Objective: We sought to explore Parkin’s role in (i) averting neuronal mtDNA dyshomeostasis/release and (ii) the activation of downstream inflammatory processes.
Background: Mutations in Parkin cause autosomal recessive Parkinson’s disease (PD). Parkin is an E3 ubiquitin ligase, and together with PINK1 is a well-established coordinator of mitophagy, a mechanism that clears dysfunctional mitochondria. However, recent studies brought new insights into mitophagy-independent regulatory roles of Parkin. This includes an involvement in mitochondrial biogenesis and in the regulation of mitochondrial membrane permeability, impeding mitochondrial DNA (mtDNA) escape and subsequent neuroinflammation. Nevertheless, direct studies of such mechanisms in patient-derived neurons and their implication in PD are lacking.
Method: Midbrain neuronal cultures were generated from induced pluripotent stem cells (iPSC) of PRKN mutation carriers and matched controls. Mitochondrial biogenesis and genome maintenance were studied using live-cell imaging, proteomic, mtDNA integrity, and gene expression analyses. Neuroinflammation was investigated through single-nuclei RNA sequencing in postmortem tissue and the quantification of interleukin expression in mtDNA/LPS-treated iPSC-derived neuron-microglia co-cultures.
Results: Deficits in mitochondrial biogenesis and mtDNA maintenance were detected in PRKN-mutant neurons causing mtDNA dyshomeostasis. These alterations were caused by a decrease in NAD+/NADH ratios seen under Parkin deficiency, which resulted in the dysregulation of SIRT1, a major regulator of mitochondrial biogenesis and clearance. Interestingly, Parkin-deficient models also presented increased mtDNA release into the cytosol. Chemical hypoxia was sufficient to lower NAD+/NADH ratios and reproduce downstream effects in WT neuronal cells. Furthermore, studies in postmortem midbrain from a PRKN-PD patient confirmed mtDNA dyshomeostasis and revealed an upregulation of microglia overexpressing proinflammatory cytokines. Lastly, an enhanced immune response was observed in neuron-microglia co-cultures generated from Parkin-deficient iPSCs, when exposed to mtDNA/LPS.
Conclusion: Our findings highlight that, in parallel to mitophagy, Parkin co-regulates mitochondrial biogenesis and mtDNA maintenance pathways, thereby exerting protective roles against neuroinflammation and degeneration.
To cite this abstract in AMA style:
K. Wasner, S. Smajić, J. Ghelfi, S. Delcambre, C. Prada-Medina, E. Knappe, G. Arena, P. Mulica, G. Agyeah, A. Rakovic, I. Boussaad, K. Badanjak, J. Ohnmacht, J. Gérardy, M. Takanashi, J. Trinh, M. Mittelbronn, N. Hattori, C. Klein, P. Antony, P. Seibler, M. Spielmann, S. Pereira, A. Grünewald. Parkin deficiency impairs mtDNA dynamics and propagates inflammation [abstract]. Mov Disord. 2022; 37 (suppl 2). https://www.mdsabstracts.org/abstract/parkin-deficiency-impairs-mtdna-dynamics-and-propagates-inflammation/. Accessed October 11, 2024.« Back to 2022 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/parkin-deficiency-impairs-mtdna-dynamics-and-propagates-inflammation/