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Mitochondrial control of inflammation

Nature Reviews Immunology volume 23, pages 159–173 (2023)Cite this article

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Abstract

Numerous mitochondrial constituents and metabolic products can function as damage-associated molecular patterns (DAMPs) and promote inflammation when released into the cytosol or extracellular milieu. Several safeguards are normally in place to prevent mitochondria from eliciting detrimental inflammatory reactions, including the autophagic disposal of permeabilized mitochondria. However, when the homeostatic capacity of such systems is exceeded or when such systems are defective, inflammatory reactions elicited by mitochondria can become pathogenic and contribute to the aetiology of human disorders linked to autoreactivity. In addition, inefficient inflammatory pathways induced by mitochondrial DAMPs can be pathogenic as they enable the establishment or progression of infectious and neoplastic disorders. Here we discuss the molecular mechanisms through which mitochondria control inflammatory responses, the cellular pathways that are in place to control mitochondria-driven inflammation and the pathological consequences of dysregulated inflammatory reactions elicited by mitochondrial DAMPs.

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Fig. 1: Main mechanisms of mitochondrial DAMP signalling.
Fig. 2: Roles of apoptosis and autophagy in the inhibition of inflammatory responses elicited by mitochondria.
Fig. 3: The mitophagy rheostat in the control of mitochondria-driven inflammation.

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References

  1. Roda, G. et al. Crohn’s disease. Nat. Rev. Dis. Prim. 6, 22 (2020).

    Article  PubMed  Google Scholar 

  2. Tansey, M. G. et al. Inflammation and immune dysfunction in Parkinson disease. Nat. Rev. Immunol. https://doi.org/10.1038/s41577-022-00684-6 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Stark, K. & Massberg, S. Interplay between inflammation and thrombosis in cardiovascular pathology. Nat. Rev. Cardiol. 18, 666–682 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  4. Basso, P. J., Andrade-Oliveira, V. & Camara, N. O. S. Targeting immune cell metabolism in kidney diseases. Nat. Rev. Nephrol. 17, 465–480 (2021).

    Article  CAS  PubMed  Google Scholar 

  5. Marchi, S., Morroni, G., Pinton, P. & Galluzzi, L. Control of host mitochondria by bacterial pathogens. Trends Microbiol. 30, 452–465 (2022).

    Article  CAS  PubMed  Google Scholar 

  6. Vesely, M. D., Kershaw, M. H., Schreiber, R. D. & Smyth, M. J. Natural innate and adaptive immunity to cancer. Annu. Rev. Immunol. 29, 235–271 (2011).

    Article  CAS  PubMed  Google Scholar 

  7. Mantovani, A., Ponzetta, A., Inforzato, A. & Jaillon, S. Innate immunity, inflammation and tumour progression: double-edged swords. J. Intern. Med. 285, 524–532 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Galluzzi, L., Humeau, J., Buqué, A., Zitvogel, L. & Kroemer, G. Immunostimulation with chemotherapy in the era of immune checkpoint inhibitors. Nat. Rev. Clin. Oncol. 17, 725–741 (2020).

    Article  PubMed  Google Scholar 

  9. Petroni, G., Buque, A., Coussens, L. M. & Galluzzi, L. Targeting oncogene and non-oncogene addiction to inflame the tumour microenvironment. Nat. Rev. Drug Discov. 21, 440–462 (2022).

    Article  CAS  PubMed  Google Scholar 

  10. Rodriguez-Ruiz, M. E., Vitale, I., Harrington, K. J., Melero, I. & Galluzzi, L. Immunological impact of cell death signaling driven by radiation on the tumor microenvironment. Nat. Immunol. 21, 120–134 (2020).

    Article  CAS  PubMed  Google Scholar 

  11. Zengeler, K. E. & Lukens, J. R. Innate immunity at the crossroads of healthy brain maturation and neurodevelopmental disorders. Nat. Rev. Immunol. 21, 454–468 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Kroemer, G., Galassi, C., Zitvogel, L. & Galluzzi, L. Immunogenic cell stress and death. Nat. Immunol. 23, 487–500 (2022).

    Article  CAS  PubMed  Google Scholar 

  13. Vanpouille-Box, C., Hoffmann, J. A. & Galluzzi, L. Pharmacological modulation of nucleic acid sensors - therapeutic potential and persisting obstacles. Nat. Rev. Drug Discov. 18, 845–867 (2019).

    Article  CAS  PubMed  Google Scholar 

  14. Elliott, M. R. et al. Nucleotides released by apoptotic cells act as a find-me signal to promote phagocytic clearance. Nature 461, 282–286 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Ghiringhelli, F. et al. Activation of the NLRP3 inflammasome in dendritic cells induces IL-1beta-dependent adaptive immunity against tumors. Nat. Med. 15, 1170–1178 (2009). Elliott et al. (2009) and Ghiringhelli et al. (2009) document the potent chemotactic and immunostimulatory effects of extracellular ATP.

    Article  CAS  PubMed  Google Scholar 

  16. Wein, T. & Sorek, R. Bacterial origins of human cell-autonomous innate immune mechanisms. Nat. Rev. Immunol. https://doi.org/10.1038/s41577-022-00705-4 (2022).

    Article  PubMed  Google Scholar 

  17. Roger, A. J., Muñoz-Gómez, S. A. & Kamikawa, R. The origin and diversification of mitochondria. Curr. Biol. 27, R1177–R1192 (2017).

    Article  CAS  PubMed  Google Scholar 

  18. Harapas, C. R. et al. Organellar homeostasis and innate immune sensing. Nat. Rev. Immunol. https://doi.org/10.1038/s41577-022-00682-8 (2022).

    Article  PubMed  Google Scholar 

  19. Galluzzi, L. et al. Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. Cell Death Differ. 25, 486–541 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  20. Galluzzi, L., Yamazaki, T. & Kroemer, G. Linking cellular stress responses to systemic homeostasis. Nat. Rev. Mol. Cell Biol. 19, 731–745 (2018).

    Article  CAS  PubMed  Google Scholar 

  21. Mehta, M. M., Weinberg, S. E. & Chandel, N. S. Mitochondrial control of immunity: beyond ATP. Nat. Rev. Immunol. 17, 608–620 (2017).

    Article  CAS  PubMed  Google Scholar 

  22. Klionsky, D. J. et al. Autophagy in major human diseases. EMBO J. 40, e108863 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Galluzzi, L., López-Soto, A., Kumar, S. & Kroemer, G. Caspases connect cell-death signaling to organismal homeostasis. Immunity 44, 221–231 (2016).

    Article  CAS  PubMed  Google Scholar 

  24. Diepstraten, S. T. et al. The manipulation of apoptosis for cancer therapy using BH3-mimetic drugs. Nat. Rev. Cancer 22, 45–64 (2022).

    Article  CAS  PubMed  Google Scholar 

  25. Decout, A., Katz, J. D., Venkatraman, S. & Ablasser, A. The cGAS-STING pathway as a therapeutic target in inflammatory diseases. Nat. Rev. Immunol. 21, 548–569 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Li, X. D. et al. Pivotal roles of cGAS-cGAMP signaling in antiviral defense and immune adjuvant effects. Science 341, 1390–1394 (2013).

    Article  CAS  PubMed  Google Scholar 

  27. Civril, F. et al. Structural mechanism of cytosolic DNA sensing by cGAS. Nature 498, 332–337 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Rongvaux, A. et al. Apoptotic caspases prevent the induction of type I interferons by mitochondrial DNA. Cell 159, 1563–1577 (2014). White et al. (2014) and Rongvaux et al. (2014) show that robust activation of apoptotic caspases downstream of MOMP suppresses cGAS signalling driven by mtDNA.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  31. Andreeva, L. et al. cGAS senses long and HMGB/TFAM-bound U-turn DNA by forming protein-DNA ladders. Nature 549, 394–398 (2017).

    Article  CAS  PubMed  Google Scholar 

  32. Zierhut, C. et al. The cytoplasmic DNA sensor cGAS promotes mitotic cell death. Cell 178, 302–315.e323 (2019). This study shows that chromatin is a poor cGAS activator and suppresses cGAS signalling elicited by naked dsDNA.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Michalski, S. et al. Structural basis for sequestration and autoinhibition of cGAS by chromatin. Nature 587, 678–682 (2020).

    Article  CAS  PubMed  Google Scholar 

  34. Zhao, B. et al. The molecular basis of tight nuclear tethering and inactivation of cGAS. Nature 587, 673–677 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Li, T. et al. Phosphorylation and chromatin tethering prevent cGAS activation during mitosis. Science 371, eabc5386 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Fuchs, Y. & Steller, H. Live to die another way: modes of programmed cell death and the signals emanating from dying cells. Nat. Rev. Mol. Cell Biol. 16, 329–344 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Domizio, J. D. et al. The cGAS-STING pathway drives type I IFN immunopathology in COVID-19. Nature 603, 145–151 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Wiens, K. E. & Ernst, J. D. The mechanism for type I interferon induction by mycobacterium tuberculosis is bacterial strain-dependent. PLoS Pathog. 12, e1005809 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  39. Sun, B. et al. Dengue virus activates cGAS through the release of mitochondrial DNA. Sci. Rep. 7, 3594 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  40. Zhou, C. M. et al. Identification of cGAS as an innate immune sensor of extracellular bacterium Pseudomonas aeruginosa. iScience 24, 101928 (2021).

    Article  CAS  PubMed  Google Scholar 

  41. Moriyama, M., Koshiba, T. & Ichinohe, T. Influenza A virus M2 protein triggers mitochondrial DNA-mediated antiviral immune responses. Nat. Commun. 10, 4624 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  42. Danthi, P. Viruses and the diversity of cell death. Annu. Rev. Virol. 3, 533–553 (2016).

    Article  CAS  PubMed  Google Scholar 

  43. McArthur, K. et al. BAK/BAX macropores facilitate mitochondrial herniation and mtDNA efflux during apoptosis. Science 359, eaao6047 (2018). These authors used super-resolution microscopy to define the roles of BAX and BAK1 in the release of mtDNA by permeabilized mitochondria.

    Article  PubMed  Google Scholar 

  44. Riley, J. S. et al. Mitochondrial inner membrane permeabilisation enables mtDNA release during apoptosis. EMBO J. 37, e99238 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  45. Bock, F. J. & Tait, S. W. G. Mitochondria as multifaceted regulators of cell death. Nat. Rev. Mol. Cell Biol. 21, 85–100 (2020).

    Article  CAS  PubMed  Google Scholar 

  46. Yamazaki, T. et al. Mitochondrial DNA drives abscopal responses to radiation that are inhibited by autophagy. Nat. Immunol. 21, 1160–1171 (2020). This study shows that mtDNA released by permeabilized mitochondria in the context of limited apoptotic caspase activation underlies the ability of radiotherapy to initiate acute cGAS signalling.

    Article  CAS  PubMed  Google Scholar 

  47. Willemsen, J. et al. TNF leads to mtDNA release and cGAS/STING-dependent interferon responses that support inflammatory arthritis. Cell Rep. 37, 109977 (2021).

    Article  CAS  PubMed  Google Scholar 

  48. Cosentino, K. et al. The interplay between BAX and BAK tunes apoptotic pore growth to control mitochondrial-DNA-mediated inflammation. Mol. Cell 82, 933–949.e939 (2022). The authors elegantly dissect the relative effects of BAX and BAK1 on the kinetics of the assembly of mtDNA-releasing pores at the OMM.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Ichim, G. et al. Limited mitochondrial permeabilization causes DNA damage and genomic instability in the absence of cell death. Mol. Cell 57, 860–872 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Galluzzi, L., Kepp, O., Trojel-Hansen, C. & Kroemer, G. Non-apoptotic functions of apoptosis-regulatory proteins. EMBO Rep. 13, 322–330 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Cao, K. et al. Mitochondrial dynamics regulate genome stability via control of caspase-dependent DNA damage. Dev. Cell 57, 1211–1225.e1216 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Brokatzky, D. et al. A non-death function of the mitochondrial apoptosis apparatus in immunity. EMBO J. 38, e100907 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  53. Tigano, M., Vargas, D. C., Tremblay-Belzile, S., Fu, Y. & Sfeir, A. Nuclear sensing of breaks in mitochondrial DNA enhances immune surveillance. Nature 591, 477–481 (2021). This article delineates a mechanism through which breaks in mtDNA initiate inflammatory responses as a consequence of mtRNA accumulation in the cytosol and RIG-I activation.

    Article  CAS  PubMed  Google Scholar 

  54. Flores-Romero, H. et al. BCL-2-family protein tBID can act as a BAX-like effector of apoptosis. EMBO J. 41, e108690 (2022).

    Article  CAS  PubMed  Google Scholar 

  55. Kim, J. et al. VDAC oligomers form mitochondrial pores to release mtDNA fragments and promote lupus-like disease. Science 366, 1531–1536 (2019). These authors suggest a role for VDACs in the pathogenic release of mtDNA that accompanies the development of a lupus-like syndrome in mice.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Bonora, M., Giorgi, C. & Pinton, P. Molecular mechanisms and consequences of mitochondrial permeability transition. Nat. Rev. Mol. Cell Biol. 23, 266–285 (2022).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  58. Yu, C. H. et al. TDP-43 triggers mitochondrial DNA release via mPTP to activate cGAS/STING in ALS. Cell 183, 636–649.e618 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Kruglov, A. G., Kharechkina, E. S., Nikiforova, A. B., Odinokova, I. V. & Kruglova, S. A. Dynamics of the permeability transition pore size in isolated mitochondria and mitoplasts. FASEB J. 35, e21764 (2021).

    Article  CAS  PubMed  Google Scholar 

  60. Heng, J. B. et al. The electromechanics of DNA in a synthetic nanopore. Biophys. J. 90, 1098–1106 (2006).

    Article  CAS  PubMed  Google Scholar 

  61. Neginskaya, M. A. et al. The very low number of calcium-induced permeability transition pores in the single mitochondrion. J. Gen. Physiol. 152, e202012631 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Ross, C. et al. Inflammatory caspases: toward a unified model for caspase activation by inflammasomes. Annu. Rev. Immunol. 40, 249–269 (2022).

    Article  PubMed  Google Scholar 

  63. Agostini, L. et al. NALP3 forms an IL-1beta-processing inflammasome with increased activity in Muckle–Wells autoinflammatory disorder. Immunity 20, 319–325 (2004).

    Article  CAS  PubMed  Google Scholar 

  64. Muruve, D. A. et al. The inflammasome recognizes cytosolic microbial and host DNA and triggers an innate immune response. Nature 452, 103–107 (2008).

    Article  CAS  PubMed  Google Scholar 

  65. Shimada, K. et al. Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis. Immunity 36, 401–414 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. 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). This article reveals the existence of a feedforward loop linking inflammasome activation and mitochondrial dysfunction that is under tonic control by autophagy.

    Article  CAS  PubMed  Google Scholar 

  67. Renaudin, X. Reactive oxygen species and DNA damage response in cancer. Int. Rev. Cell Mol. Biol. 364, 139–161 (2021).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  69. Zhou, R., Tardivel, A., Thorens, B., Choi, I. & Tschopp, J. Thioredoxin-interacting protein links oxidative stress to inflammasome activation. Nat. Immunol. 11, 136–140 (2010).

    Article  CAS  PubMed  Google Scholar 

  70. Saxena, G., Chen, J. & Shalev, A. Intracellular shuttling and mitochondrial function of thioredoxin-interacting protein. J. Biol. Chem. 285, 3997–4005 (2010).

    Article  CAS  PubMed  Google Scholar 

  71. Iyer, S. S. et al. Mitochondrial cardiolipin is required for Nlrp3 inflammasome activation. Immunity 39, 311–323 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Pervaiz, S., Bellot, G. L., Lemoine, A. & Brenner, C. Redox signaling in the pathogenesis of human disease and the regulatory role of autophagy. Int. Rev. Cell Mol. Biol. 352, 189–214 (2020).

    Article  CAS  PubMed  Google Scholar 

  73. Bauernfeind, F. et al. Cutting edge: reactive oxygen species inhibitors block priming, but not activation, of the NLRP3 inflammasome. J. Immunol. 187, 613–617 (2011).

    Article  CAS  PubMed  Google Scholar 

  74. Niemi, K. et al. Serum amyloid A activates the NLRP3 inflammasome via P2X7 receptor and a cathepsin B-sensitive pathway. J. Immunol. 186, 6119–6128 (2011).

    Article  CAS  PubMed  Google Scholar 

  75. Billingham, L. K. et al. Mitochondrial electron transport chain is necessary for NLRP3 inflammasome activation. Nat. Immunol. 23, 692–704 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Zhong, Z. et al. New mitochondrial DNA synthesis enables NLRP3 inflammasome activation. Nature 560, 198–203 (2018). The authors elegantly reveal that mtDNA neosynthesis is required for the generation of oxidized mtDNA species that elicit NLRP3 inflammasome activation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Kang, D., Kim, S. H. & Hamasaki, N. Mitochondrial transcription factor A (TFAM): roles in maintenance of mtDNA and cellular functions. Mitochondrion 7, 39–44 (2007).

    Article  CAS  PubMed  Google Scholar 

  79. Xu, Y., Johansson, M. & Karlsson, A. Human UMP-CMP kinase 2, a novel nucleoside monophosphate kinase localized in mitochondria. J. Biol. Chem. 283, 1563–1571 (2008).

    Article  CAS  PubMed  Google Scholar 

  80. Xian, H. et al. Metformin inhibition of mitochondrial ATP and DNA synthesis abrogates NLRP3 inflammasome activation and pulmonary inflammation. Immunity 54, 1463–1477.e1411 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Allam, R. et al. Mitochondrial apoptosis is dispensable for NLRP3 inflammasome activation but non-apoptotic caspase-8 is required for inflammasome priming. EMBO Rep. 15, 982–990 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Vince, J. E. et al. The mitochondrial apoptotic effectors BAX/BAK activate caspase-3 and -7 to trigger NLRP3 inflammasome and caspase-8 driven IL-1β activation. Cell Rep. 25, 2339–2353.e2334 (2018).

    Article  CAS  PubMed  Google Scholar 

  83. Chauhan, D. et al. BAX/BAK-induced apoptosis results in caspase-8-dependent IL-1β maturation in macrophages. Cell Rep. 25, 2354–2368.e2355 (2018).

    Article  CAS  PubMed  Google Scholar 

  84. Wang, Y. et al. Chemotherapy drugs induce pyroptosis through caspase-3 cleavage of a gasdermin. Nature 547, 99–103 (2017).

    Article  CAS  PubMed  Google Scholar 

  85. Rogers, C. et al. Gasdermin pores permeabilize mitochondria to augment caspase-3 activation during apoptosis and inflammasome activation. Nat. Commun. 10, 1689 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  86. Platnich, J. M. et al. Shiga toxin/lipopolysaccharide activates caspase-4 and gasdermin D to trigger mitochondrial reactive oxygen species upstream of the NLRP3 inflammasome. Cell Rep. 25, 1525–1536.e1527 (2018).

    Article  CAS  PubMed  Google Scholar 

  87. Guarnieri, J. W. et al. SARS-CoV-2 viroporins activate the NLRP3-inflammasome via the mitochondrial permeability transition pore. Preprint at bioRxiv https://doi.org/10.1101/2022.02.19.481139 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  88. Dang, E. V., McDonald, J. G., Russell, D. W. & Cyster, J. G. Oxysterol restraint of cholesterol synthesis prevents AIM2 inflammasome activation. Cell 171, 1057–1071.e1011 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Fernandes-Alnemri, T., Yu, J. W., Datta, P., Wu, J. & Alnemri, E. S. AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA. Nature 458, 509–513 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Rathinam, V. A. et al. The AIM2 inflammasome is essential for host defense against cytosolic bacteria and DNA viruses. Nat. Immunol. 11, 395–402 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Di Micco, A. et al. AIM2 inflammasome is activated by pharmacological disruption of nuclear envelope integrity. Proc. Natl Acad. Sci. USA 113, E4671–E4680 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  92. Crane, D. D., Bauler, T. J., Wehrly, T. D. & Bosio, C. M. Mitochondrial ROS potentiates indirect activation of the AIM2 inflammasome. Front. Microbiol. 5, 438 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  93. Xu, L. et al. Mitochondrial DNA enables AIM2 inflammasome activation and hepatocyte pyroptosis in nonalcoholic fatty liver disease. Am. J. Physiol. Gastrointest. Liver Physiol. 320, G1034–G1044 (2021).

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  95. Riley, J. S. & Tait, S. W. Mitochondrial DNA in inflammation and immunity. EMBO Rep. 21, e49799 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Zhang, Q. et al. Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature 464, 104–107 (2010). This study shows that mitochondrial products that are released into the circulation as a consequence of cell death, including mtDNA and formylated peptides, contribute to the aetiology of systemic inflammatory response syndrome.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Tian, J. et al. Toll-like receptor 9-dependent activation by DNA-containing immune complexes is mediated by HMGB1 and RAGE. Nat. Immunol. 8, 487–496 (2007).

    Article  CAS  PubMed  Google Scholar 

  98. Mangelinck, A. & Mann, C. DNA methylation and histone variants in aging and cancer. Int. Rev. Cell Mol. Biol. 364, 1–110 (2021).

    Article  CAS  PubMed  Google Scholar 

  99. Hemmi, H. et al. A Toll-like receptor recognizes bacterial DNA. Nature 408, 740–745 (2000).

    Article  CAS  PubMed  Google Scholar 

  100. Lamkanfi, M. et al. Inflammasome-dependent release of the alarmin HMGB1 in endotoxemia. J. Immunol. 185, 4385–4392 (2010).

    Article  CAS  PubMed  Google Scholar 

  101. Liu, Y. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Little, J. P. et al. Mitochondrial transcription factor A (Tfam) is a pro-inflammatory extracellular signaling molecule recognized by brain microglia. Mol. Cell. Neurosci. 60, 88–96 (2014).

    Article  CAS  PubMed  Google Scholar 

  103. Oka, T. et al. Mitochondrial DNA that escapes from autophagy causes inflammation and heart failure. Nature 485, 251–255 (2012). The authors show that deletion of a lysosomal nuclease-encoding gene results in inefficient mtDNA disposal by autophagy, culminating in pathogenic TLR9 activation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  105. Rabas, N. et al. PINK1 drives production of mtDNA-containing extracellular vesicles to promote invasiveness. J. Cell Biol. 220, e202006049 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Todkar, K. et al. Selective packaging of mitochondrial proteins into extracellular vesicles prevents the release of mitochondrial DAMPs. Nat. Commun. 12, 1971 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Cadete, V. J. et al. Formation of mitochondrial-derived vesicles is an active and physiologically relevant mitochondrial quality control process in the cardiac system. J. Physiol. 594, 5343–5362 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Konecna, B. et al. Monocyte exocytosis of mitochondrial danger-associated molecular patterns in sepsis suppresses neutrophil chemotaxis. J. Trauma. Acute Care Surg. 90, 46–53 (2021).

    Article  CAS  PubMed  Google Scholar 

  109. Sansone, P. et al. Packaging and transfer of mitochondrial DNA via exosomes regulate escape from dormancy in hormonal therapy-resistant breast cancer. Proc. Natl Acad. Sci. USA 114, E9066–E9075 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Hur, S. Double-stranded RNA sensors and modulators in innate immunity. Annu. Rev. Immunol. 37, 349–375 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Dhir, A. et al. Mitochondrial double-stranded RNA triggers antiviral signalling in humans. Nature 560, 238–242 (2018). This study shows that mtRNA can function as a DAMP and initiate MDA5-dependent inflammatory responses in eukaryotic cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Seth, R. B., Sun, L., Ea, C. K. & Chen, Z. J. Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-kappaB and IRF 3. Cell 122, 669–682 (2005).

    Article  CAS  PubMed  Google Scholar 

  113. Coomans de Brachène, A. et al. Endogenous mitochondrial double-stranded RNA is not an activator of the type I interferon response in human pancreatic beta cells. Auto. Immun. Highlights 12, 6 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  114. Li, S. et al. The mitochondrial protein ERAL1 suppresses RNA virus infection by facilitating RIG-I-like receptor signaling. Cell Rep. 34, 108631 (2021).

    Article  CAS  PubMed  Google Scholar 

  115. Vanpouille-Box, C., Demaria, S., Formenti, S. C. & Galluzzi, L. Cytosolic DNA sensing in organismal tumor control. Cancer Cell 34, 361–378 (2018).

    Article  CAS  PubMed  Google Scholar 

  116. Franchi, L. et al. Cytosolic double-stranded RNA activates the NLRP3 inflammasome via MAVS-induced membrane permeabilization and K+ efflux. J. Immunol. 193, 4214–4222 (2014).

    Article  CAS  PubMed  Google Scholar 

  117. Galluzzi, L. et al. Essential versus accessory aspects of cell death: recommendations of the NCCD 2015. Cell. Death Differ. 22, 58–73 (2015).

    Article  CAS  PubMed  Google Scholar 

  118. McArthur, K. & Kile, B. T. Apoptotic caspases: multiple or mistaken identities? Trends Cell Biol. 28, 475–493 (2018).

    Article  CAS  PubMed  Google Scholar 

  119. Gyrd-Hansen, M. & Meier, P. IAPs: from caspase inhibitors to modulators of NF-kappaB, inflammation and cancer. Nat. Rev. Cancer 10, 561–574 (2010).

    Article  CAS  PubMed  Google Scholar 

  120. Vince, J. E. et al. IAP antagonists target cIAP1 to induce TNFalpha-dependent apoptosis. Cell 131, 682–693 (2007).

    Article  CAS  PubMed  Google Scholar 

  121. Varfolomeev, E. et al. IAP antagonists induce autoubiquitination of c-IAPs, NF-kappaB activation, and TNFalpha-dependent apoptosis. Cell 131, 669–681 (2007).

    Article  CAS  PubMed  Google Scholar 

  122. Giampazolias, E. et al. Mitochondrial permeabilization engages NF-kappaB-dependent anti-tumour activity under caspase deficiency. Nat. Cell Biol. 19, 1116–1129 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Zhang, J. et al. Ubiquitin ligases cIAP1 and cIAP2 limit cell death to prevent inflammation. Cell Rep. 27, 2679–2689.e2673 (2019).

    Article  CAS  PubMed  Google Scholar 

  124. Lecis, D. et al. Smac mimetics induce inflammation and necrotic tumour cell death by modulating macrophage activity. Cell Death Dis. 4, e920 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Rizk, J. et al. SMAC mimetics promote NIK-dependent inhibition of CD4+ TH17 cell differentiation. Sci. Signal. 12, eaaw3469 (2019).

    Article  PubMed  Google Scholar 

  126. Boada-Romero, E., Martinez, J., Heckmann, B. L. & Green, D. R. The clearance of dead cells by efferocytosis. Nat. Rev. Mol. Cell Biol. 21, 398–414 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Leslie, D. S. et al. Serum lipids regulate dendritic cell CD1 expression and function. Immunology 125, 289–301 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Dieudé, M. et al. Cardiolipin binds to CD1d and stimulates CD1d-restricted γδ T cells in the normal murine repertoire. J. Immunol. 186, 4771–4781 (2011).

    Article  PubMed  Google Scholar 

  129. Gouveia, A., Bajwa, E. & Klegeris, A. Extracellular cytochrome c as an intercellular signaling molecule regulating microglial functions. Biochim. Biophys. Acta Gen. Subj. 1861, 2274–2281 (2017).

    Article  CAS  PubMed  Google Scholar 

  130. Pullerits, R., Bokarewa, M., Jonsson, I. M., Verdrengh, M. & Tarkowski, A. Extracellular cytochrome c, a mitochondrial apoptosis-related protein, induces arthritis. Rheumatology 44, 32–39 (2005).

    Article  CAS  PubMed  Google Scholar 

  131. Kepp, O. et al. ATP and cancer immunosurveillance. EMBO J. 40, e108130 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Bolivar, B. E. et al. Noncanonical roles of caspase-4 and caspase-5 in heme-driven IL-1beta release and cell death. J. Immunol. 206, 1878–1889 (2021).

    Article  CAS  PubMed  Google Scholar 

  133. Wang, Y. et al. Autophagy-dependent ATP release from dying cells via lysosomal exocytosis. Autophagy 9, 1624–1625 (2013).

    Article  CAS  PubMed  Google Scholar 

  134. Ma, Y. et al. Anticancer chemotherapy-induced intratumoral recruitment and differentiation of antigen-presenting cells. Immunity 38, 729–741 (2013).

    Article  CAS  PubMed  Google Scholar 

  135. Lin, S. et al. Heme activates TLR4-mediated inflammatory injury via MyD88/TRIF signaling pathway in intracerebral hemorrhage. J. Neuroinflamm. 9, 46 (2012).

    Article  CAS  Google Scholar 

  136. May, O. et al. The receptor for advanced glycation end products is a sensor for cell-free heme. FEBS J. 288, 3448–3464 (2021).

    Article  CAS  PubMed  Google Scholar 

  137. Belcher, J. D. et al. Heme triggers TLR4 signaling leading to endothelial cell activation and vaso-occlusion in murine sickle cell disease. Blood 123, 377–390 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Han, C. et al. Tumor cells suppress radiation-induced immunity by hijacking caspase 9 signaling. Nat. Immunol. 21, 546–554 (2020).

    Article  CAS  PubMed  Google Scholar 

  139. Rodriguez-Ruiz, M. E. et al. Apoptotic caspases inhibit abscopal responses to radiation and identify a new prognostic biomarker for breast cancer patients. Oncoimmunology 8, e1655964 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  140. Ning, X. et al. Apoptotic caspases suppress type I interferon production via the cleavage of cGAS, MAVS, and IRF3. Mol. Cell 74, 19–31.e17 (2019).

    Article  CAS  PubMed  Google Scholar 

  141. Segawa, K. et al. Caspase-mediated cleavage of phospholipid flippase for apoptotic phosphatidylserine exposure. Science 344, 1164–1168 (2014).

    Article  CAS  PubMed  Google Scholar 

  142. Fadok, V. A. et al. Exposure of phosphatidylserine on the surface of apoptotic lymphocytes triggers specific recognition and removal by macrophages. J. Immunol. 148, 2207–2216 (1992).

    Article  CAS  PubMed  Google Scholar 

  143. Buqué, A., Rodriguez-Ruiz, M. E., Fucikova, J. & Galluzzi, L. Apoptotic caspases cut down the immunogenicity of radiation. Oncoimmunology 8, e1655364 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  144. Bernardini, J. P. et al. Parkin inhibits BAK and BAX apoptotic function by distinct mechanisms during mitophagy. EMBO J. 38, e99916 (2019).

    Article  PubMed  Google Scholar 

  145. Lindqvist, L. M. et al. Autophagy induced during apoptosis degrades mitochondria and inhibits type I interferon secretion. Cell Death Differ. 25, 784–796 (2018).

    Article  PubMed  Google Scholar 

  146. Galluzzi, L. et al. Molecular definitions of autophagy and related processes. EMBO J. 36, 1811–1836 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Sliter, D. A. et al. Parkin and PINK1 mitigate STING-induced inflammation. Nature 561, 258–262 (2018). This study shows that PINK1- and PRKN-dependent mitophagy has a major role in restricting STING1 signalling by clearing permeabilized, mtDNA-releasing mitochondria.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Mouton-Liger, F. et al. Parkin deficiency modulates NLRP3 inflammasome activation by attenuating an A20-dependent negative feedback loop. Glia 66, 1736–1751 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  149. Zhang, N. P., Liu, X. J., Xie, L., Shen, X. Z. & Wu, J. Impaired mitophagy triggers NLRP3 inflammasome activation during the progression from nonalcoholic fatty liver to nonalcoholic steatohepatitis. Lab. Invest. 99, 749–763 (2019).

    Article  CAS  PubMed  Google Scholar 

  150. Shi, C. S. et al. Activation of autophagy by inflammatory signals limits IL-1β production by targeting ubiquitinated inflammasomes for destruction. Nat. Immunol. 13, 255–263 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Richter, B. et al. Phosphorylation of OPTN by TBK1 enhances its binding to Ub chains and promotes selective autophagy of damaged mitochondria. Proc. Natl Acad. Sci. USA 113, 4039–4044 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Di Rita, A. et al. HUWE1 E3 ligase promotes PINK1/PARKIN-independent mitophagy by regulating AMBRA1 activation via IKKα. Nat. Commun. 9, 3755 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Michaud, M. et al. Autophagy-dependent anticancer immune responses induced by chemotherapeutic agents in mice. Science 334, 1573–1577 (2011).

    Article  CAS  PubMed  Google Scholar 

  155. Wang, Y. et al. Inflammasome activation triggers caspase-1-mediated cleavage of cGAS to regulate responses to DNA virus infection. Immunity 46, 393–404 (2017).

    Article  CAS  PubMed  Google Scholar 

  156. Corrales, L. et al. Antagonism of the STING pathway via activation of the AIM2 inflammasome by intracellular DNA. J. Immunol. 196, 3191–3198 (2016).

    Article  CAS  PubMed  Google Scholar 

  157. Melki, I. et al. Platelets release mitochondrial antigens in systemic lupus erythematosus. Sci. Transl. Med. 13, eaav5928 (2021).

    Article  CAS  PubMed  Google Scholar 

  158. Caielli, S. et al. Oxidized mitochondrial nucleoids released by neutrophils drive type I interferon production in human lupus. J. Exp. Med. 213, 697–713 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Caielli, S. et al. Erythroid mitochondrial retention triggers myeloid-dependent type I interferon in human SLE. Cell 184, 4464–4479.e4419 (2021). This is an elegant demonstration of the links between defective mitophagy in erythroid precursors and the formation of mitochondria-containing erythrocytes that drive pathogenic type I interferon responses in SLE.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Lood, C. et al. Neutrophil extracellular traps enriched in oxidized mitochondrial DNA are interferogenic and contribute to lupus-like disease. Nat. Med. 22, 146–153 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Cadwell, K. et al. A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells. Nature 456, 259–263 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Adolph, T. E. et al. Paneth cells as a site of origin for intestinal inflammation. Nature 503, 272–276 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Khaloian, S. et al. Mitochondrial impairment drives intestinal stem cell transition into dysfunctional Paneth cells predicting Crohn’s disease recurrence. Gut 69, 1939–1951 (2020).

    Article  CAS  PubMed  Google Scholar 

  164. Jackson, D. N. et al. Mitochondrial dysfunction during loss of prohibitin 1 triggers Paneth cell defects and ileitis. Gut 69, 1928–1938 (2020).

    Article  CAS  PubMed  Google Scholar 

  165. Benmerzoug, S. et al. STING-dependent sensing of self-DNA drives silica-induced lung inflammation. Nat. Commun. 9, 5226 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Wiegman, C. H. et al. Oxidative stress-induced mitochondrial dysfunction drives inflammation and airway smooth muscle remodeling in patients with chronic obstructive pulmonary disease. J. Allergy Clin. Immunol. 136, 769–780 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Giordano, L. et al. Extracellular release of mitochondrial DNA: triggered by cigarette smoke and detected in COPD. Cells 11, 369 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Maekawa, H. et al. Mitochondrial damage causes inflammation via cGAS-STING signaling in acute kidney injury. Cell Rep. 29, 1261–1273.e1266 (2019).

    Article  CAS  PubMed  Google Scholar 

  169. Chung, K. W. et al. Mitochondrial damage and activation of the STING pathway lead to renal inflammation and fibrosis. Cell Metab. 30, 784–799.e785 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Chen, K. et al. Optineurin inhibits NLRP3 inflammasome activation by enhancing mitophagy of renal tubular cells in diabetic nephropathy. FASEB J. 33, 4571–4585 (2019).

    Article  CAS  PubMed  Google Scholar 

  171. Tang, C. et al. PINK1-PRKN/PARK2 pathway of mitophagy is activated to protect against renal ischemia-reperfusion injury. Autophagy 14, 880–897 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Kasten, M. et al. Genotype-phenotype relations for the Parkinson’s disease genes Parkin, PINK1, DJ1: MDSGene systematic review. Mov. Disord. 33, 730–741 (2018).

    Article  PubMed  Google Scholar 

  173. Borsche, M. et al. Mitochondrial damage-associated inflammation highlights biomarkers in PRKN/PINK1 parkinsonism. Brain 143, 3041–3051 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  174. Noda, S. et al. Loss of Parkin contributes to mitochondrial turnover and dopaminergic neuronal loss in aged mice. Neurobiol. Dis. 136, 104717 (2020).

    Article  CAS  PubMed  Google Scholar 

  175. Wilkins, H. M. et al. Mitochondrial lysates induce inflammation and Alzheimer’s disease-relevant changes in microglial and neuronal cells. J. Alzheimers Dis. 45, 305–318 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Fang, E. F. et al. Mitophagy inhibits amyloid-β and tau pathology and reverses cognitive deficits in models of Alzheimer’s disease. Nat. Neurosci. 22, 401–412 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Roca-Agujetas, V. et al. Cholesterol alters mitophagy by impairing optineurin recruitment and lysosomal clearance in Alzheimer’s disease. Mol. Neurodegener. 16, 15 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Bellenguez, C. et al. New insights into the genetic etiology of Alzheimer’s disease and related dementias. Nat. Genet. 54, 412–436 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. King, K. R. et al. IRF3 and type I interferons fuel a fatal response to myocardial infarction. Nat. Med. 23, 1481–1487 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Kwon, W. Y. et al. Circulating mitochondrial N-formyl peptides contribute to secondary nosocomial infection in patients with septic shock. Proc. Natl Acad. Sci. USA 118, e2018538118 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  182. Bai, J. et al. DsbA-L prevents obesity-induced inflammation and insulin resistance by suppressing the mtDNA release-activated cGAS-cGAMP-STING pathway. Proc. Natl Acad. Sci. USA 114, 12196–12201 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Christensen, M. H. et al. HSV-1 ICP27 targets the TBK1-activated STING signalsome to inhibit virus-induced type I IFN expression. EMBO J. 35, 1385–1399 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Saffran, H. A., Pare, J. M., Corcoran, J. A., Weller, S. K. & Smiley, J. R. Herpes simplex virus eliminates host mitochondrial DNA. EMBO Rep. 8, 188–193 (2007).

    Article  CAS  PubMed  Google Scholar 

  185. Chen, H. et al. HBx inhibits DNA sensing signaling pathway via ubiquitination and autophagy of cGAS. Virol. J. 19, 55 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Yum, S., Li, M., Fang, Y. & Chen, Z. J. TBK1 recruitment to STING activates both IRF3 and NF-kappaB that mediate immune defense against tumors and viral infections. Proc. Natl Acad. Sci. USA 118, e2100225118 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Thomsen, M. K. et al. Lack of immunological DNA sensing in hepatocytes facilitates hepatitis B virus infection. Hepatology 64, 746–759 (2016).

    Article  CAS  PubMed  Google Scholar 

  188. Galluzzi, L. et al. Autophagy in malignant transformation and cancer progression. EMBO J. 34, 856–880 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Buque, A. et al. Immunoprophylactic and immunotherapeutic control of hormone receptor-positive breast cancer. Nat. Commun. 11, 3819 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Li, S. et al. SFTSV infection induces BAK/BAX-dependent mitochondrial DNA release to trigger NLRP3 inflammasome activation. Cell Rep. 30, 4370–4385.e4377 (2020).

    Article  CAS  PubMed  Google Scholar 

  191. Costa, T. J. et al. Mitochondrial DNA and TLR9 activation contribute to SARS-CoV-2-induced endothelial cell damage. Vasc. Pharmacol. 142, 106946 (2022).

    Article  CAS  Google Scholar 

  192. Neufeldt, C. J. et al. SARS-CoV-2 infection induces a pro-inflammatory cytokine response through cGAS-STING and NF-κB. Commun. Biol. 5, 45 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Kuo, C. L. et al. Mitochondrial oxidative stress by Lon-PYCR1 maintains an immunosuppressive tumor microenvironment that promotes cancer progression and metastasis. Cancer Lett. 474, 138–150 (2020).

    Article  CAS  PubMed  Google Scholar 

  194. Singel, K. L. et al. Mitochondrial DNA in the tumour microenvironment activates neutrophils and is associated with worse outcomes in patients with advanced epithelial ovarian cancer. Br. J. Cancer 120, 207–217 (2019).

    Article  CAS  PubMed  Google Scholar 

  195. Bao, D. et al. Mitochondrial fission-induced mtDNA stress promotes tumor-associated macrophage infiltration and HCC progression. Oncogene 38, 5007–5020 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Li, C. et al. PINK1 and PARK2 suppress pancreatic tumorigenesis through control of mitochondrial iron-mediated immunometabolism. Dev. Cell 46, 441–455.e448 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  197. Dorflinger, B. et al. Mitochondria supply sub-lethal signals for cytokine secretion and DNA-damage in H. pylori infection. Cell Death Differ. https://doi.org/10.1038/s41418-022-01009-9 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  198. Schmidts, A., Wehrli, M. & Maus, M. V. Toward better understanding and management of CAR-T cell-associated toxicity. Annu. Rev. Med. 72, 365–382 (2021).

    Article  CAS  PubMed  Google Scholar 

  199. Le Naour, J., Zitvogel, L., Galluzzi, L., Vacchelli, E. & Kroemer, G. Trial watch: STING agonists in cancer therapy. Oncoimmunology 9, 1777624 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  200. Glab, J. A., Cao, Z. & Puthalakath, H. Bcl-2 family proteins, beyond the veil. Int. Rev. Cell Mol. Biol. 351, 1–22 (2020).

    Article  CAS  PubMed  Google Scholar 

  201. Mason, K. D. et al. Programmed anuclear cell death delimits platelet life span. Cell 128, 1173–1186 (2007).

    Article  CAS  PubMed  Google Scholar 

  202. Galluzzi, L., Zitvogel, L. & Kroemer, G. Immunological mechanisms underneath the efficacy of cancer therapy. Cancer Immunol. Res. 4, 895–902 (2016).

    Article  CAS  PubMed  Google Scholar 

  203. Lopez, A. et al. Co-targeting of BAX and BCL-XL proteins broadly overcomes resistance to apoptosis in cancer. Nat. Commun. 13, 1199 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Reyna, D. E. et al. Direct activation of BAX by BTSA1 overcomes apoptosis resistance in acute myeloid leukemia. Cancer Cell 32, 490–505.e410 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Spitz, A. Z., Zacharioudakis, E., Reyna, D. E., Garner, T. P. & Gavathiotis, E. Eltrombopag directly inhibits BAX and prevents cell death. Nat. Commun. 12, 1134 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Amgalan, D. et al. A small-molecule allosteric inhibitor of BAX protects against doxorubicin-induced cardiomyopathy. Nat. Cancer 1, 315–328 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. Yamazaki, T. & Galluzzi, L. BAX and BAK dynamics control mitochondrial DNA release during apoptosis. Cell Death Differ. 29, 1296–1298 (2022).

    Article  CAS  PubMed  Google Scholar 

  208. Swanson, S. K. et al. Cyclosporin-mediated inhibition of bovine calcineurin by cyclophilins A and B. Proc. Natl Acad. Sci. USA 89, 3741–3745 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. Galluzzi, L., Bravo-San Pedro, J. M., Levine, B., Green, D. R. & Kroemer, G. Pharmacological modulation of autophagy: therapeutic potential and persisting obstacles. Nat. Rev. Drug Discov. 16, 487–511 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  210. Lekakis, V. & Cholongitas, E. The impact of emricasan on chronic liver diseases: current data. Clin. J. Gastroenterol. 15, 271–285 (2022).

    Article  PubMed  Google Scholar 

  211. Galluzzi, L., Vanpouille-Box, C., Bakhoum, S. F. & Demaria, S. SnapShot: CGAS-STING signaling. Cell 173, 276–276.e271 (2018).

    Article  CAS  PubMed  Google Scholar 

  212. Yatim, N. et al. RIPK1 and NF-κB signaling in dying cells determines cross-priming of CD8+ T cells. Science 350, 328–334 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Bakhoum, S. F. et al. Chromosomal instability drives metastasis through a cytosolic DNA response. Nature 553, 467–472 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Li, H., Zimmerman, S. E. & Weyemi, U. Genomic instability and metabolism in cancer. Int. Rev. Cell Mol. Biol. 364, 241–265 (2021).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

S.M. is supported by the Italian Ministry of Health (GR-2016-02364602), Nanoblend and local funds from Marche Polytechnic University (Ancona, Italy). S.W.G.T. is supported by funding from Cancer Research UK, Prostate Cancer UK, Tenovus Scotland and the Swiss National Science Foundation. The laboratory of L.G. (as a principal investigator unless otherwise indicated) is or has been supported by two Breakthrough Level 2 grants from the US Department of Defense Breast Cancer Research Program (BC180476P1 and BC210945), by a Transformative Breast Cancer Consortium Grant from the US Department of Defense Breast Cancer Research Program (W81XWH2120034; principal investigator Formenti), by a U54 grant from the NCI of the NIH (CA274291; principal investigators Deasy, Formenti and Weichselbaum), by the 2019 Laura Ziskin Prize in Translational Research (ZP-6177; principal investigator Formenti) from Stand Up to Cancer, by a Mantle Cell Lymphoma Research Initiative grant from the Leukaemia and Lymphoma Society (principal investigator Chen-Kiang), by a Rapid Response Grant from the Functional Genomics Initiative (New York, USA), by start-up funds from the Department of Radiation Oncology at Weill Cornell Medicine (New York, USA), by industrial collaborations with Lytix Biopharma (Oslo, Norway) and Promontory (New York, USA), and by donations from Promontory (New York, USA), the Luke Heller TECPR2 Foundation (Boston, USA), Sotio a.s. (Prague, Czech Republic), Lytix Biopharma (Oslo, Norway), Onxeo (Paris, France), Ricerchiamo (Brescia, Italy) and Noxopharm (Chatswood, Australia).

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  1. These authors contributed equally: Saverio Marchi, Emma Guilbaud.

Authors and Affiliations

  1. Department of Clinical and Molecular Sciences, Marche Polytechnic University, Ancona, Italy

    Saverio Marchi

  2. Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA

    Emma Guilbaud, Takahiro Yamazaki & Lorenzo Galluzzi

  3. Cancer Research UK Beatson Institute, Glasgow, UK

    Stephen W. G. Tait

  4. Institute of Cancer Sciences, University of Glasgow, Glasgow, UK

    Stephen W. G. Tait

  5. Sandra and Edward Meyer Cancer Center, New York, NY, USA

    Lorenzo Galluzzi

  6. Caryl and Israel Englander Institute for Precision Medicine, New York, NY, USA

    Lorenzo Galluzzi

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  1. Saverio Marchi
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  3. Stephen W. G. Tait
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  4. Takahiro Yamazaki
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Contributions

T.Y. and L.G. conceived the idea for the Review. S.M. and E.G. prepared the first version of the manuscript, with constructive input from S.W.G.T. and under the supervision of T.Y. and L.G. E.G. prepared display items under the supervision of T.Y. and L.G. All authors approved the final version of the manuscript.

Corresponding authors

Correspondence to Takahiro Yamazaki or Lorenzo Galluzzi.

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Competing interests

L.G. has held research contracts with Lytix Biopharma and Promontory, has received consulting/advisory honoraria from Boehringer Ingelheim, AstraZeneca, OmniSEQ, Onxeo, The Longevity Labs, Inzen, Sotio, Promontory, Noxopharm, EduCom and the Luke Heller TECPR2 Foundation, and holds Promontory stock options. All other authors declare no conflicts of interest.

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Glossary

Cancer immunosurveillance

A process through which the immune system recognizes and eliminates the majority of newly formed cancer cell precursors, hence suppressing oncogenesis.

Type II cells

Mammalian cells that (in contrast to type I cells) require mitochondrial outer membrane permeabilization to enable death receptors to induce full activation of executioner caspases during apoptosis.

Regulated cell death

(RCD). A type of cell death that depends on a genetically encoded machinery and hence can be modulated by pharmacological or genetic interventions.

Mitochondrial outer membrane permeabilization

(MOMP). A key event in apoptotic cell death, culminating in the release of mitochondrial components into the cytosol and activation of proapoptotic caspases.

Autophagy

An evolutionarily conserved, lysosome-dependent mechanism through which eukaryotic cells clear the cytoplasm of potentially cytotoxic or superfluous material to preserve homeostasis.

Caspase

A member of a family of cysteine-dependent proteases that regulate the timing and immunological effects of various forms of cell death.

Programmed cell death

A variant of regulated cell death that is triggered as a part of physiological programmes (such as embryonic development or preservation of adult tissue homeostasis) and not as a consequence of failing adaptation to stress.

Mitophagy

A type of autophagy response that preferentially degrades permeabilized or otherwise dysfunctional mitochondria.

Mitochondrial permeability transition

(MPT). A regulated process resulting in the abrupt loss of the impermeability of the inner mitochondrial membrane to solutes and water, resulting in osmotic swelling of the mitochondrial matrix and, ultimately, cell death.

Inhibitor of apoptosis protein

(IAP). A member of a protein family that inhibits apoptosis by antagonizing the catalytic activity of caspases and functioning as a ubiquitin ligase to control upstream apoptotic signal transduction.

Ripoptosome

A supramolecular complex containing receptor-interacting serine/threonine kinase 1 (RIPK1) and RIPK3 that promotes cell death coupled to inflammatory responses in various stress conditions (for example, exposure to genotoxins and allergens).

Non-canonical NF-κB signalling

A transcriptional response generally initiated by the NIK-driven activation of NF-κB heterodimers composed of RELB and p52.

Canonical NF-κB signalling

A transcriptional response generally initiated by the TAK1-driven activation of NF-κB heterodimers composed of RELA and p50.

Immunogenic cell death

A variant of regulated cell death that is sufficient, in immunocompetent and syngeneic settings, to elicit an adaptive immune response to dead cell-associated antigens.

BH3 mimetics

Pharmacological agents that mimic the ability of natural BH3-only proteins to directly or indirectly promote mitochondrial outer membrane permeabilization.

Neutrophil extracellular traps

Networks of extracellular fibres enriched in DNA and proteins that are released by neutrophils in response to activating stimuli (such as pathogens).

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Marchi, S., Guilbaud, E., Tait, S.W.G. et al. Mitochondrial control of inflammation. Nat Rev Immunol 23, 159–173 (2023). https://doi.org/10.1038/s41577-022-00760-x

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