Release of the mitochondrial endosymbiont helps explain sterile inflammation

A recent article by Iyer et al. (1) raises several interesting questions concerning the nature of inflammation in a sterile setting, as initiated by damage-associated molecular patterns (DAMPs) derived from necrotic cells. Most notably, their data concerning the stimulatory capacity of fractionated cellular constituents clearly demonstrates that isolated mitochondria from different cell types can contribute to the innate inflammatory response through activation of an Nlrp3 inflammasome. This contribution is in contrast with cytosolic, plasma membrane, and nuclear fractions, which, when tested, exhibited no such stimulatory capacity. In this regard it is tempting to refer to the endosymbiont hypothesis which highlights the similarities between mitochondria and certain strains of bacteria in support of the notion that eukaryotic cellular organelles were derived evolutionarily through the fusion of separate species. Similar to prokaryotes, mitochondria have a double-membrane structure and their own genome with the ability to replicate independent of the nucleus. The most recent genetic analysis favors the view that mitochondria are likely to have derived from an α-Protobacteria (2). Although it is difficult to speculate about which innate immune pathways may have recognized the ancient α-Protobacteria that first became an endosymbiont in an amitochondrial cell, current species such as Rickettsia can trigger a potent inflammatory response (3).

The ability of bacterially derived molecular patterns to promote innate immune responses through both Toll-like receptor and inflammasome-mediated signaling pathways has been characterized extensively. More elusive, and somewhat controversial, has been the effort to identify endogenously derived molecular patterns which promote so-called “sterile inflammation,” presumably through similar mechanisms. The identification of mitochondria as a source of DAMP-mediated immune stimulation raises the possibility of an evolutionarily conserved mechanistic link between pathogenic bacteria and the original endosymbionts. Notwithstanding the authors’ demonstration that ATP produced by live respiring mitochondria contributes at least in part toward this response, it would be interesting to subject the organelle to further fractionation in an effort to identify other specific molecular patterns that may activate the innate immune system. Indeed, it has been reported that mitochondrial DNA contains unmethylated CpG motifs that exhibit an immune stimulatory capacity similar to that of its bacterial counterpart (4), and the necrotic release of mitochondrial proteins can also activate innate immune cells (5). Such observations further raise the possibility that, in certain settings, endogenous DAMPs that drive sterile inflammation may be more closely related to pathogen-derived molecular patterns than previously recognized.