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 phenotypes5,6,7. Mitochondrial stress can lead to the release of damage-associated molecular patterns (DAMPs) that can activate innate immunity8,9,10,11,12, 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 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.
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We thank the animal husbandry staff at NINDS and the staff of the Murine Phenotyping Core Facility at NHLBI; the Clinical Pathology Group in the Cellular & Molecular Pathology Branch at NIEHS for serum creatine kinase; K. Gerrish and B. Elgart from the NIEHS Molecular Genomics Core for serum mitochondrial and nuclear DNA isolation and quantification; J. Vargas and S. Humble for experimental assistance and T. Finkel, J. Kowalak, A. Oberst and M. Ward for helpful suggestions. This work was supported by the NINDS Intramural Research Program (R.J.Y.), NIH Intramural Research Program 1ZIAES10328601 (J.M.), the NIA Intramural Research Program (H.C.) the DFG FOR2488; P2 and a Pilot Grant from the Excellence Cluster Inflammation at Interfaces (C.K.), and by a career development award from the Hermann and Lilly Schilling Foundation (C.K.).
Nature thanks Z. Chen, I. Dikic and the other anonymous reviewer(s) for their contribution to the peer review of this work.