Parkin and PINK1 mitigate STING-induced inflammation.

Abstract

Although serum from Parkinson’s disease (PD) patients displays elevated levels of numerous pro-inflammatory cytokines including IL-6, TNFα, IL-1β, and IFNβ1, 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 PD2,3. Working in the same biochemical pathway, PINK1 and Parkin remove damaged mitochondria from cells in culture and in animal models via a selective form of autophagy, called mitophagy4. The role of mitophagy in vivo, however, is unclear in part because mice lacking PINK1 or Parkin have no substantial PD-relevant phenotypes5–7. As mitochondrial stress can lead to the release of damage-associated molecular patterns (DAMPs) that can activate innate immunity8–12, mitophagy may mitigate inflammation. Here we report a strong inflammatory phenotype in both Parkin−/− and PINK1−/− mice following exhaustive exercise (EE) and in Parkin−/−;Mutator mice, which accumulate mitochondrial DNA mutations with age13,14. Inflammation resulting from both EE and 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 (DA) neurons from the substantia nigra pars compacta (SNc) and the motor defect observed in aged Parkin−/−;Mutator mice are also rescued by loss of STING, suggesting that inflammation facilitates this phenotype. Humans with mono- and biallelic Parkin mutations also display elevated cytokines. These results support a role for PINK1- and Parkin-mediated mitophagy in restraining innate immunity.