Parkin and PINK1 mitigate STING-induced inflammation

Danielle A. Sliter, Jennifer Martinez, Ling Hao, Xi Chen, Nuo Sun, Tara D. Fischer, Jonathon L. Burman, Yan Li, Zhe Zhang, Derek P. Narendra, Huaibin Cai, Max Borsche, Christine Klein and Richard J. Youle ()
Additional contact information
Danielle A. Sliter: National Institute of Neurological Disorders and Stroke, National Institutes of Health
Jennifer Martinez: National Institute of Environmental Health Sciences, National Institutes of Health
Ling Hao: National Institute of Neurological Disorders and Stroke, National Institutes of Health
Xi Chen: National Institute of Aging, National Institutes of Health
Nuo Sun: National Heart, Lung and Blood Institute, National Institutes of Health
Tara D. Fischer: National Institute of Neurological Disorders and Stroke, National Institutes of Health
Jonathon L. Burman: National Institute of Neurological Disorders and Stroke, National Institutes of Health
Yan Li: National Institute of Neurological Disorders and Stroke, National Institutes of Health
Zhe Zhang: National Institute of Neurological Disorders and Stroke, National Institutes of Health
Derek P. Narendra: National Institute of Neurological Disorders and Stroke, National Institutes of Health
Huaibin Cai: National Institute of Aging, National Institutes of Health
Max Borsche: Institute of Neurogenetics, University of Lübeck
Christine Klein: Institute of Neurogenetics, University of Lübeck
Richard J. Youle: National Institute of Neurological Disorders and Stroke, National Institutes of Health

Nature, 2018, vol. 561, issue 7722, 258-262

Abstract: Abstract 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.

Keywords: Pinker; Mitophagy; Mitochondrial Stress; Exhaustive Exercise (EE); Tandem Ubiquitin Binding Entities (search for similar items in EconPapers)
Date: 2018
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DOI: 10.1038/s41586-018-0448-9

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