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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  1. 1.

    Dzamko, N., Geczy, C. L. & Halliday, G. M. Inflammation is genetically implicated in Parkinson’s disease. Neuroscience 302, 89–102 (2015).

  2. 2.

    Kitada, T. et al. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 392, 605–608 (1998).

  3. 3.

    Valente, E. M. et al. PINK1 mutations are associated with sporadic early-onset parkinsonism. Ann. Neurol. 56, 336–341 (2004).

  4. 4.

    Pickrell, A. M. & Youle, R. J. The roles of PINK1, parkin, and mitochondrial fidelity in Parkinson’s Disease. Neuron 85, 257–273 (2015).

  5. 5.

    Goldberg, M. S. et al. Parkin-deficient mice exhibit nigrostriatal deficits but not loss of dopaminergic neurons. J. Biol. Chem. 278, 43628–43635 (2003).

  6. 6.

    Kitada, T. et al. Impaired dopamine release and synaptic plasticity in the striatum of PINK1-deficient mice. Proc. Natl Acad. Sci. USA 104, 11441–11446 (2007).

  7. 7.

    Perez, F. A. & Palmiter, R. D. Parkin-deficient mice are not a robust model of parkinsonism. Proc. Natl Acad. Sci. USA 102, 2174–2179 (2005).

  8. 8.

    Nakahira, K. et al. Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat. Immunol. 12, 222–230 (2011).

  9. 9.

    Zhou, R., Yazdi, A. S., Menu, P. & Tschopp, J. A role for mitochondria in NLRP3 inflammasome activation. Nature 469, 221–225 (2011).

  10. 10.

    Rongvaux, A. et al. Apoptotic caspases prevent the induction of type I interferons by mitochondrial DNA. Cell 159, 1563–1577 (2014).

  11. 11.

    White, M. J. et al. Apoptotic caspases suppress mtDNA-induced STING-mediated Type I IFN production. Cell 159, 1549–1562 (2014).

  12. 12.

    West, A. P. et al. Mitochondrial DNA stress primes the antiviral innate immune response. Nature 520, 553–557 (2015).

  13. 13.

    Pickrell, A. M. et al. Endogenous Parkin preserves dopaminergic substantia nigral neurons following mitochondrial DNA mutagenic stress. Neuron 87, 371–381 (2015).

  14. 14.

    Trifunovic, A. et al. Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature 429, 417–423 (2004).

  15. 15.

    Chen, Q., Sun, L. & Chen, Z. J. Regulation and function of the cGAS–STING pathway of cytosolic DNA sensing. Nat. Immunol. 17, 1142–1149 (2016).

  16. 16.

    Ishikawa, H. & Barber, G. N. STING is an endoplasmic reticulum adaptor that facilitates innate immune signaling. Nature 455, 674–678 (2008).

  17. 17.

    Sun, N. et al. Measuring in vivo mitophagy. Mol. Cell 60, 685–696 (2015).

  18. 18.

    Zhong, Z. et al. NF-κB restricts inflammasome activation via elimination of damaged mitochondria. Cell 164, 896–910 (2016).

  19. 19.

    Guo, H., Callaway, J. B. & Ting, J. P. Y. Inflammasomes: mechanism of action, role in disease, and therapeutics. Nat. Med. 21, 677–687 (2015).

  20. 20.

    Sauer, J.-D. et al. The N-ethyl-N-nitrosourea-induced goldenticket mouse mutant reveals an essential function of Sting in the in vivo interferon response to listeria monocytogenes and cyclic dinucleotides. Infect. Immun. 79, 688–694 (2011).

  21. 21.

    Sheehan, K. C. F. et al. Blocking monoclonal antibodies specific for mouse IFN-α/β receptor subunit 1 (IFNAR-1) from mice immunized by in vivo hydrodynamic transfection. J. Interferon Cytokine Res. 26, 804–819 (2006).

  22. 22.

    Brancaccio, P., Lippi, G. & Maffulli, N. Biochemical markers of muscular damage. Clin. Chem. Lab. Med. 48, 757–767 (2010).

  23. 23.

    Greene, J. C. et al. Mitochondrial pathology and apoptotic muscle degeneration in Drosophila parkin mutants. Proc. Natl Acad. Sci. USA 100, 4078–4083 (2003).

  24. 24.

    Greene, J. C., Whitworth, A.J., Andrews, L.A., Parker, T. J., and Pallanck, L. J. Genetic and genomic studies of Drosophila parkin mutants implicate oxidative stress and innate immune responses in pathogenesis. Hum. Mol. Gene. 14, 799–811 (2005).

  25. 25.

    Matsuura, K., Kabuto, H., Makino, H. & Ogawa, N. Pole test is a useful method for evaluating the mouse movement disorder caused by striatal dopamine depletion. J. Neurosci. Methods 73, 45–48 (1997).

  26. 26.

    Ogawa, N., Hirose, Y., Ohara, S., Ono, T. & Watanabe, Y. A simple quantitative bradykinesia test in MPTP-treated mice. Res. Commun. Chem. Pathol. Pharmacol. 50, 534–541 (1985).

  27. 27.

    Matheoud, D. et al. Parkinson’s disease-related proteins PINK1 and Parkin repress mitochondrial antigen presentation. Cell 166, 314–327 (2016).

  28. 28.

    Benkler, M. et al. Immunology, autoimmunity, and autoantibodies in Parkinson’s disease. Clin. Rev. Allergy Immunol. 42, 164–171 (2012).

  29. 29.

    Noyce, A. J. et al. Meta-analysis of early nonmotor features and risk factors for Parkinson disease. Ann. Neurol. 72, 893–901 (2012).

  30. 30.

    Guzman, J. N. et al. Systemic isradipine treatment diminishes calcium-dependent mitochondrial oxidant stress. J. Clin. Invest. 128, 2266–2280 (2018).

  31. 31.

    Herzig, M. C. et al. LRRK2 protein levels are determined by kinase function and are crucial for kidney and lung homeostasis in mice. Hum. Mol. Genet. 20, 4209–4223 (2011).

  32. 32.

    Kujoth, G. C. et al. Mitochondrial DNA mutations, oxidative stress and apoptosis in mammalian aging. Science 309, 481–484 (2005).

  33. 33.

    Horder, M. et al. International Federation of Clinical Chemistry, Scientific Division Committee on Enzymes: approved recommendation on IFCC methods for the measurement of catalytic concentration of enzymes. Part 7. IFCC method for creatine kinase (ATP: creatine N-phosphotransferase, EC Eur. J. Clin. Chem. Clin. Biochem. 29, 435–456 (1991).

  34. 34.

    Ye, W. et al. Accurate quantitation of circulating cell-free mitochondrial DNA in plasma by droplet digital PCR. Anal. Bioanal. Chem. 409, 2727–2735 (2017).

  35. 35.

    MacLean, B. et al. Skyline: an open source document editor for creating and analyzing targeted proteomics experiments. Bioinformatics 26, 966–968 (2010).

  36. 36.

    Phu, L. et al. Improved quantitative mass spectrometry methods for characterizing complex ubiquitin signals. Mol. Cell. Proteomics 10, M110.003756 (2011).

  37. 37.

    Gao, D. et al. Activation of cyclic GMP-AMP synthase by self-DNA causes autoimmune diseases. Proc. Natl Acad. Sci. USA 112, E5699–E5705 (2015).

  38. 38.

    Sun, N. et al. A fluorescence-based imaging method to measure in vitro and in vivo mitophagy using mt-Keima. Nat. Protoc. 12, 1576 (2017).

  39. 39.

    Kasten, M., et. al. Cohort profile: a population based cohort of study non-motor symptoms in parkinsonism (EPIPARK). Int. J. Epidemiol. 42, 128–128 (2013).

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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.).

Reviewer information

Nature thanks Z. Chen, I. Dikic and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Author information


  1. Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA

    • Danielle A. Sliter
    • , Ling Hao
    • , Tara D. Fischer
    • , Jonathon L. Burman
    • , Zhe Zhang
    •  & Richard J. Youle
  2. Immunity, Inflammation, and Disease Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA

    • Jennifer Martinez
  3. Transgenics Section, Laboratory of Neurogenetics, National Institute of Aging, National Institutes of Health, Bethesda, MD, USA

    • Xi Chen
    •  & Huaibin Cai
  4. Center for Molecular Medicine, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA

    • Nuo Sun
  5. The Protein/Peptide Sequencing Facility, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA

    • Yan Li
  6. Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA

    • Derek P. Narendra
  7. Institute of Neurogenetics, University of Lübeck, Lübeck, Germany

    • Max Borsche
    •  & Christine Klein


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The project was conceived by D.A.S., J.M. and R.J.Y. Mouse experiments including EE, sample collection and behavioural studies were conducted by D.A.S. Serum analysis was performed by J.M. Mass spectrometry was performed by L.H. and Y.L. Neuron counting was performed by X.C. and H.C. mt-Keima analysis was performed by N.S. LRRK2 mutant mice were exercised by T.D.F. J.L.B. and Z.Z. provided technical assistance. Human patient samples were provided by D.P.N., M.B. and C.K. Writing and editing by D.A.S., J.M., C.K. and R.J.Y. Funding was provided to J.M., H.C, D.P.N, C.K. and R.J.Y.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Richard J. Youle.

Extended data figures and tables

  1. Extended Data Fig. 1 Inflammation in Prkn−/− and Pink1−/− mice.

    a, d, Heat maps depicting average cytokine concentration in serum from mice (n = 10). b, Average time to exhaustion on each trial day. Small graphs show individual run times (n = 10). c, pS65-ubiquitin in Prkn−/− heart tissue expressed as fmol per mg total protein (n = 3). ek, Serum cytokine concentrations from EE mice are plotted as mean ± s.d. (n = 10). l, Heat map depicting serum cytokine levels of Lrrk2G2019S/G2019S (n = 4). Using t-tests, no differences in cytokine concentrations were found between pre-trial (baseline) and post-trial (immediate). ns, not significant. Source data

  2. Extended Data Fig. 2 Inflammatory cytokines are increased in mice and humans with heterozygous loss of parkin or PINK1.

    af, Serum cytokine concentrations from Prkn−/+ (n = 4) and Pink1−/+ (n = 6) EE mice. gi, Serum cytokine concentrations from human control (HC) (n = 62), PINK1 heterozygotes (P1H) (n = 6), unaffected PRKN heterozygotes (UPH) (n = 7), affected PRKN biallelic mutants (APB) (n = 7) and patients with idiopathic Parkinson’s disease (IPD) (n = 9). Data are mean ± s.d. Source data

  3. Extended Data Fig. 3 Loss of STING prevents increased cytokine levels in Prkn−/− and Pink1−/−mice following EE.

    a, Average time to exhaustion on each trial day (n = 6). b, c, Heat map depicting the average baseline serum cytokine concentration for EE mice (n = 6) and the average serum cytokines from SED mice (n = 6). di, Serum cytokine concentrations from mice are plotted as mean ± s.d. (n = 6 baseline, post-trial immediate; n = 3, post-trial 2 days, post-trial 6 days). Source data

  4. Extended Data Fig. 4 cGAMP is increased in Prkn−/− and Pink1−/− EE heart tissue and inflammation is inhibited by anti-IFNAR1 treatment.

    a, Representative plot of signal intensity for cGAMP measured in heart tissue. cGAMP was not detected in wild-type EE or in SED mice. Average signal intensity for n = 3 samples is shown in the inset. b, Average time to exhaustion on each trial day (n = 6). cg, Serum cytokine concentrations from EE Prkn−/− mice treated with anti-IFNAR1 antibody or IgG control (n = 6). Data are mean ± s.d. Source data

  5. Extended Data Fig. 5 Elevated serum creatine kinase following EE in Prkn−/− and Pink1−/− mice is not rescued by inhibition of inflammation and is not increased by chronic mitochondrial dysfunction.

    ac, Serum creatine kinase (CK) levels (n < 3). Data are mean ± s.d. Source data

  6. Extended Data Fig. 6 Inflammation in aged Prkn−/−;mutator mice is rescued by loss of STING.

    ah, Serum cytokine concentrations from 12, 20 and 40-week-old mice (n = 4, 6). Data are mean ± s.d. Source data

  7. Extended Data Fig. 7 STING mediates inflammation under chronic mitochondrial stress.

    a, b, Copy number per μl of cell-free mtDNA (ND1) or nuclear DNA (ACTB) in serum (n < 3). c, Ratio of mtDNA to nuclear DNA. (n < 3). d, The time required for 12-week-old mice to descend the pole (n = 6). e, TH+-neurons counted by stereology in the substantia nigra (SNc) of 52-week-old mice (n = 3). f, Representative images of TH+ neurons (green) and total neurons (NeuN, red). g, Serum levels of antinuclear antibodies (ANA) 6 weeks post-EE. dsDNA antibodies were not detected and ANAs were not detected at baseline or immediately post-EE (n = 4, 6). h, Serum levels of anti-dsDNA antibodies (n = 4, 6). ANA antibodies were not detected. Data are mean ± s.d. (n = 6). Source data

Supplementary information

  1. Supplementary Table

    Clinical information relevant to human samples. The file provides information relevant to the human samples presented in Fig.2a and Extended Data Fig. 2g-i, including whether the patient is affected with PD or unaffected, the nature of the mutation identified, the year of diagnosis, age at examination and the IL-6 values reported. 5 patient samples are not graphed and these are indicated with an asterisk.

  2. Reporting Summary

  3. Video 1

    Pole Test of a representative 40-week-old Prkn-/-;mutator mouse. The video shows a representative Pole Test performed by a 40-week-old Prkn-/-; mutator mouse. As the Prkn-/-;mutator mouse fails to descend the pole in 180 seconds, the video speed was increased 20x. This video pertains to data presented in Figure 4d.

  4. Video 2

    Pole Test of 40-week-old Prkn-/-;mutator;STINGgt/gt mouse. The video shows a representative Pole Test performed by a 40-week-old Prkn-/-; mutator;STINGgt/gt mouse. This video pertains to data presented in Figure 4d.

  5. Video 3

    Pole Test of 40-week-old WT mouse. The video shows a representative Pole Test performed by a 40-week-old WT mouse. This video pertains to data presented in Figure 4d.

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