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Review
. 2020 May 28;16(5):e1008470.
doi: 10.1371/journal.ppat.1008470. eCollection 2020 May.

Mitochondrial reactive oxygen species as major effectors of antimicrobial immunity

Elena Shekhova  1
Affiliations
Review

Mitochondrial reactive oxygen species as major effectors of antimicrobial immunity

Elena Shekhova. PLoS Pathog. .
No abstract available

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Conflict of interest statement

The author has declared that no competing interests exist.

Figures

Fig 1
Fig 1. ROS contribute to the direct killing of microbes and regulate the production of proinflammatory cytokines.
(A) TLR signaling increases the production of antibacterial mitoROS. MitoROS can reach the pathogen-containing phagosome because of the close proximity of mitochondria and phagosome. Juxtaposition of mitochondria and phagosome is regulated by the kinases Mst1 and Mst2, which act by activating small GTPase Rac. The activated Rac is required for translocation of the TLR signaling component TRAF6 to mitochondria [10]. Here, TRAF6 reacts with mitochondrial ECSIT, which is responsible for an assembly of the ETC complex I. The engagement of TRAF6 with mitochondrial ECSIT promotes the ubiquitination of the latter, which consequently augments mitoROS formation through disassembly of complex I of the ETC [11]. MitoROS can also reach phagosome through mitochondria-derived vesicles containing Sod [12]. TLRs activate ERE1α in the ER of infected phagocytes. Activated ERE1α promotes the formation of mitochondrial vesicles, which become accumulated inside the phagosome. These vesicles contain superoxide dismutase and thus contribute to mitoROS accumulation in the pathogen-containing phagosome [12]. (B) TLR signaling promotes inflammation through mitoROS. TLR signaling elevates generation of cytosolic ROS through the activity of NOX. Cytosolic ROS cause oxidation and a subsequent activation of redox-sensitive Src-type tyrosine kinase Fgr [13]. The activated Fgr increases the activity of mitochondrial complex II, which is required for the increase in mitoROS production via reverse electron transport in the ETC. MitoROS, in turn, may increase levels of proinflammatory cytokine IL1β, probably via inflammasome activation [8]. Independently of the activities of NOX, mitoROS can induce inflammation in response to invading pathogens. TLR signaling through TRAF6 can induce mitoROS generation in response to infection. Increased mitoROS levels induce oxidative modifications, in particular, intramolecular disulfide bonds, in NEMO. This redox modification of NEMO is required for binding and activating the IKK complex and leads to the activation of ERK1 and ERK2 and NF-κB pathways to increase the synthesis of proinflammatory cytokines IL1β, TNFα, and IL6 [18]. ECSIT, evolutionarily conserved signaling intermediate in Toll pathways; ERE1α, inositol-requiring enzyme 1α; ERK1/2, extracellular signal-regulated protein kinase 1/2; ETC, electron transport chain; Fgr, Gardner-Rasheed feline sarcoma viral (v-fgr) oncogene homolog; IKK, inhibitor of nuclear factor-κB (IκB) kinase; IL, interleukin; mitoROS, mitochondrial ROS; MST1/2, mammalian sterile 20-like kinases; NEMO, NF-κB essential modulator; NOX, NADPH oxidase; Rac, small guanosine triphosphate-binding protein; ROS, reactive oxygen species; Sod, superoxide dismutase; Src, proto-oncogene tyrosine-protein kinase; TLR, Toll-like receptor; TNFα, tumor necrosis factor α; TRAF6, tumor necrosis factor receptor-associated factor 6.
See this image and copyright information in PMC

References

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