Review Article | Published:

Mitochondrial DNA in innate immune responses and inflammatory pathology

Nature Reviews Immunology volume 17, pages 363375 (2017) | Download Citation

Abstract

Mitochondrial DNA (mtDNA) — which is well known for its role in oxidative phosphorylation and maternally inherited mitochondrial diseases — is increasingly recognized as an agonist of the innate immune system that influences antimicrobial responses and inflammatory pathology. On entering the cytoplasm, extracellular space or circulation, mtDNA can engage multiple pattern-recognition receptors in cell-type- and context-dependent manners to trigger pro-inflammatory and type I interferon responses. Here, we review the expanding research field of mtDNA in innate immune responses to highlight new mechanistic insights and discuss the physiological and pathological relevance of this exciting area of mitochondrial biology.

Key points

  • Mitochondrial DNA (mtDNA), which is well known for its role in oxidative phosphorylation and cellular energetics, is increasingly being recognized as an agonist of the innate immune system that engages various pattern-recognition receptors, including Toll-like receptors (TLRs), NOD-like receptors (NLRs) and interferon-stimulatory DNA receptors.

  • Several features of mtDNA are potentially immunomodulatory. Unique methylation signatures and/or hypomethylation may cause mtDNA to appear more 'foreign' than 'self'. The three-stranded D-loop regulatory region or unique nucleic acid species generated during mtDNA replication and/or transcription may accumulate rapidly or resist degradation by cellular nucleases.

  • Loss of mitochondrial membrane integrity, cellular damage or a failure to fully degrade mitochondrial constituents by autophagy can result in mtDNA-dependent triggering of endolysosomal TLR9 or cytosolic inflammasomes, such as NOD, LRR and Pyrin domain-containing protein 3 (NLRP3) and absent in melanoma 2 (AIM2), causing pro-inflammatory responses. These include cytokine and chemokine secretion (of interleukin-1β, CXC-chemokine ligand 8 and tumour necrosis factor, for example), and immune cell chemotaxis and recruitment.

  • Intracellular mtDNA triggers type I interferon responses by engaging TLR9 or the cytosolic cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) signalling pathway. These responses culminate in the activation of interferon regulatory factors to enhance interferon secretion and interferon-stimulated gene expression. Extracellular mtDNA can also be taken up by neighbouring dendritic cells or macrophages, where it activates cGAS- or TLR9-dependent interferon expression.

  • An ever-growing clinical and experimental literature implicates mtDNA in human inflammatory, metabolic and infectious diseases. Unravelling the mechanistic aspects of mtDNA release, sensing and resulting inflammatory pathology should have important implications for understanding the mitochondrial aetiology of human disease and ageing.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    & Mitochondrial form and function. Nature 505, 335–343 (2014).

  2. 2.

    & Mitochondrial DNA maintenance in vertebrates. Annu. Rev. Biochem. 66, 409–435 (1997).

  3. 3.

    & Mitochondrial ROS signaling in organismal homeostasis. Cell 163, 560–569 (2015).

  4. 4.

    , & Mitochondria in innate immune responses. Nat. Rev. Immunol. 11, 389–402 (2011).

  5. 5.

    , & Mitochondria in the regulation of innate and adaptive immunity. Immunity 42, 406–417 (2015).

  6. 6.

    , & The roles of mitochondrial damage-associated molecular patterns in diseases. Antioxid. Redox Signal. 23, 1329–1350 (2015).

  7. 7.

    & The mitochondrial proteome and human disease. Annu. Rev. Genomics Hum. Genet. 11, 25–44 (2010).

  8. 8.

    , & Initiation and beyond: multiple functions of the human mitochondrial transcription machinery. Mol. Cell 24, 813–825 (2006).

  9. 9.

    , , & Regionally specific and genome-wide analyses conclusively demonstrate the absence of CpG methylation in human mitochondrial DNA. Mol. Cell. Biol. 33, 2683–2690 (2013).

  10. 10.

    5-Methylcytidylic acid: absence from mitochondrial DNA of frogs and HeLa cells. Science 184, 80–81 (1974).

  11. 11.

    et al. Methylation of mitochondrial DNA is not a useful marker for cancer detection. Clin. Chem. 50, 1480–1481 (2004).

  12. 12.

    et al. The control region of mitochondrial DNA shows an unusual CpG and non-CpG methylation pattern. DNA Res. 20, 537–547 (2013).

  13. 13.

    , , , & DNA methyltransferase 1, cytosine methylation, and cytosine hydroxymethylation in mammalian mitochondria. Proc. Natl Acad. Sci. USA 108, 3630–3635 (2011).

  14. 14.

    & Mitochondrial DNA in mortal and immortal human cells. Genome number, integrity, and methylation. J. Biol. Chem. 258, 9078–9085 (1983).

  15. 15.

    , , , & Methylation pattern of mouse mitochondrial DNA. Nucleic Acids Res. 12, 4811–4824 (1984).

  16. 16.

    Differential methylation of mitochondrial and nuclear DNA in cultured mouse, hamster and virus-transformed hamster cells. In vivo and in vitro methylation. J. Mol. Biol. 80, 155–175 (1973).

  17. 17.

    , & In vivo methylation of mtDNA reveals the dynamics of protein–mtDNA interactions. Nucleic Acids Res. 37, 6701–6715 (2009).

  18. 18.

    et al. High-resolution enzymatic mapping of genomic 5-hydroxymethylcytosine in mouse embryonic stem cells. Cell Rep. 3, 567–576 (2013).

  19. 19.

    , & Hydroxymethyl cytosine marks in the human mitochondrial genome are dynamic in nature. Mitochondrion 27, 25–31 (2016).

  20. 20.

    et al. DNA methylation on N6-adenine in mammalian embryonic stem cells. Nature 532, 329–333 (2016).

  21. 21.

    & Similarity of human mitochondrial transcription factor 1 to high mobility group proteins. Science 252, 965–969 (1991).

  22. 22.

    & Accessorizing the human mitochondrial transcription machinery. Trends Biochem. Sci. 38, 283–291 (2013).

  23. 23.

    , & Minimizing the damage: repair pathways keep mitochondrial DNA intact. Nat. Rev. Mol. Cell Biol. 13, 659–671 (2012).

  24. 24.

    , , , & Mitochondrial dysfunction due to oxidative mitochondrial DNA damage is reduced through cooperative actions of diverse proteins. Mol. Cell. Biol. 22, 4086–4093 (2002).

  25. 25.

    , , , & Protecting the mitochondrial powerhouse. Trends Cell Biol. 25, 158–170 (2015).

  26. 26.

    et al. Monocyte activation by necrotic cells is promoted by mitochondrial proteins and formyl peptide receptors. Crit. Care Med. 37, 2000–2009 (2009).

  27. 27.

    et al. Mitochondrial transcription factor A serves as a danger signal by augmenting plasmacytoid dendritic cell responses to DNA. J. Immunol. 189, 433–443 (2012).

  28. 28.

    , , , & Endogenously oxidized mitochondrial DNA induces in vivo and in vitro inflammatory responses. J. Leukoc. Biol. 75, 995–1000 (2004).

  29. 29.

    , , & Nucleic acid recognition by the innate immune system. Annu. Rev. Immunol. 29, 185–214 (2011).

  30. 30.

    et al. Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature 464, 104–107 (2010). A seminal report documenting pro-inflammatory roles for mitochondrial DAMPs in sterile injury and trauma.

  31. 31.

    , & Mitochondrial DNA is released by shock and activates neutrophils via p38 map kinase. Shock 34, 55–59 (2010).

  32. 32.

    et al. Mitochondrial DNA that escapes from autophagy causes inflammation and heart failure. Nature 485, 251–255 (2012). This study shows that the accumulation of mtDNA activates cell-intrinsic, TLR9-dependent inflammation leading to cardiomyopathy.

  33. 33.

    et al. Hypoxia induced HMGB1 and mitochondrial DNA interactions mediate tumor growth in hepatocellular carcinoma through Toll-like receptor 9. J. Hepatol. 63, 114–121 (2015).

  34. 34.

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

  35. 35.

    et al. Autophagosome–lysosome fusion triggers a lysosomal response mediated by TLR9 and controlled by OCRL. Nat. Cell Biol. 18, 839–850 (2016).

  36. 36.

    & Converging roles of caspases in inflammasome activation, cell death and innate immunity. Nat. Rev. Immunol. 16, 7–21 (2016).

  37. 37.

    & Initiation and perpetuation of NLRP3 inflammasome activation and assembly. Immunol. Rev. 265, 35–52 (2015).

  38. 38.

    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 (2010). This important study shows that mROS and mtDNA contribute to macrophage NLRP3 and AIM2 inflammasome activation.

  39. 39.

    et al. Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis. Immunity 36, 401–414 (2012). This study describes that oxidized mtDNA is detected by the NLRP3 inflammasome during apoptosis.

  40. 40.

    et al. Inflammasome activation leads to caspase-1-dependent mitochondrial damage and block of mitophagy. Proc. Natl Acad. Sci. USA 111, 15514–15519 (2014).

  41. 41.

    et al. Endoplasmic reticulum stress activates the inflammasome via NLRP3- and caspase-2-driven mitochondrial damage. Immunity 43, 451–462 (2015).

  42. 42.

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

  43. 43.

    et al. Ogg1-dependent DNA repair regulates NLRP3 inflammasome and prevents atherosclerosis. Circ. Res. 119, e76–e90 (2016).

  44. 44.

    et al. Mitochondrial damage contributes to Pseudomonas aeruginosa activation of the inflammasome and is downregulated by autophagy. Autophagy 11, 166–182 (2015).

  45. 45.

    et al. Mitochondrial DNA has a pro-inflammatory role in AMD. Biochim. Biophys. Acta 1853, 2897–2906 (2015).

  46. 46.

    et al. Defects in mitochondrial clearance predispose human monocytes to interleukin-1β hypersecretion. J. Biol. Chem. 289, 5000–5012 (2014).

  47. 47.

    & Ambiguities in NLRP3 inflammasome regulation: is there a role for mitochondria? Biochim. Biophys. Acta 1840, 1433–1440 (2014).

  48. 48.

    , , , & The adaptor MAVS promotes NLRP3 mitochondrial localization and inflammasome activation. Cell 153, 348–361 (2013).

  49. 49.

    Mitochondrial DNA variation in human radiation and disease. Cell 163, 33–38 (2015).

  50. 50.

    et al. Mutation in cytochrome b gene of mitochondrial DNA in a family with fibromyalgia is associated with NLRP3-inflammasome activation. J. Med. Genet. 53, 113–122 (2016).

  51. 51.

    et al. Severe septic patients with mitochondrial DNA haplogroup JT show higher survival rates: a prospective, multicenter, observational study. PLoS ONE 8, e73320 (2013).

  52. 52.

    et al. Inherited mitochondrial DNA variants can affect complement, inflammation and apoptosis pathways: insights into mitochondrial-nuclear interactions. Hum. Mol. Genet. 23, 3537–3551 (2014).

  53. 53.

    , & Recognition of endogenous nucleic acids by the innate immune system. Immunity 44, 739–754 (2016).

  54. 54.

    , & Regulation and function of the cGAS–STING pathway of cytosolic DNA sensing. Nat. Immunol. 17, 1142–1149 (2016).

  55. 55.

    STING: infection, inflammation and cancer. Nat. Rev. Immunol. 15, 760–770 (2015).

  56. 56.

    et al. Cyclic GMP–AMP synthase is an innate immune sensor of HIV and other retroviruses. Science 341, 903–906 (2013).

  57. 57.

    et al. Cyclic GMP–AMP synthase is an innate immune DNA sensor for Mycobacterium tuberculosis. Cell Host Microbe 17, 820–828 (2015).

  58. 58.

    , , & cGAS and Ifi204 cooperate to produce type I IFNs in response to Francisella infection. J. Immunol. 194, 3236–3245 (2015).

  59. 59.

    et al. The cytosolic sensor cGAS detects Mycobacterium tuberculosis DNA to induce type I interferons and activate autophagy. Cell Host Microbe 17, 811–819 (2015).

  60. 60.

    et al. Pan-viral specificity of IFN-induced genes reveals new roles for cGAS in innate immunity. Nature 505, 691–695 (2014).

  61. 61.

    & Aicardi–Goutières syndrome and the type I interferonopathies. Nat. Rev. Immunol. 15, 429–440 (2015).

  62. 62.

    et al. Ribonuclease H2 mutations induce a cGAS/STING-dependent innate immune response. EMBO J. 35, 831–844 (2016).

  63. 63.

    , , & Cutting edge: cGAS is required for lethal autoimmune disease in the Trex1-deficient mouse model of Aicardi–Goutières syndrome. J. Immunol. 195, 1939–1943 (2015).

  64. 64.

    et al. Carcinoma–astrocyte gap junctions promote brain metastasis by cGAMP transfer. Nature 533, 493–498 (2016).

  65. 65.

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

  66. 66.

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

  67. 67.

    & Mitochondrial DNA fragments released through the permeability transition pore correspond to specific gene size. Life Sci. 81, 1160–1166 (2007).

  68. 68.

    et al. Mitochondrial permeability transition triggers the release of mtDNA fragments. Cell. Mol. Life Sci. 61, 3100–3103 (2004).

  69. 69.

    et al. The vaccine adjuvant chitosan promotes cellular immunity via DNA sensor cGAS–STING-dependent induction of type I interferons. Immunity 44, 597–608 (2016).

  70. 70.

    et al. Cyclosporin A inhibits the early phase of NF-kappaB/RelA activation induced by CD28 costimulatory signaling to reduce the IL-2 expression in human peripheral T cells. Int. Immunopharmacol. 5, 699–710 (2005).

  71. 71.

    et al. Cyclosporine and tacrolimus have inhibitory effects on Toll-like receptor signaling after liver transplantation. Liver Transpl. 19, 1099–1107 (2013).

  72. 72.

    , & Innate immune recognition of mtDNA — an undercover signal? Cell Metab. 21, 793–794 (2015).

  73. 73.

    et al. An uncoupling channel within the c-subunit ring of the F1FO ATP synthase is the mitochondrial permeability transition pore. Proc. Natl Acad. Sci. USA 111, 10580–10585 (2014).

  74. 74.

    , , & The mitochondrial permeability transition pore: channel formation by F-ATP synthase, integration in signal transduction, and role in pathophysiology. Physiol. Rev. 95, 1111–1155 (2015).

  75. 75.

    , , , & Cell death disguised: the mitochondrial permeability transition pore as the c-subunit of the F1FO ATP synthase. Pharmacol. Res. 99, 382–392 (2015).

  76. 76.

    & Membrane-associated DNA transport machines. Cold Spring Harb. Perspect. Biol. 2, a000406 (2010).

  77. 77.

    et al. The conjugative DNA translocase TrwB is a structure-specific DNA-binding protein. J. Biol. Chem. 285, 17537–17544 (2010).

  78. 78.

    et al. Mitochondrial DNA stress primes the antiviral innate immune response. Nature 520, 553–557 (2015). This paper shows that mtDNA instability induced by TFAM deficiency or herpesvirus infection triggers cGAS activation and type I IFN responses. References 65, 66 and 78, were the first to document that mtDNA engages the cGAS–STING axis.

  79. 79.

    , & Association of a protein structure of probable membrane derivation with HeLa cell mitochondrial DNA near its origin of replication. Proc. Natl Acad. Sci. USA 74, 1348–1352 (1977).

  80. 80.

    et al. Human mitochondrial DNA–protein complexes attach to a cholesterol-rich membrane structure. Sci. Rep. 5, 15292 (2015).

  81. 81.

    , & ER-mitochondria contacts couple mtDNA synthesis with mitochondrial division in human cells. Science 353, aaf5549 (2016).

  82. 82.

    Replication of animal mitochondrial DNA. Cell 28, 693–705 (1982).

  83. 83.

    , , , & Herpes simplex virus eliminates host mitochondrial DNA. EMBO Rep. 8, 188–193 (2007). This paper was the first to document that alphaherpesviruses target mtDNA through the UL12.5 nuclease.

  84. 84.

    , , & Herpes simplex virus UL12.5 targets mitochondria through a mitochondrial localization sequence proximal to the N terminus. J. Virol. 83, 2601–2610 (2009).

  85. 85.

    et al. Elimination of mitochondrial DNA is not required for herpes simplex virus 1 replication. J. Virol. 88, 2967–2976 (2014).

  86. 86.

    , , , & Type I interferons in infectious disease. Nat. Rev. Immunol. 15, 87–103 (2015).

  87. 87.

    et al. Mycobacterium tuberculosis differentially activates cGAS- and inflammasome-dependent intracellular immune responses through ESX-1. Cell Host Microbe 17, 799–810 (2015).

  88. 88.

    & The mechanism for type I interferon induction by Mycobacterium tuberculosis is bacterial strain-dependent. PLoS Pathog. 12, e1005809 (2016).

  89. 89.

    , , , & Neutrophil extracellular trap mitochondrial DNA and its autoantibody in systemic lupus erythematosus and a proof-of-concept trial of metformin. Arthritis Rheumatol. 67, 3190–3200 (2015).

  90. 90.

    et al. Neutrophil extracellular traps enriched in oxidized mitochondrial DNA are interferogenic and contribute to lupus-like disease. Nat. Med. 22, 146–153 (2016). This paper documents a role for mtDNA in NET-mediated type I IFN responses in lupus.

  91. 91.

    et al. Oxidized mitochondrial nucleoids released by neutrophils drive type I interferon production in human lupus. J. Exp. Med. 213, 697–713 (2016). This paper shows that oxidized mtDNA nucleoids are released from lupus neutrophils to trigger type I IFN responses.

  92. 92.

    et al. Mitochondrial DNA neutrophil extracellular traps are formed after trauma and subsequent surgery. J. Crit Care 29, 1133.e1–1133.e5 (2014).

  93. 93.

    et al. TLR signalling augments macrophage bactericidal activity through mitochondrial ROS. Nature 472, 476–480 (2011).

  94. 94.

    et al. Oxidative modification enhances the immunostimulatory effects of extracellular mitochondrial DNA on plasmacytoid dendritic cells. Free Radic. Biol. Med. 77, 281–290 (2014).

  95. 95.

    et al. Hexokinase is an innate immune receptor for the detection of bacterial Peptidoglycan. Cell 166, 624–636 (2016).

  96. 96.

    & In D-loop: 40 years of mitochondrial 7S DNA. Exp. Gerontol. 56, 175–181 (2014).

  97. 97.

    et al. Mitochondrial DNA replication proceeds via a 'bootlace' mechanism involving the incorporation of processed transcripts. Nucleic Acids Res. 41, 5837–5850 (2013).

  98. 98.

    , , & The genomic landscape of polymorphic human nuclear mitochondrial insertions. Nucleic Acids Res. 42, 12640–12649 (2014).

  99. 99.

    , , & Fidelity of capture-enrichment for mtDNA genome sequencing: influence of NUMTs. Nucleic Acids Res. 40, e137 (2012).

  100. 100.

    Targeted and robust amplification of mitochondrial DNA in the presence of nuclear-encoded mitochondrial pseudogenes using Φ29 DNA polymerases. Methods Mol. Biol. 1167, 255–263 (2014).

  101. 101.

    , , & Preventing the pollution of mitochondrial datasets with nuclear mitochondrial paralogs (numts). Mitochondrion 11, 246–254 (2011).

  102. 102.

    et al. Cytosolic RNA:DNA hybrids activate the cGAS–STING axis. EMBO J. 33, 2937–2946 (2014).

  103. 103.

    et al. Hepatocyte mitochondrial DNA drives nonalcoholic steatohepatitis by activation of TLR9. J. Clin. Invest. 126, 859–864 (2016).

  104. 104.

    et al. Mitochondrial DNA released by trauma induces neutrophil extracellular traps. PLoS ONE 10, e0120549 (2015).

  105. 105.

    et al. Mitochondrial DNA: an endogenous trigger for immune paralysis. Anesthesiology 124, 923–933 (2016).

  106. 106.

    et al. Induction of type I IFN is a physiological immune reaction to apoptotic cell-derived membrane microparticles. J. Immunol. 189, 1747–1756 (2012).

  107. 107.

    et al. Identification of novel oligonucleotides from mitochondrial DNA that spontaneously induce plasmacytoid dendritic cell activation. J. Leukoc. Biol. 94, 123–135 (2013).

  108. 108.

    et al. Cigarette smoke-induced necroptosis and DAMP release trigger neutrophilic airway inflammation in mice. Am. J. Physiol. Lung Cell. Mol. Physiol. 310, L377–L386 (2016).

  109. 109.

    , , , & Extracellular mitochondrial DNA and oxidatively damaged DNA in synovial fluid of patients with rheumatoid arthritis. Arthritis Res. Ther. 5, R234–R240 (2003).

  110. 110.

    et al. Role of mitochondrial DNA in septic AKI via Toll-like receptor 9. J. Am. Soc. Nephrol. 27, 2009–2020 (2016).

  111. 111.

    et al. Mitochondrial ROS induces cardiac inflammation via a pathway through mtDNA damage in a pneumonia-related sepsis model. PLoS ONE 10, e0139416 (2015).

  112. 112.

    et al. Mitochondrial DNA damage-associated molecular patterns mediate a feed-forward cycle of bacteria-induced vascular injury in perfused rat lungs. Am. J. Physiol. Lung Cell. Mol. Physiol. 308, L1078–L1085 (2015).

  113. 113.

    et al. Circulating mitochondrial DNA and Toll-like receptor 9 are associated with vascular dysfunction in spontaneously hypertensive rats. Cardiovasc. Res. 107, 119–130 (2015).

  114. 114.

    et al. Oxidant stress in mitochondrial DNA damage, autophagy and inflammation in atherosclerosis. Sci. Rep. 3, 1077 (2013).

  115. 115.

    et al. Mitochondrial DNA–LL-37 complex promotes atherosclerosis by escaping from autophagic recognition. Immunity 43, 1137–1147 (2015).

  116. 116.

    et al. Investigating mitochondria as a target for treating age-related macular degeneration. J. Neurosci. 35, 7304–7311 (2015).

  117. 117.

    , , & Mitochondrial DNA damage as a potential mechanism for age-related macular degeneration. Invest. Ophthalmol. Vis. Sci. 51, 5470–5479 (2010).

  118. 118.

    et al. Circulating mitochondrial DNA increases with age and is a familiar trait: implications for “inflamm-aging”. Eur. J. Immunol. 44, 1552–1562 (2014).

  119. 119.

    et al. Circulating TNF and mitochondrial DNA are major determinants of neutrophil phenotype in the advanced-age, frail elderly. Mol. Immunol. 65, 148–156 (2015).

  120. 120.

    et al. Chemokines and mitochondrial products activate neutrophils to amplify organ injury during mouse acute liver failure. Hepatology 56, 1971–1982 (2012).

Download references

Acknowledgements

The authors thank B. Kaufman for helpful comments on the manuscript, and we acknowledge L. Ciaccia West for assistance with the figures. G.S.S. is the Joseph A. and Lucille K. Madri Endowed Professor of Experimental Pathology, and this work was supported by US National Institutes of Health grant R01 AG047632.

Author information

Affiliations

  1. Department of Microbial Pathogenesis and Immunology, Texas A&M University Health Science Center, 470 Reynolds Medical Building, TAMU 1114, College Station, Texas 77843, USA.

    • A. Phillip West
  2. Departments of Pathology and Genetics and Yale Center for Research on Aging, Yale School of Medicine, 310 Cedar Street, BML 371, New Haven, Connecticut 06520, USA.

    • Gerald S. Shadel

Authors

  1. Search for A. Phillip West in:

  2. Search for Gerald S. Shadel in:

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to A. Phillip West or Gerald S. Shadel.

Glossary

Pattern-recognition receptors

(PRRs). Evolutionarily conserved receptors of the innate immune system that detect foreign viral, bacterial and/or fungal constituents, as well as endogenous molecules released from injured cells and tissues.

Damage-associated molecular patterns

(DAMPs). Molecules that are exposed or released by injured, necrotic or dying cells and are recognized by pattern-recognition receptors.

Nucleoids

Functional mitochondrial DNA packaging complexes in the mitochondrial matrix that consist of one or more mitochondrial DNA genomes and associated proteins.

Transcription factor A, mitochondrial

(TFAM). A dual high-mobility-group box protein in mitochondria that promotes packaging of mitochondrial DNA and regulates transcription from mitochondrial DNA promoters.

Inflammasomes

Multi-protein complexes that activate caspase 1 to induce processing of pro-interleukin-1β and pro-interleukin-18 into mature and secreted forms.

Haplogroups

Clusters of single-nucleotide polymorphisms in mitochondrial DNA that define inherited lineages.

Cyclic GMP–AMP synthase

(cGAS). A cytosolic DNA sensor that catalyses the production of the second messenger cyclic GMP–AMP (cGAMP) on binding to DNA.

Stimulator of interferon genes

(STING). An endoplasmic reticulum-resident adaptor protein that binds to cyclic GMP–AMP (cGAMP) to trigger type I interferon production.

Aicardi–Goutières syndrome

A disease in which mutations in the cytosolic enzyme 3 repair exonuclease 1 (TREX1) or other nucleases lead to the intracellular accumulation of endogenous nucleic acids, triggering chronic type I interferon responses that cause debilitating autoinflammatory and neurodegenerative pathology.

D-loop

A stable three-stranded DNA structure in mammalian mitochondrial DNA that is caused by premature termination of replication.

Systemic lupus erythematosus

(SLE). A chronic autoimmune disease that is linked to aberrant type I interferon responses in which autoantibodies specific for DNA, RNA or proteins associated with nucleic acids form immune complexes that accumulate in multiple tissues to cause pathology.

About this article

Publication history

Published

DOI

https://doi.org/10.1038/nri.2017.21

Further reading