Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Mitochondria in innate immune responses

Key Points

  • The innate immune system has a key role in the mammalian immune response. Recent research has demonstrated that mitochondria participate in a broad range of innate immune pathways, including RIG-I-like receptor (RLR) signalling, antibacterial immunity and the sterile inflammatory response.

  • RLR signalling in response to viral infection requires mitochondrial antiviral signalling protein (MAVS), a mitochondrially localized adaptor that induces nuclear factor-κB (NF-κB) and interferon regulatory factor 3 (IRF3) and IRF7 signalling to initiate the production of pro-inflammatory cytokines and type I interferons (IFNs). The mechanisms of MAVS signalling remain under investigation, although recent studies have indicated that mitochondrial proteins such as translocase of the outer membrane 70 (TOM70), mitofusin 1 (MFN1), MFN2 and NLR family member X1 (NLRX1) influence MAVS signalling.

  • Mitochondrial fusion regulates MAVS signalling, as cells deficient in mitofusins display decreased antiviral innate immune responses. Mitochondrial fusion facilitates proper interactions between MAVS and downstream signalling molecules (such as stimulator of interferon genes (STING)), and maintains mitochondrial membrane potential, which is necessary for MAVS signalling.

  • Mitochondrial reactive oxygen species (mROS) appear to influence both RLR signalling and antibacterial innate immune responses. Mitophagy-deficient cells accumulate damaged, mROS-producing mitochondria, and consequently produce more IFNβ. mROS-deficient macrophages and mice display increased susceptibility to bacteria and protozoan parasites, and Toll-like receptor (TLR) signalling can directly augment mROS generation for enhanced bactericidal activity.

  • Mitochondrial damage-associated molecular patterns (DAMPs; such as mtDNA and N-formylated peptides) are released following cellular necrosis and activate innate immune receptors, which initiate sterile inflammatory responses. Exposure to DAMPs promotes mROS generation, which initiates NOD-, LRR- and pyrin domain-containing 3 (NLRP3) inflammasome signalling, caspase 1 activation and IL-1β and IL-18 secretion.

Abstract

The innate immune system has a key role in the mammalian immune response. Recent research has demonstrated that mitochondria participate in a broad range of innate immune pathways, functioning as signalling platforms and contributing to effector responses. In addition to regulating antiviral signalling, mounting evidence suggests that mitochondria facilitate antibacterial immunity by generating reactive oxygen species and contribute to innate immune activation following cellular damage and stress. Therefore, in addition to their well-appreciated roles in cellular metabolism and programmed cell death, mitochondria appear to function as centrally positioned hubs in the innate immune system. Here, we review the emerging knowledge about the roles of mitochondria in innate immunity.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Mitochondrial antiviral signalling pathways.
Figure 2: Mitochondrial dynamics regulate MAVS signalling.
Figure 3: Mitochondrial ROS and innate immune responses.
Figure 4: Mitochondrial involvement in cellular damage responses.

Similar content being viewed by others

References

  1. Hayden, M. S., West, A. P. & Ghosh, S. NF-κB and the immune response. Oncogene 25, 6758–6780 (2006).

    CAS  PubMed  Google Scholar 

  2. West, A. P., Koblansky, A. A. & Ghosh, S. Recognition and signaling by Toll-like receptors. Annu. Rev. Cell Dev. Biol. 22, 409–437 (2006).

    CAS  PubMed  Google Scholar 

  3. Kerrigan, A. M. & Brown, G. D. Syk-coupled C-type lectin receptors that mediate cellular activation via single tyrosine based activation motifs. Immunol. Rev. 234, 335–352 (2010).

    CAS  PubMed  Google Scholar 

  4. Takeuchi, O. & Akira, S. Innate immunity to virus infection. Immunol. Rev. 227, 75–86 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Bonawitz, N. D., Clayton, D. A. & Shadel, G. S. Initiation and beyond: multiple functions of the human mitochondrial transcription machinery. Mol. Cell 24, 813–825 (2006).

    CAS  PubMed  Google Scholar 

  6. Ryan, M. T. & Hoogenraad, N. J. Mitochondrial–nuclear communications. Annu. Rev. Biochem. 76, 701–722 (2007).

    CAS  PubMed  Google Scholar 

  7. Soubannier, V. & McBride, H. M. Positioning mitochondrial plasticity within cellular signaling cascades. Biochim. Biophys. Acta 1793, 154–170 (2009).

    CAS  PubMed  Google Scholar 

  8. Hamanaka, R. B. & Chandel, N. S. Mitochondrial reactive oxygen species regulate cellular signaling and dictate biological outcomes. Trends Biochem. Sci. 35, 505–513 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Arnoult, D., Carneiro, L., Tattoli, I. & Girardin, S. E. The role of mitochondria in cellular defense against microbial infection. Semin. Immunol. 21, 223–232 (2009).

    CAS  PubMed  Google Scholar 

  10. Ohta, A. & Nishiyama, Y. Mitochondria and viruses. Mitochondrion 11, 1–12 (2011).

    CAS  PubMed  Google Scholar 

  11. Brennan, K. & Bowie, A. G. Activation of host pattern recognition receptors by viruses. Curr. Opin. Microbiol. 13, 503–507 (2010).

    CAS  PubMed  Google Scholar 

  12. Satoh, T. et al. LGP2 is a positive regulator of RIG-I- and MDA5-mediated antiviral responses. Proc. Natl Acad. Sci. USA 107, 1512–1517 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Kawai, T. et al. IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction. Nature Immunol. 6, 981–988 (2005).

    CAS  Google Scholar 

  14. Meylan, E. et al. Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus. Nature 437, 1167–1172 (2005).

    CAS  PubMed  Google Scholar 

  15. Seth, R. B., Sun, L., Ea, C.-K. & Chen, Z. J. Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-κB and IRF3. Cell 122, 669–682 (2005). This paper demonstrates that MAVS signalling originates at the OMM.

    CAS  PubMed  Google Scholar 

  16. Xu, L.-G. et al. VISA is an adapter protein required for virus-triggered IFN-β signaling. Mol. Cell 19, 727–740 (2005). References 13–16 were the first to describe MAVS (also termed IPS1, CARDIF and VISA) as an RLR signalling adaptor molecule.

    CAS  PubMed  Google Scholar 

  17. Seth, R. B., Sun, L. & Chen, Z. J. Antiviral innate immunity pathways. Cell Res. 16, 141–147 (2006).

    CAS  PubMed  Google Scholar 

  18. Potter, J. A., Randall, R. E. & Taylor, G. L. Crystal structure of human IPS-1/MAVS/VISA/Cardif caspase activation recruitment domain. BMC Struct. Biol. 8, 11 (2008).

    PubMed  PubMed Central  Google Scholar 

  19. Saha, S. K. et al. Regulation of antiviral responses by a direct and specific interaction between TRAF3 and Cardif. EMBO J. 25, 3257–3263 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Tang, E. D. & Wang, C.-Y. MAVS self-association mediates antiviral innate immune signaling. J. Virol. 83, 3420–3428 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Tang, E. D. & Wang, C.-Y. TRAF5 is a downstream target of MAVS in antiviral innate immune signaling. PLoS ONE 5, e9172 (2010).

    PubMed  PubMed Central  Google Scholar 

  22. Michallet, M.-C. et al. TRADD protein is an essential component of the RIG-like helicase antiviral pathway. Immunity 28, 651–661 (2008).

    CAS  PubMed  Google Scholar 

  23. Lin, R. et al. Dissociation of a MAVS/IPS-1/VISA/Cardif-IKKɛ molecular complex from the mitochondrial outer membrane by hepatitis C virus NS3-4A proteolytic cleavage. J. Virol. 80, 6072–6083 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Wang, Y. Y. et al. WDR5 is essential for assembly of the VISA-associated signaling complex and virus-triggered IRF3 and NF-κB activation. Proc. Natl Acad. Sci. USA 107, 815–820 (2010).

    CAS  PubMed  Google Scholar 

  25. Neupert, W. & Herrmann, J. M. Translocation of proteins into mitochondria. Annu. Rev. Biochem. 76, 723–749 (2007).

    CAS  PubMed  Google Scholar 

  26. Yang, K. et al. Hsp90 regulates activation of interferon regulatory factor 3 and TBK-1 stabilization in Sendai virus-infected cells. Mol. Biol. Cell 17, 1461–1471 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Liu, X.-Y., Wei, B., Shi, H.-X., Shan, Y.-F. & Wang, C. Tom70 mediates activation of interferon regulatory factor 3 on mitochondria. Cell Res. 20, 994–1011 (2010).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Zhong, B. et al. The adaptor protein MITA links virus-sensing receptors to IRF3 transcription factor activation. Immunity 29, 538–550 (2008). References 28 and 29 characterize STING (also termed MITA) as a crucial component of the RLR signalling machinery.

    Article  CAS  PubMed  Google Scholar 

  30. Sun, W. et al. ERIS, an endoplasmic reticulum IFN stimulator, activates innate immune signaling through dimerization. Proc. Natl Acad. Sci. USA 106, 8653–8658 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Jin, L. et al. MPYS, a novel membrane tetraspanner, is associated with major histocompatibility complex class II and mediates transduction of apoptotic signals. Mol. Cell. Biol. 28, 5014–5026 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Castanier, C., Garcin, D., Vazquez, A. & Arnoult, D. Mitochondrial dynamics regulate the RIG-I-like receptor antiviral pathway. EMBO Rep. 11, 133–138 (2010). An important mechanistic paper detailing the role of mitochondrial fusion in RLR signalling.

    CAS  PubMed  Google Scholar 

  33. Giorgi, C., De Stefani, D., Bononi, A., Rizzuto, R. & Pinton, P. Structural and functional link between the mitochondrial network and the endoplasmic reticulum. Int. J. Biochem. Cell Biol. 41, 1817–1827 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Vance, J. E. Phospholipid synthesis in a membrane fraction associated with mitochondria. J. Biol. Chem. 265, 7248–7256 (1990).

    CAS  PubMed  Google Scholar 

  35. You, F. et al. PCBP2 mediates degradation of the adaptor MAVS via the HECT ubiquitin ligase AIP4. Nature Immunol. 10, 1300–1308 (2009).

    CAS  Google Scholar 

  36. Jia, Y. et al. Negative regulation of MAVS-mediated innate immune response by PSMA7. J. Immunol. 183, 4241–4248 (2009).

    CAS  PubMed  Google Scholar 

  37. Salonen, A., Ahola, T. & Kääriäinen, L. Viral RNA replication in association with cellular membranes. Curr. Top. Microbiol. Immunol. 285, 139–173 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Bowie, A. G. & Unterholzner, L. Viral evasion and subversion of pattern-recognition receptor signalling. Nature Rev. Immunol. 8, 911–922 (2008).

    CAS  Google Scholar 

  39. Li, X.-D., Sun, L., Seth, R. B., Pineda, G. & Chen, Z. J. Hepatitis C virus protease NS3/4A cleaves mitochondrial antiviral signaling protein off the mitochondria to evade innate immunity. Proc. Natl Acad. Sci. USA 102, 17717–17722 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Chen, Z. et al. GB virus B disrupts RIG-I signaling by NS3/4A-mediated cleavage of the adaptor protein MAVS. J. Virol. 81, 964–976 (2007).

    CAS  PubMed  Google Scholar 

  41. Yang, Y. et al. Disruption of innate immunity due to mitochondrial targeting of a picornaviral protease precursor. Proc. Natl Acad. Sci. USA 104, 7253–7258 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Wei, C. et al. The hepatitis B virus X protein disrupts innate immunity by downregulating mitochondrial antiviral signaling protein. J. Immunol. 185, 1158–1168 (2010).

    CAS  PubMed  Google Scholar 

  43. Peerschke, E. I. B. & Ghebrehiwet, B. The contribution of gC1qR/p33 in infection and inflammation. Immunobiology 212, 333–342 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Jiang, J., Zhang, Y., Krainer, A. R. & Xu, R. M. Crystal structure of human p32, a doughnut-shaped acidic mitochondrial matrix protein. Proc. Natl Acad. Sci. USA 96, 3572–3577 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Fogal, V. et al. Mitochondrial p32 protein is a critical regulator of tumor metabolism via maintenance of oxidative phosphorylation. Mol. Cell. Biol. 30, 1303–1318 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Xu, L., Xiao, N., Liu, F., Ren, H. & Gu, J. Inhibition of RIG-I and MDA5-dependent antiviral response by gC1qR at mitochondria. Proc. Natl Acad. Sci. USA 106, 1530–1535 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Dedio, J., Jahnen-Dechent, W., Bachmann, M. & Müller-Esterl, W. The multiligand-binding protein gC1qR, putative C1q receptor, is a mitochondrial protein. J. Immunol. 160, 3534–3542 (1998).

    CAS  PubMed  Google Scholar 

  48. Moore, C. B. et al. NLRX1 is a regulator of mitochondrial antiviral immunity. Nature 451, 573–577 (2008). In this paper, NLRX1 is shown to localize to mitochondria and inhibit MAVS signalling.

    CAS  PubMed  Google Scholar 

  49. Tattoli, I. et al. NLRX1 is a mitochondrial NOD-like receptor that amplifies NF-κB and JNK pathways by inducing reactive oxygen species production. EMBO Rep. 9, 293–300 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Arnoult, D. et al. An N-terminal addressing sequence targets NLRX1 to the mitochondrial matrix. J. Cell Sci. 122, 3161–3168 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Chan, D. C. Mitochondrial fusion and fission in mammals. Annu. Rev. Cell Dev. Biol. 22, 79–99 (2006).

    CAS  PubMed  Google Scholar 

  52. Detmer, S. A. & Chan, D. C. Functions and dysfunctions of mitochondrial dynamics. Nature Rev. Mol. Cell Biol. 8, 870–879 (2007).

    CAS  Google Scholar 

  53. de Brito, O. M. & Scorrano, L. Mitofusin 2 tethers endoplasmic reticulum to mitochondria. Nature 456, 605–610 (2008).

    PubMed  Google Scholar 

  54. Yasukawa, K. et al. Mitofusin 2 inhibits mitochondrial antiviral signaling. Sci. Signal. 2, ra47 (2009).

    PubMed  Google Scholar 

  55. Onoguchi, K. et al. Virus-infection or 5′ppp-RNA activates antiviral signal through redistribution of IPS-1 mediated by MFN1. PLoS Pathog. 6, e1001012 (2010). This study demonstrates that RIG-I, mitochondria and MAVS localize around cytoplasmic centres of viral replication, and that this is regulated by MFN1.

    PubMed  PubMed Central  Google Scholar 

  56. Koshiba, T., Yasukawa, K., Yanagi, Y. & Kawabata, S. Mitochondrial membrane potential is required for MAVS-mediated antiviral signaling. Sci. Signal. 4, ra7 (2011). This paper details the roles of MFN1 and MFN2 in RLR signalling; these roles include preserving mitochondrial fusion and membrane potential.

    PubMed  Google Scholar 

  57. Jin, L., Lenz, L. & Cambier, J. Cellular reactive oxygen species inhibit MPYS induction of IFNβ. PLoS ONE 5, e15142 (2010).

    PubMed  PubMed Central  Google Scholar 

  58. Soucy-Faulkner, A. et al. Requirement of NOX2 and reactive oxygen species for efficient RIG-I-mediated antiviral response through regulation of MAVS expression. PLoS Pathog. 6, e1000930 (2010).

    PubMed  PubMed Central  Google Scholar 

  59. Tal, M. C. et al. Absence of autophagy results in reactive oxygen species-dependent amplification of RLR signaling. Proc. Natl Acad. Sci. USA 106, 2770–2775 (2009). An important study showing that mROS can augment RLR signalling and that autophagy and mitophagy regulate antiviral responses by limiting mROS production.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Jounai, N. et al. The Atg5–Atg12 conjugate associates with innate antiviral immune responses. Proc. Natl Acad. Sci. USA 104, 14050–14055 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Koopman, W. J. et al. Mammalian mitochondrial complex I: biogenesis, regulation and reactive oxygen species generation. Antioxid. Redox Signal. 12, 1431–1470 (2010).

    CAS  PubMed  Google Scholar 

  62. Murphy, M. P. How mitochondria produce reactive oxygen species. Biochem. J. 417, 1–13 (2009).

    CAS  PubMed  Google Scholar 

  63. Reeves, M. B., Davies, A. A., McSharry, B. P., Wilkinson, G. W. & Sinclair, J. H. Complex I binding by a virally encoded RNA regulates mitochondria-induced cell death. Science 316, 1345–1348 (2007).

    CAS  PubMed  Google Scholar 

  64. Arsenijevic, D. et al. Disruption of the uncoupling protein-2 gene in mice reveals a role in immunity and reactive oxygen species production. Nature Genet. 26, 435–439 (2000). The first study to demonstrate that macrophages with increased mROS display heightened resistance to microbial infection.

    CAS  PubMed  Google Scholar 

  65. Brand, M. D. & Esteves, T. C. Physiological functions of the mitochondrial uncoupling proteins UCP2 and UCP3. Cell. Metab. 2, 85–93 (2005).

    CAS  PubMed  Google Scholar 

  66. Lambeth, J. D. NOX enzymes and the biology of reactive oxygen. Nature Rev. Immunol. 4, 181–189 (2004).

    CAS  Google Scholar 

  67. Underhill, D. M. & Ozinsky, A. Phagocytosis of microbes: complexity in action. Annu. Rev. Immunol. 20, 825–852 (2002).

    CAS  PubMed  Google Scholar 

  68. Fleury, C. et al. Uncoupling protein-2: a novel gene linked to obesity and hyperinsulinemia. Nature Genet. 15, 269–272 (1997).

    CAS  PubMed  Google Scholar 

  69. Rousset, S. et al. The uncoupling protein 2 modulates the cytokine balance in innate immunity. Cytokine 35, 135–142 (2006).

    CAS  PubMed  Google Scholar 

  70. Kizaki, T. et al. Uncoupling protein 2 plays an important role in nitric oxide production of lipopolysaccharide-stimulated macrophages. Proc. Natl Acad. Sci. USA 99, 9392–9397 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Emre, Y. et al. Mitochondria contribute to LPS-induced MAPK activation via uncoupling protein UCP2 in macrophages. Biochem. J. 402, 271–278 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Bai, Y. et al. Persistent nuclear factor-κB activation in Ucp2−/− mice leads to enhanced nitric oxide and inflammatory cytokine production. J. Biol. Chem. 280, 19062–19069 (2005).

    CAS  PubMed  Google Scholar 

  73. Nishio, K., Qiao, S. & Yamashita, H. Characterization of the differential expression of uncoupling protein 2 and ROS production in differentiated mouse macrophage-cells (Mm1) and the progenitor cells (M1). J. Mol. Histol. 36, 35–44 (2005).

    CAS  PubMed  Google Scholar 

  74. Giguère, V. Transcriptional control of energy homeostasis by the estrogen-related receptors. Endocr. Rev. 29, 677–696 (2008).

    PubMed  Google Scholar 

  75. Sonoda, J. et al. Nuclear receptor ERRα and coactivator PGC-1β are effectors of IFN-γ-induced host defense. Genes Dev. 21, 1909–1920 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. West, A. P. et al. TLR signaling augments macrophage bactericidal activity through mitochondrial reactive oxygen species. Nature 472, 476–480 (2011). This study demonstrates that TLR signalling directly induces mROS, leading to enhanced antibacterial activity.

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Kopp, E. et al. ECSIT is an evolutionarily conserved intermediate in the Toll/IL-1 signal transduction pathway. Genes Dev. 13, 2059–2071 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Vogel, R. O. et al. Cytosolic signaling protein Ecsit also localizes to mitochondria where it interacts with chaperone NDUFAF1 and functions in complex I assembly. Genes Dev. 21, 615–624 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Kono, H. & Rock, K. L. How dying cells alert the immune system to danger. Nature Rev. Immunol. 8, 279–289 (2008).

    CAS  Google Scholar 

  80. Rock, K. L. & Kono, H. The inflammatory response to cell death. Annu. Rev. Pathol. 3, 99–126 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Chen, G. Y. & Nuñez, G. Sterile inflammation: sensing and reacting to damage. Nature Rev. Immunol. 10, 826–837 (2010).

    CAS  Google Scholar 

  82. Cassel, S. L., Joly, S. & Sutterwala, F. S. The NLRP3 inflammasome: a sensor of immune danger signals. Semin. Immunol. 21, 194–198 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Collins, L. V., Hajizadeh, S., Holme, E., Jonsson, I.-M. & Tarkowski, A. Endogenously oxidized mitochondrial DNA induces in vivo and in vitro inflammatory responses. J. Leukoc. Biol. 75, 995–1000 (2004).

    CAS  PubMed  Google Scholar 

  84. Zhang, Q., Itagaki, K. & Hauser, C. J. Mitochondrial DNA is released by shock and activates neutrophils via p38 MAP kinase. Shock 34, 55–59 (2010).

    PubMed  Google Scholar 

  85. Zhang, Q. et al. Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature 464, 104–107 (2010). In this study, mitochondrial N -formylated peptides and mtDNA are demonstrated to function as DAMPs by signalling via PRRs and inducing innate immune responses.

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Rabiet, M.-J., Huet, E. & Boulay, F. The N-formyl peptide receptors and the anaphylatoxin C5a receptors: an overview. Biochimie 89, 1089–1106 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Carp, H. Mitochondrial N-formylmethionyl proteins as chemoattractants for neutrophils. J. Exp. Med. 155, 264–275 (1982).

    CAS  PubMed  Google Scholar 

  88. Rabiet, M.-J., Huet, E. & Boulay, F. Human mitochondria-derived N-formylated peptides are novel agonists equally active on FPR and FPRL1, while Listeria monocytogenes-derived peptides preferentially activate FPR. Eur. J. Immunol. 35, 2486–2495 (2005).

    CAS  PubMed  Google Scholar 

  89. Raoof, M., Zhang, Q., Itagaki, K. & Hauser, C. J. Mitochondrial peptides are potent immune activators that activate human neutrophils via FPR-1. J. Trauma 68, 1328–1332 (2010).

    CAS  PubMed  Google Scholar 

  90. McDonald, B. et al. Intravascular danger signals guide neutrophils to sites of sterile inflammation. Science 330, 362–366 (2010).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Tschopp, J. & Schroder, K. NLRP3 inflammasome activation: the convergence of multiple signalling pathways on ROS production? Nature Rev. Immunol. 10, 210–215 (2010).

    CAS  Google Scholar 

  93. Iyer, S. S. et al. Necrotic cells trigger a sterile inflammatory response through the Nlrp3 inflammasome. Proc. Natl Acad. Sci. USA 106, 20388–20393 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Nakahira, K. et al. Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nature Immunol. 12, 222–230 (2011). This paper demonstrates that mROS and mtDNA contribute to macrophage inflammasome activation by LPS and ATP, and that this is supressed by mitophagy.

    CAS  Google Scholar 

  95. Meissner, F., Molawi, K. & Zychlinsky, A. Superoxide dismutase 1 regulates caspase-1 and endotoxic shock. Nature Immunol. 9, 866–872 (2008).

    CAS  Google Scholar 

  96. van Bruggen, R. et al. Human NLRP3 inflammasome activation is Nox1–4 independent. Blood 115, 5398–5400 (2010).

    CAS  PubMed  Google Scholar 

  97. Zhou, R., Yazdi, A. S., Menu, P. & Tschopp, J. A role for mitochondria in NLRP3 inflammasome activation. Nature 469, 221–225 (2011). This study shows that NLRP3 and ASC localize to mitochondria and MAMs upon exposure of macrophages to DAMPs and that mROS activate the NLRP3 inflammasome.

    CAS  PubMed  Google Scholar 

  98. Tal, M. C. & Iwasaki, A. Autophagic control of RLR signaling. Autophagy 5, 749–750 (2009).

    CAS  PubMed  Google Scholar 

  99. Yu, H. B. & Finlay, B. B. The caspase-1 inflammasome: a pilot of innate immune responses. Cell Host Microbe 4, 198–208 (2008).

    CAS  PubMed  Google Scholar 

  100. Robinson, M. J., Sancho, D., Slack, E. C., LeibundGut-Landmann, S. & Reis e Sousa, C. Myeloid C-type lectins in innate immunity. Nature Immunol. 7, 1258–1265 (2006).

    CAS  Google Scholar 

  101. Orrenius, S., Gogvadze, V. & Zhivotovsky, B. Mitochondrial oxidative stress: implications for cell death. Annu. Rev. Pharmacol. Toxicol. 47, 143–183 (2007).

    CAS  PubMed  Google Scholar 

  102. Han, D., Antunes, F., Canali, R., Rettori, D. & Cadenas, E. Voltage-dependent anion channels control the release of the superoxide anion from mitochondria to cytosol. J. Biol. Chem. 278, 5557–5563 (2003).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We regret that several important studies could only be cited indirectly through comprehensive reviews, owing to space and reference number limitations. We thank L. Ciaccia for assistance with the figures. This work was supported by grants from the US National Institutes of Health to S.G. (R37-AI33443) and G.S. (ES-011,163).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Sankar Ghosh.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Glossary

Programmed cell death

A common form of cell death that is also referred to as apoptosis. Many physiological and developmental stimuli cause apoptosis, and this mechanism is frequently used to delete unwanted, superfluous or potentially harmful cells, such as those undergoing transformation.

Oxidative phosphorylation

The metabolic pathway that occurs at the inner mitochondrial membrane and uses an electrochemical gradient created by the oxidation of electron carriers to generate ATP.

Mitochondrial dynamics

Mitochondrial dynamics refers to the movement of mitochondria along the cytoskeleton and the regulation of mitochondrial morphology and distribution mediated by tethering, and fusion and fission events.

Sterile inflammation

Inflammation that results from trauma, ischaemia–reperfusion injury or chemically induced injury that typically occurs in the absence of any microorganisms.

Canonical NF-κB signalling

A typical pathway of NF-κB activation that involves phosphorylation and degradation of the prototypical NF-κB inhibitor, IκBα.

TOM complex

The translocase of the outer membrane (TOM) is a complex of proteins localized to the outer mitochondrial membrane that recognizes and imports nuclear-encoded mitochondrial proteins into the intermembrane space.

Heat shock protein

(HSP). A member of a class of functionally related proteins that function as molecular chaperones and have crucial roles in protein folding and intracellular trafficking.

Mitochondria-associated membranes

(MAMs). Regions of the endoplasmic reticulum that are closely juxtaposed to mitochondria and support communication between the organelles via calcium and phospholipid exchange.

E3 ubiquitin ligase

An enzyme that is required to attach the molecular tag ubiquitin to proteins. Depending on the number of ubiquitin molecules that are attached and the positioning of the links between them, the ubiquitin tag can target proteins for degradation in the proteasomal complex, sort them to specific subcellular compartments or modify their biological activity.

Mitofusin

An outer mitochondrial membrane protein that regulates mitochondrial fusion and ER–mitochondrial interactions by tethering adjacent organelles.

Mitophagy

A term referring to the selective removal of mitochondria by macroautophagy under conditions of nutrient starvation or mitochondrial stress.

Mitochondrial uncoupling

A process involving the disassociation of mitochondrial respiration from ATP generation that is characterized by increased permeability of the inner mitochondrial membrane to protons and subsequent dissipation of mitochondrial membrane potential.

Respiratory burst

A large increase in oxygen consumption and reactive oxygen species generation that accompanies the exposure of neutrophils to microorganisms and/or inflammatory mediators.

NADPH oxidase

A plasma membrane- and phagosomal membrane-bound enzyme complex that transfers electrons from NADPH to molecular oxygen, promoting the generation of the reactive oxygen species superoxide.

Necrosis

The premature death of living cells or tissue, resulting in the release of cellular constituents that promote inflammatory responses.

Haemorrhagic shock

A condition often caused by traumatic injury that results in reduced tissue perfusion and leads to inadequate delivery of oxygen and nutrients to cells and tissues.

Rights and permissions

Reprints and permissions

About this article

Cite this article

West, A., Shadel, G. & Ghosh, S. Mitochondria in innate immune responses. Nat Rev Immunol 11, 389–402 (2011). https://doi.org/10.1038/nri2975

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri2975

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing