-deficient cells. This observation was mirrored in cells treated with (i) hydrogen peroxide to increase ROS signalling, (ii) 6-hydroxydopamine (6-OHDA) to induce respiratory chain dysfunction, or (iii) thapsigargin to interfere with calcium homeostasis. The Parkin-mediated protection was particularly pronounced under the impact of 6-OHDA and hydrogen peroxide. The tested stressors had varying effects on mitochondrial mass and mtDNA abundance per cell. Interestingly, while treatment of the cells with fumarate led to a rescue of mitochondrial mass, total mtDNA levels remained unchanged

Conclusion: Taken together, our findings support the existence of a link between mitochondrial metabolism and inflammation in PD. To further elucidate the mechanisms underlying Parkin-conferred protection against mtDNA release, we are currently performing transcriptomic and metabolomic analyses in cells exposed to the above-mentioned stress and rescue conditions. Ultimately, we hope that our work will uncover new entry points for metabolic therapies that can prevent or slow down the progression of PD

References: Wasner, K., Smajic, S., Ghelfi, J., Delcambre, S., Prada-Medina, C.A., Knappe, E., Arena, G., Mulica, P., Agyeah, G., Rakovic, A., Boussaad, I., Badanjak, K., Ohnmacht, J., Gérardy, J.-J., Takanashi, M., Trinh, J., Mittelbronn, M., Hattori, N., Klein, C., Antony, P., Seibler, P., Spielmann, M., Pereira, S.L. and Grünewald, A. (2022), Parkin Deficiency Impairs Mitochondrial DNA Dynamics and Propagates Inflammation. Mov Disord, 37: 1405-1415. https://doi.org/10.1002/mds.29025

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MDS Abstracts - https://www.mdsabstracts.org/abstract/metabolic-regulators-of-mitochondrial-dna-release-in-cellular-models-of-prkn-linked-parkinsons-disease/