Parkin and PINK1 mitigate STING-induced inflammation

By Danielle A. Sliter, Jennifer Martinez, Ling Hao, Xi Chen, Nuo Sun, Tara D. Fischer, Jonathon L Burman, Yan Li, Zhe Zhang, Derek P. Narendra and 4 more. Nature, 2018

1,155 citations recorded by the source corpus.

Although serum from patients with Parkinson’s disease contains elevated levels of numerous pro-inflammatory cytokines including IL-6, TNF, IL-1β, and IFNγ, whether inflammation contributes to or is a consequence of neuronal loss remains unknown1. Mutations in parkin, an E3 ubiquitin ligase, and PINK1, a ubiquitin kinase, cause early onset Parkinson’s disease2,3. Both PINK1 and parkin function within the same biochemical pathway and remove damaged mitochondria from cells in culture and in animal models via mitophagy, a selective form of autophagy4. The in vivo role of mitophagy, however, is unclear, partly because mice that lack either PINK1 or parkin have no substantial Parkinson’s-disease-relevant phenotypes5–7. Mitochondrial stress can lead to the release of damage-associated molecular patterns (DAMPs) that can activate innate immunity8–12, suggesting that mitophagy may mitigate inflammation. Here we report a strong inflammatory phenotype in both Prkn−/− and Pink1−/− mice following exhaustive exercise and in Prkn−/−;mutator mice, which accumulate mutations in mitochondrial DNA (mtDNA)13,14. Inflammation resulting from either exhaustive exercise or mtDNA mutation is completely rescued by concurrent loss of STING, a central regulator of the type I interferon response to cytosolic DNA15,16. The loss of dopaminergic neurons from the substantia nigra pars compacta and the motor defect observed in aged Prkn−/−;mutator mice are also rescued by loss of STING, suggesting that inflammation facilitates this phenotype. Humans with mono- and biallelic PRKN mutations also display elevated cytokines. These results support a role for PINK1- and parkin-mediated mitophagy in restraining innate immunity. Acute and chronic mitochondrial stress in mice require PINK1 and parkin to restrain STING-mediated innate immunity.

Subfields: Epidemiology, Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/58599d3b78c731228a0419d1d05768a531a41174

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In Epidemiology

1. Guido Kroemer
2. D. Tang
3. R. Kang
4. V. Deretic
5. D. Klionsky
6. Beth Levine
7. Jiao Liu
8. N. Mizushima

In Immunology

1. Guido Kroemer
2. R. Kang
3. V. Deretic
4. D. Tang
5. L. Zitvogel

In Molecular Biology

1. Guido Kroemer
2. D. Tang
3. R. Kang
4. D. Klionsky
5. Jiao Liu
6. V. Deretic
7. S. Masters
8. Beth Levine

Citations in the corpus

• The mitophagy pathway and its implications in human diseases (2023, background): “In PINK1 and parkin KO mice, acute (exhaustive exercise-induced) and chronic (mtDNA mutation-induced) mitochondrial stress induces stimulator of interferon genes (STING, a central regulator of the type I Interferon response to cytosolic DNA)-mediated type I interferon response.(304) After binding to”
• Autophagy in inflammation, infection, and immunometabolism (2021, background): “Both phenotypes could be rescued by eliminating STING in these mice, connecting the dots between mitophagy failure, mitochondrial DAMP release, and the cytosolic DNA sensing system working though STING to induce inflammation (Sliter et al., 2018).”
• Role of neuroinflammation in neurodegeneration development (2023, background): “Multiple studies have revealed that loss of PRKN and PINK1 dysregulated mitophagy and increased mitochondria stress, leading to mito-inflammation,(267) which was recently suggested to be involved in PD pathology in PINK1 and PRKN deficient mice.(268) In addition to mito-inflammation, both PRKN and P”
• TDP-43 Triggers Mitochondrial DNA Release via mPTP to Activate cGAS/STING in ALS (2020, background): “Inflammation is gaining increased recognition for its role in neurodegeneration, and the cGAS/STING pathway is now specifically implicated in conditions such as Parkinson’s disease (Sliter et al., 2018).”
• Autophagy-Dependent Ferroptosis: Machinery and Regulation (2020, background): “Impaired mitophagy enhances cell death, tissue injury and inflammation in mouse models, suggesting a major homeostatic role for this type of selective autophagy (Kang et al., 2016; Li et al., 2018; Sliter et al., 2018).”
• Molecular mechanisms and physiological functions of mitophagy (2021, neutral): “Mitophagy also contributes to the maintenance of mtDNA (Kurihara et al , 2011; Karavaeva et al , 2017).”