Parkin Deficiency Impairs Mitochondrial DNA Dynamics and Propagates Inflammation

Kobi Wasner, Semra Smajic, Jenny Ghelfi, Sylvie Delcambre, Cesar A. Prada-Medina, Evelyn Knappe, Giuseppe Arena, Patrycja Mulica, Gideon Agyeah, Aleksandar Rakovic, Ibrahim Boussaad, Katja Badanjak, Jochen Ohnmacht, Jean Jacques Gérardy, Masashi Takanashi, Joanne Trinh, Michel Mittelbronn, Nobutaka Hattori, Christine Klein, Paul AntonyPhilip Seibler, Malte Spielmann, Sandro L. Pereira, Anne Grünewald*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

6 Citations (Scopus)

Abstract

Background: Mutations in the E3 ubiquitin ligase parkin cause autosomal recessive Parkinson's disease (PD). Together with PTEN-induced kinase 1 (PINK1), parkin regulates the clearance of dysfunctional mitochondria. New mitochondria are generated through an interplay of nuclear- and mitochondrial-encoded proteins, and recent studies suggest that parkin influences this process at both levels. In addition, parkin was shown to prevent mitochondrial membrane permeability, impeding mitochondrial DNA (mtDNA) escape and subsequent neuroinflammation. However, parkin's regulatory roles independent of mitophagy are not well described in patient-derived neurons. Objectives: We sought to investigate parkin's role in preventing neuronal mtDNA dyshomeostasis, release, and glial activation at the endogenous level. Methods: We generated induced pluripotent stem cell (iPSC)–derived midbrain neurons from PD patients with parkin (PRKN) mutations and healthy controls. Live-cell imaging, proteomic, mtDNA integrity, and gene expression analyses were employed to investigate mitochondrial biogenesis and genome maintenance. To assess neuroinflammation, we performed single-nuclei RNA sequencing in postmortem tissue and quantified interleukin expression in mtDNA/lipopolysaccharides (LPS)-treated iPSC-derived neuron–microglia co-cultures. Results: Neurons from patients with PRKN mutations revealed deficits in the mitochondrial biogenesis pathway, resulting in mtDNA dyshomeostasis. Moreover, the energy sensor sirtuin 1, which controls mitochondrial biogenesis and clearance, was downregulated in parkin-deficient cells. Linking mtDNA disintegration to neuroinflammation, in postmortem midbrain with PRKN mutations, we confirmed mtDNA dyshomeostasis and detected an upregulation of microglia overexpressing proinflammatory cytokines. Finally, parkin-deficient neuron–microglia co-cultures elicited an enhanced immune response when exposed to mtDNA/LPS. Conclusions: Our findings suggest that parkin coregulates mitophagy, mitochondrial biogenesis, and mtDNA maintenance pathways, thereby protecting midbrain neurons from neuroinflammation and degeneration.

Original languageEnglish
Pages (from-to)1405-1415
Number of pages11
JournalMovement Disorders
Volume37
Issue number7
Early online date23 Apr 2022
DOIs
Publication statusPublished - Jul 2022

Keywords

  • induced pluripotent stem cells
  • mitochondrial DNA
  • parkin; neuroinflammation
  • Parkinson's disease

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