Elevated levels of plasma mitochondrial DNA DAMPs are linked to clinical outcome in severely injured human subjects

Multiple organ dysfunction syndrome (MODS) is a common and potentially fatal consequence of severe injury. Although mitochondrial and bioenergetic dysfunction have been incriminated in the pathogenesis of MODS for many years,1–6 involvement of mitochondria-derived mediators may be more dynamic than previously appreciated. In this regard, fragments of the mitochondrial genome released into the circulation after injury—termed mtDNA damage-associated molecular patterns (DAMPs)—have been postulated to function as intercellular signals propagating damage from the initial site of injury to distant organs through Toll-like-receptor– mediated activation of inflammatory and resident cells.7,8 The evidence incriminating mtDNA DAMPs in MODS is derived from cell culture studies, isolated perfused organ, and intact animal models and from indirect observations in human subjects.7,9–11 In the latter context, although it is known that mtDNA DAMPs can be mobilized by long bone fracture or reparative operative procedures (eg, femoral reaming), and that isolated mtDNA DAMPs given to intact animals or to immune cells in vitro recapitulate many of the attributes of the systemic inflammatory response syndrome,7 the association between mtDNA DAMPs and human MODS remains largely speculative. Accordingly, to provide evidence linking mtDNA DAMPs to MODS we executed a prospective cohort study to determine the relationships between plasma mtDNA DAMP levels and the occurrence of MODS, SIRS, and mortality in severely injured human patients.