Journal Article

RETRACTED ARTICLE: Parkin and PINK1 mitigate STING-induced inflammation

Hao, Ling, Chen, Xi, Burman, Jonathon L., Sliter, Danielle A., Sun, Nuo, Borsche, Max, Narendra, Derek P., Zhang, Zhe, Martinez, Jennifer, Fischer, Tara D., Cai, Huaibin, Li, Yan, Klein, Christine, Youle, Richard J.

2018

Overview

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 unknown 1 . Mutations in parkin, an E3 ubiquitin ligase, and PINK1, a ubiquitin kinase, cause early onset Parkinson’s disease 2 , 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 autophagy 4 . 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 phenotypes 5 , 6 – 7 . Mitochondrial stress can lead to the release of damage-associated molecular patterns (DAMPs) that can activate innate immunity 8 , 9 , 10 , 11 – 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 DNA 15 , 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/21 / 14/19 / 631/250/256/2515 / 631/250/256/2516 / 631/378/1934 / 64/60 / 82/58 / Humanities and Social Sciences / Letter / multidisciplinary / Science