Mitochondria and inflammation.

Endosymbiotic theory of mitochondrial origin contributed to research the role of mitochondria in the immune system activation, inflammation and the pathogenesis of inflammatory diseases. Factors that are referred to as mitochondrial damage-associated molecular patterns (mtDAMPs) are one of a number of DAMPs, which are an endogenous molecules that activates an inflammatory response in case of cell damage or death. Activation of the immune system cells via mtDAMPS is caused by mitochondrial N-formyl peptides, mitochondrial cardiolipnin, ATP, mitochondrial DNA (mtDNA) and reactive oxygen species (mROS). In mitochondrial dysfunction, mtDAMPs release within the cell contributes to the recognition of the cell by pattern recognition receptors (PRRs) of innate immunity. Mitochondria are able to perceive signals of inflammation initiating danger by activating and managing the innate immune system. This review provides the information on the relationship of the immune signaling receptors (Toll-like receptors (TLR); RIG-1-like receptors (RLR); NOD-like receptors (NLR)) with mitochondrial functions and describes the role of mitochondria in the initiation and development of inflammation.

Susceptibility of monocytes to activation correlates with atherogenic mitochondrial DNA mutations.

We have recently evaluated the susceptibility of circulating monocytes to pro- and anti-inflammatory activation comparing samples from healthy individuals and patients with asymptomatic carotid atherosclerosis. Surprisingly, we found a dramatic individual difference in susceptibility to activation between monocytes isolated from the blood of different subjects, regardless of the presence or absence of atherosclerosis. In the present study the monocyte susceptibility to pro-inflammatory activation was evaluated in comparison with mitochondrial DNA mutations that have previously been shown to correlate with the degree of carotid atherosclerosis assessed by intima-media thickness. Among the mutations associated with atherosclerosis were both homoplasmic (absence or presence of the mutation) or heteroplasmic (different proportions of mutant allele). It was found that two homoplasmic mutations, A1811G and G9477A, tended to correlate with the degree of monocyte susceptibility to activation. At the same time, the mutation G9477A inversely correlated with the degree of monocyte activability, that is, the mutation was more prevalent in monocytes with a low degree of activability. We have found that at least three heteroplasmic mutations of mtDNA (G14459A, A1555G, G12315A) earlier known to be associated with human atherosclerosis, also correlate with proinflammatory activation of circulating human monocytes. We suggest that some mutations can cause mitochondrial dysfunction, which in turn may lead to changes of macrophage activities in atherosclerosis.