The source of cell-free mitochondrial DNA in trauma and potential therapeutic strategies

Mitochondria play a key role in the pathophysiology of post-injury inflammation. Cell-free mitochondrial DNA (cf-mtDNA) is now understood to catalyse sterile inflammation after trauma. Observations in trauma cohorts have identified high cf-mtDNA in patients with systemic inflammatory response syndrome and multiple organ failure as well as following major surgery. The source of cf-mtDNA can be various cells affected by mechanical and hypoxic injury (passive mechanism) or induced by inflammatory mechanisms (active mechanism). Multiple forms of cf-mtDNA exist; mtDNA fragments, mtDNA in microparticles/vesicles and cell-free mitochondria. Trauma to cells that are rich in mitochondria are believed to release more cf-mtDNA. This review describes the current understanding of the mechanisms of cf-mtDNA release, its systemic effects and the potential therapeutic implications related to its modification. Although current understanding is insufficient to change trauma management, focussed research goals have been identified to pave the way for monitoring and manipulation of cf-mtDNA release and effects in trauma.