Mitochondria are unique mammalian organelles known as the energy factories of the cell and believed to have evolved from aerobic bacteria. They are important for cellular metabolism and apoptosis. Growing evidence suggests that they also play a central role in innate immunity and may contribute to inflammatory diseases. Following infection and stress, damaged mitochondria release their constituents, including mitochondrial DNA (mtDNA), which acts as a potent danger-associated molecular pattern (DAMP). It induces inflammatory responses mediated by various pattern recognition receptors (PRRs). The major PRRs involved in mtDNA recognition are Toll-like receptor 9 (TLR9), Nod-like receptor family, pyrin domain containing 3 (NLRP3) and cyclic GMP-AMP (cGAMP) synthase (cGAS).
Mitochondrial DNA resembles bacterial DNA, as it contains unmethylated CpG dinucleotide repeats, which are recognized by the endosomal receptor TLR9. Several studies have demonstrated that mtDNA released in the circulation after injury directly activates TLR9, causing the activation of NF-кB and the production of pro-inflammatory cytokines such as TNF-α and IL-61-3. Blockade of TLR9, either by using TLR9 inhibitory ODNs1, 2 or by deleting the Tlr9 gene4, has been shown to attenuate the inflammatory response, thus confirming the involvement of TLR9 in the recognition of mtDNA.
Another inflammatory pathway activated by mtDNA is the one triggered by formation of the NLRP3 inflammasome that results in caspase-1-dependent secretion of the inflammatory cytokines IL-1β and IL-18. Recent data suggest that mtDNA released in the cytosol induces the activation of the NLRP3 inflammasome. Depletion of mtDNA resulted in the inhibition of IL-1β and IL-18 secretion in cells stimulated with inflammasome inducers5. Furthermore, oxidized mtDNA was found to directly bind and activate NLRP36.
Mitochondrial DNA is also inflammatory by engaging the cGAS-STING pathway to initiate the production of type I interferons (IFNs). Recently, mtDNA released in the cytosol of cells undergoing apoptosis was shown to activate cGAS to recruit stimulator of interferon genes (STING) through the second messenger cGAMP7,8. STING induces type I IFN transcription via the TBK1–IRF3 signaling axis. This pathway was also recently found to be activated in response to mtDNA stress induced by herpesvirus infection9.
The inflammatory response triggered by mtDNA is closely linked to autophagy. Autophagy is a potent adaptive mechanism that protects cells from stress-induced injury by removing unwanted cytosolic contents (e.g. DNA, proteins, mitochondria and intracellular pathogens) through their sequestration in a double-membraned vacuole, the autophagosome, and their subsequent degradation following fusion with lysosomes. In addition, autophagy can limit excessive inflammatory response by modulating the activity of key immune mediators, such as NF‑кB10 and STING11. In pathological conditions such as microbial infection or major trauma, dysfunctional mitochondria and damaged mtDNA accumulate in the cytosol to a level exceeding the degradative capacity of autophagy, thus resulting in the loss of its negative regulatory function. This results in increased inflammatory responses, often accompanied by chronic inflammation, due to aberrant regulation of TLR92,12, NLRP35,10 and/or cGAS-STING signaling13. Further studies are required to better understand the role of mtDNA in mitochondria-related diseases, including infectious and autoimmune diseases as well as cancer.
References:
1. Zhang Q. et al., 2010. Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature. 464(7285):104-7.
2. Oka T. et al., 2012. Mitochondrial DNA that escapes from autophagy causes inflammation and heart failure. Nature. 485(7397):251-5.
3. Garcia-Martinez I. et al., 2016. Hepatocyte mitochondrial DNA drives nonalcoholic steatohepatitis by activation of TLR9. J Clin Invest. 126(3):859-64.
4. Wei X. et al., 2015. Cationic nanocarriers induce cell necrosis through impairment of Na(+)/K(+)-ATPase and cause subsequent inflammatory response. Cell Res. 25(2):237-53.
5. Nakahira K. et al., 2011. Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat Immunol. 12(3):222-30.
6. Shimada K. et al., 2012. Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis. Immunity. 36(3):401-14.
7. White MJ. et al., 2014. Apoptotic caspases suppress mtDNA-induced STING-mediated type I IFN production. Cell. 159(7):1549-62.
8. Rongvaux A. et al., 2014. Apoptotic caspases prevent the induction of type I interferons by mitochondrial DNA. Cell. 159(7):1563-77.
9. West AP. et al., 2015. Mitochondrial DNA stress primes the antiviral innate immune response. Nature. 520(7548):553-7.
10. Zhong Z. et al., 2016. NF-κB Restricts Inflammasome Activation via Elimination of Damaged Mitochondria. Cell. 164(5):896-910.
11. Saitoh T. et al., 2009. Atg9a controls dsDNA-driven dynamic translocation of STING and the innate immune response. PNAS;106(49):20842-6.
12. De Leo MG. et al, 2016. Autophagosome-lysosome fusion triggers a lysosomal response mediated by TLR9 and controlled by OCRL. Nat Cell Biol. 18(8):839-50.
13. Lan YY. et al, 2014. Dnase2a deficiency uncovers lysosomal clearance of damaged nuclear DNA via autophagy. Cell Rep. 9(1):180-92.
