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. 2019 May 9;10:1064. doi: 10.3389/fimmu.2019.01064

Figure 1.

Figure 1

An overview of mtDNA fragments life: from their generation to spreading and their role as DAMPs in inflammation. Following cellular stress/injury (1) mitochondria are compromised due to either a direct damage or an increased attempt to cope with metabolic cell demand. Thus, an increased amount of ROS in the three complexes of the respiratory chain, directly affects mtDNA integrity (2). This leads to the accumulation of oxidized mtDNA fragments, which along with ROS, are released in the cytosol as free molecules or engulfed into mitochondrial derived vesicles (MDV). The accumulation of mtDNA within a highly oxidative environment is likely to overcome the attempt of autophagy to digest damaged mitochondria and mtDNA fragments (3). This leads to the spreading of free- or exosomes/MDV engulfed- mtDNA fragments in the extracellular space (4). At the same time, intracellular mtDNA fragments trigger an inflammatory response already within the cytosol. In fact, mtDNA behave as DAMPs to activate TLR9 on the endo-lysosomal membrane (5). This promotes the activation of NFkB and the transcription of pro-inflammatory genes such as interferons (INFs) and pro-interleukines (ILs). Such an effect is magnified by an mtDNA-depended activation of two other components (6, 7), the nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain containing-3 (NLRP3) (inflammasome) and the stimulator of interferon genes (STING) system. In this way, cytokines including IFN3/7 and IL-1β are produced and released extracellularly along with cell-free mtDNA. ccf-mtDNAs are spread into the bloodstream where they add on IL-1β activity to recruit and activate leucocytes while promoting tissue leukocyte infiltration (8a). Within blood leucocytes, ccf-mtDNA behave as DAMPs to promote inflammatory reaction, which favors cytokines release from the blood (9a). Again, ccf-mtDNA are spread within neighboring cells (such as tissue resident macrophages), either via exosome endocytosis or via binding to receptors for advanced glycated end-products (RAGEs) (8b). This is key to activate macrophages and fuel mtDNA-TLR9 dependent inflammation (9b). The result of such a domino-like cascade promoted by ccf-mtDNA is a vicious inflammatory cycle, which fosters tissue and cell injury along with progressive mitochondrial damage (1).