Abstract
Besides their role in cell metabolism, mitochondria display many other functions. Mitochondrial DNA (mtDNA), the own genome of the organelle, plays an important role in modulating the inflammatory immune response. When released from the mitochondrion to the cytosol, mtDNA is recognized by cGAS, a cGAMP which activates a pathway leading to enhanced expression of type I interferons, and by NLRP3 inflammasome, which promotes the activation of pro-inflammatory cytokines Interleukin-1beta and Interleukin-18. Furthermore, mtDNA can be bound by Toll-like receptor 9 in the endosome and activate a pathway that ultimately leads to the expression of pro-inflammatory cytokines. mtDNA is released in the extracellular space in different forms (free DNA, protein-bound DNA fragments) either as free circulating molecules or encapsulated in extracellular vesicles. In this review, we discussed the latest findings concerning the molecular mechanisms that regulate the release of mtDNA from mitochondria, and the mechanisms that connect mtDNA misplacement to the activation of inflammation in different pathophysiological conditions.
Highlights
It is organized in nucleoprotein structures, named nucleoids, whose packaging is maintained by the mitochondrial transcription factor A (TFAM). Mitochondrial DNA (mtDNA) and other mitochondrial components have been described as damage-associated molecular patterns (DAMPs), to exogenous microbial products known as pathogen-associated molecule patterns (PAMPs) [13,16,17]
The results showed a mitochondrial retention by circulating sickle cell disease (SCD) red blood cells, the authors suggested that this could be the source of the elevated levels of cf-mtDNA
The intense research in this field in the last 10 years has revealed that multiple mechanisms to sense mtDNA exist, and that they evolved to detect mtDNA from different sources—extracellular and intracellular—and in different forms, such as cf-mtDNA, as protein-bound DNA, or as part of whole mitochondria
Summary
Mitochondria are traditionally defined as the “powerhouse of the cell”, as their primary role is to produce ATP that fuel cell functions by means of oxidative phosphorylation (OXPHOS). This definition is extremely limitative, as it does not include the plethora of metabolic and non-metabolic functions played by mitochondria within the cell. It has been demonstrated that mitochondria do play a direct role in the activation of the immune response, as different mitochondrial products, when released from the organelle, can directly trigger an innate immune response [3]. We critically discuss the most recent observations that link mtDNA with innate immunity, paying particular attention to the molecular mechanisms that link release of mtDNA in the bloodstream, mtDNA binding, and activation of the immune response
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