Mitochondrial DNA Release in Innate Immune Signaling

Abstract

According to the endosymbiotic theory, most of the DNA of the original bacterial endosymbiont has been lost or transferred to the nucleus, leaving a much smaller (∼16 kb in mammals), circular molecule that is the present-day mitochondrial DNA (mtDNA). The ability of mtDNA to escape mitochondria and integrate into the nuclear genome was discovered in budding yeast, along with genes that regulate this process. Mitochondria have emerged as key regulators of innate immunity, and it is now recognized that mtDNA released into the cytoplasm, outside of the cell, or into circulation activates multiple innate immune signaling pathways. Here, we first review the mechanisms through which mtDNA is released into the cytoplasm, including several inducible mitochondrial pores and defective mitophagy or autophagy. Next, we cover how the different forms of released mtDNA activate specific innate immune nucleic acid sensors and inflammasomes. Finally, we discuss how intracellular and extracellular mtDNA release, including circulating cell-free mtDNA that promotes systemic inflammation, are implicated in human diseases, bacterial and viral infections, senescence and aging.

References 232

1. 1.

   Thorsness PE, Fox TD. 1990. Escape of DNA from mitochondria to the nucleus in Saccharomyces cerevisiae. Nature 346:376–79

   Not in our library10.1038/346376a0

2. 2.

   Thorsness PE, Fox TD. 1993. Nuclear mutations in Saccharomyces cerevisiae that affect the escape of DNA from mitochondria to the nucleus. Genetics 134:21–28

   Not in our library10.1093/genetics/134.1.21

3. 3.
   Cellular pyrimidine imbalance triggers mitochondrial DNA–dependent innate immunity · 2021

   No notice
4. 4.
   ER-lysosome lipid transfer protein VPS13C/PARK23 prevents aberrant mtDNA-dependent STING signaling · 2022

   No notice
5. 5.

   Sliter DA, Martinez J, Hao L, Chen X, Sun N, 2018. Parkin and PINK1 mitigate STING-induced inflammation. Nature 561:258–62

   Not in our library10.1038/s41586-018-0448-9

6. 6.

   Matsui H, Ito J, Matsui N, Uechi T, Onodera O, Kakita A. 2021. Cytosolic dsDNA of mitochondrial origin induces cytotoxicity and neurodegeneration in cellular and zebrafish models of Parkinson’s disease. Nat. Commun. 12:3101

   Not in our library10.1038/s41467-021-23452-x

7. 7.
   LRRK2 maintains mitochondrial homeostasis and regulates innate immune responses to Mycobacterium tuberculosis · 2020

   No notice
8. 8.

   West AP, Shadel GS. 2017. Mitochondrial DNA in innate immune responses and inflammatory pathology. Nat. Rev. Immunol. 17:363–75

   Not in our library10.1038/nri.2017.21

9. 9.

   Shadel GS, Clayton DA. 1997. Mitochondrial DNA maintenance in vertebrates. Annu. Rev. Biochem. 66:409–35

   Not in our library10.1146/annurev.biochem.66.1.409

10. 10.

    Falkenberg M, Gustafsson CM. 2020. Mammalian mitochondrial DNA replication and mechanisms of deletion formation. Crit. Rev. Biochem. Mol. Biol. 55:509–24

    Not in our library10.1080/10409238.2020.1818684

11. 11.

    Garrido N, Griparic L, Jokitalo E, Wartiovaara J, van der Bliek AM, Spelbrink JN. 2003. Composition and dynamics of human mitochondrial nucleoids. Mol. Biol. Cell 14:1583–96

    Not in our library10.1091/mbc.e02-07-0399

12. 12.

    Kukat C, Wurm CA, Spåhr H, Falkenberg M, Larsson N-G, Jakobs S. 2011. Super-resolution microscopy reveals that mammalian mitochondrial nucleoids have a uniform size and frequently contain a single copy of mtDNA. PNAS 108:13534–39

    Not in our library10.1073/pnas.1109263108

13. 13.

    Kukat C, Davies KM, Wurm CA, Spåhr H, Bonekamp NA, 2015. Cross-strand binding of TFAM to a single mtDNA molecule forms the mitochondrial nucleoid. PNAS 112:11288–93

    Not in our library10.1073/pnas.1512131112

14. 14.

    Ngo HB, Lovely GA, Phillips R, Chan DC. 2014. Distinct structural features of TFAM drive mitochondrial DNA packaging versus transcriptional activation. Nat. Commun. 5:3077

    Not in our library10.1038/ncomms4077

15. 15.

    Kazak L, Reyes A, Holt IJ. 2012. Minimizing the damage: Repair pathways keep mitochondrial DNA intact. Nat. Rev. Mol. Cell Biol. 13:659–71

    Not in our library10.1038/nrm3439

16. 16.

    Bonawitz ND, Clayton DA, Shadel GS. 2006. Initiation and beyond: multiple functions of the human mitochondrial transcription machinery. Mol. Cell 24:813–25

    Not in our library10.1016/j.molcel.2006.11.024

17. 17.

    Tan BG, Mutti CD, Shi Y, Xie X, Zhu X, 2022. The human mitochondrial genome contains a second light strand promoter. Mol. Cell 82:3646–60.e9

    Not in our library10.1016/j.molcel.2022.08.011

18. 18.

    Nicholls TJ, Gustafsson CM. 2018. Separating and segregating the human mitochondrial genome. Trends Biochem. Sci. 43:869–81

    Not in our library10.1016/j.tibs.2018.08.007

19. 19.

    Nicholls TJ, Nadalutti CA, Motori E, Sommerville EW, Gorman GS, 2018. Topoisomerase 3α is required for decatenation and segregation of human mtDNA. Mol. Cell 69:9–23.e6

    Not in our library10.1016/j.molcel.2017.11.033

20. 20.

    Wu Z, Sainz AG, Shadel GS. 2021. Mitochondrial DNA: cellular genotoxic stress sentinel. Trends Biochem. Sci. 46:812–21

    Not in our library10.1016/j.tibs.2021.05.004

21. 21.

    Bruni F, Lightowlers RN, Chrzanowska-Lightowlers ZM. 2017. Human mitochondrial nucleases. FEBS J. 284:1767–77

    Not in our library10.1111/febs.13981

22. 22.

    Dhir A, Dhir S, Borowski LS, Jimenez L, Teitell M, 2018. Mitochondrial double-stranded RNA triggers antiviral signalling in humans. Nature 560:238–42

    Not in our library10.1038/s41586-018-0363-0

23. 23.

    Tigano M, Vargas DC, Tremblay-Belzile S, Fu Y, Sfeir A. 2021. Nuclear sensing of breaks in mitochondrial DNA enhances immune surveillance. Nature 591:477–81

    Not in our library10.1038/s41586-021-03269-w

24. 24.

    McArthur K, Whitehead LW, Heddleston JM, Li L, Padman BS, 2018. BAK/BAX macropores facilitate mitochondrial herniation and mtDNA efflux during apoptosis. Science 359:eaao6047

    Not in our library10.1126/science.aao6047

25. 25.
    Mitochondrial inner membrane permeabilisation enables mtDNA release during apoptosis · 2018

    No notice
26. 26.

    Chen L, Dong J, Liao S, Wang S, Wu Z, 2022. Loss of Sam50 in hepatocytes induces cardiolipin-dependent mitochondrial membrane remodeling to trigger mtDNA release and liver injury. Hepatology 76(5):1389–408

    Not in our library10.1002/hep.32471

27. 27.

    Maekawa H, Inoue T, Ouchi H, Jao T-M, Inoue R, 2019. Mitochondrial damage causes inflammation via cGAS-STING signaling in acute kidney injury. Cell Rep. 29:1261–73.e6

    Not in our library10.1016/j.celrep.2019.09.050

28. 28.

    Zhang Y-F, Zhou L, Mao H-Q, Yang F-H, Chen Z, Zhang L. 2021. Mitochondrial DNA leakage exacerbates odontoblast inflammation through gasdermin D-mediated pyroptosis. Cell Death Discov. 7:381

    Not in our library10.1038/s41420-021-00770-z

29. 29.
    Perfluoroalkyl substance pollutants activate the innate immune system through the AIM2 inflammasome · 2021

    Corrected
30. 30.
    The interplay between BAX and BAK tunes apoptotic pore growth to control mitochondrial-DNA-mediated inflammation · 2022

    No notice
31. 31.

    Kim J, Gupta R, Blanco LP, Yang S, Shteinfer-Kuzmine A, 2019. VDAC oligomers form mitochondrial pores to release mtDNA fragments and promote lupus-like disease. Science 366:1531–36

    Not in our library10.1126/science.aav4011

32. 32.

    García N, Chávez E. 2007. Mitochondrial DNA fragments released through the permeability transition pore correspond to specific gene size. Life Sci. 81:1160–66

    Not in our library10.1016/j.lfs.2007.08.019

33. 33.

    Collins LV, Hajizadeh S, Holme E, Jonsson I-M, Tarkowski A. 2004. Endogenously oxidized mitochondrial DNA induces in vivo and in vitro inflammatory responses. J. Leukocyte Biol. 75:995–1000

    Not in our library10.1189/jlb.0703328

34. 34.

    Xian H, Watari K, Sanchez-Lopez E, Offenberger J, Onyuru J, 2022. Oxidized DNA fragments exit mitochondria via mPTP- and VDAC-dependent channels to activate NLRP3 inflammasome and interferon signaling. Immunity 55(8):1370–85.e8

    Not in our library10.1016/j.immuni.2022.06.007

35. 35.

    He W-R, Cao L-B, Yang Y-L, Hua D, Hu M-M, Shu H-B. 2021. VRK2 is involved in the innate antiviral response by promoting mitostress-induced mtDNA release. Cell. Mol. Immunol. 18:1186–96

    Not in our library10.1038/s41423-021-00673-0

36. 36.

    Luzwick JW, Dombi E, Boisvert RA, Roy S, Park S, 2021. MRE11-dependent instability in mitochondrial DNA fork protection activates a cGAS immune signaling pathway. Sci. Adv. 7:eabf9441

    Not in our library10.1126/sciadv.abf9441

37. 37.

    Magnani L, Colantuoni M, Mortellaro A. 2022. Gasdermins: new therapeutic targets in host defense, inflammatory diseases, and cancer. Front. Immunol. 13:898298

    Not in our library10.3389/fimmu.2022.898298

38. 38.

    Huang LS, Hong Z, Wu W, Xiong S, Zhong M, 2020. mtDNA activates cGAS signaling and suppresses the YAP-mediated endothelial cell proliferation program to promote inflammatory injury. Immunity 52:475–86.e5

    Not in our library10.1016/j.immuni.2020.02.002

39. 39.

    Torre-Minguela C, Gómez AI, Couillin I, Pelegrín P. 2021. Gasdermins mediate cellular release of mitochondrial DNA during pyroptosis and apoptosis. FASEB J. 35(8):e21757

    Not in our library10.1096/fj.202100085r

40. 40.

    Rodríguez-Nuevo A, Díaz-Ramos A, Noguera E, Díaz-Sáez F, Duran X, 2018. Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency. EMBO J. 37:e96553

    Not in our library10.15252/embj.201796553

Cited by papers we hold 2

• Updated insights into the molecular networks for NLRP3 inflammasome activation · 2025
  No notice
• Mitochondrial DNA-triggered innate immune response: mechanisms and diseases · 2023
  No notice

Reads

A person counts once a day per paper. We keep no cookie and no address: a reader is a hash that changes every day. Any month under five reads shows no number.