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Review
. 2018 Dec:202:52-68.
doi: 10.1016/j.trsl.2018.07.014. Epub 2018 Aug 7.

Mitochondria in innate immune signaling

Balaji Banoth  1 , Suzanne L Cassel  2
Affiliations
Review

Mitochondria in innate immune signaling

Balaji Banoth et al. Transl Res. 2018 Dec.

Abstract

Mitochondria are functionally versatile organelles. In addition to their conventional role of meeting the cell's energy requirements, mitochondria also actively regulate innate immune responses against infectious and sterile insults. Components of mitochondria, when released or exposed in response to dysfunction or damage, can be directly recognized by receptors of the innate immune system and trigger an immune response. In addition, despite initiation that may be independent from mitochondria, numerous innate immune responses are still subject to mitochondrial regulation as discrete steps of their signaling cascades occur on mitochondria or require mitochondrial components. Finally, mitochondrial metabolites and the metabolic state of the mitochondria within an innate immune cell modulate the precise immune response and shape the direction and character of that cell's response to stimuli. Together, these pathways result in a nuanced and very specific regulation of innate immune responses by mitochondria.

Keywords: ASC, Apoptosis Associated Speck like protein containing CARD; ASK1, apoptosis signal-regulating kinase 1; ATP, adenosine tri-phosphate; CAPS, cryopyrin associated periodic syndromes; CARD, caspase activation and recruitment domain; CL, cardiolipin; CLR, C-type lectin receptor; CREB, cAMP response element binding protein; Cgas, cyclic GMP-AMP synthase; DAMP, damage associated molecular pattern; ESCIT, evolutionarily conserved signaling intermediate in the toll pathway; ETC, electron transport chain; FPR, formyl peptide receptor; HIF, hypoxia-inducible factor; HMGB1, high mobility group box protein 1; IFN, interferon; IL, interleukin; IRF, interferon regulatory factor; JNK, cJUN NH2-terminal kinase; LPS, lipopolysaccharide; LRR, leucine rich repeat; MAPK, mitogen-activated protein kinase; MARCH5, membrane-associated ring finger (C3HC4) 5; MAVS, mitochondrial antiviral signaling; MAVS, mitochondrial antiviral signaling protein; MFN1/2, mitofusin; MOMP, mitochondrial outer membrane permeabilization; MPT, mitochondrial permeability transition; MyD88, myeloid differentiation primary response 88; NADH, nicotinamide adenine dinucleotide; NBD, nucleotide binding domain; NFκB, Nuclear factor κ B; NLR, NOD like receptor; NOD, nucleotide-binding oligomerization domain; NRF2, nuclear factor erythroid 2-related factor 2; PAMP, pathogen associated molecular pattern; PPAR, peroxisome proliferator-accelerated receptor; PRRs, pathogen recognition receptors; RIG-I, retinoic acid inducible gene I; RLR, retinoic acid inducible gene like receptor; ROS, reactive oxygen species; STING, stimulator of interferon gene; TAK1, transforming growth factor-β-activated kinase 1; TANK, TRAF family member-associated NFκB activator; TBK1, TANK Binding Kinase 1; TCA, Tri-carboxylic acid; TFAM, mitochondrial transcription factor A; TLR, Toll Like Receptor; TRAF6, tumor necrosis factor receptor-associated factor 6; TRIF, TIR-domain-containing adapter-inducing interferon β; TUFM, Tu translation elongation factor.; fMet, N-formylated methionine; mROS, mitochondrial ROS; mtDNA, mitochondrial DNA; n-fp, n-formyl peptides.

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Figures

Figure 1.
Figure 1.. Mitochondrial regulation of innate immune responses.
Mitochondrial DAMPs activate a number of innate immune pathways. Mitochondrial DNA that escapes to the cytosol from damaged mitochondria is recognized by cGAS and signals through cGAMP and STING to activate inflammatory gene transcription. Mitochondrial DNA leaked from a cell can be phagocytosed and bind endosomal TLR9, triggering MyD88-dependent signaling to interferons and pro-inflammatory cytokines. These inflammatory cascades also serve to prime the NLRP3 inflammasome and upregulate pro-lL-1 β. The NLRP3 inflammasome is then activated by oxidized mtDNA from dysfunctional mitochondria. Cardiolipin, which moves to the outer mitochondrial membrane in response to mitochondrial dysfunction, tethers the NLRP3 inflammasome to the mitochondrion and can also trigger its activation. ATP that leaks from a damaged cell can bind to the P2X7 receptor on adjacent cells, triggering NLRP3 inflammasome activation within those nearby cells. Similarly, formyl peptides are also released by damaged cells and are recognized by FPRs on neutrophils and result in neutrophil activation including chemotaxis and the respiratory burst. Modulation of innate immune signaling pathways also depend upon mitochondria. Mitochondria- independent activation of TLRs results in signals through the mitochondrial protein ECSIT, generating mROS and enhancing inflammatory gene output. Activation of the RLRs MDA5 and RIG-I by viral RNA is initiated in the cytosol but signaling depends upon the mitochondria, as both MDA5 and RIG-I must bind MAVS on the outer mitochondrial membrane to activate their downstream signaling pathways. This results in upregulation of interferons and other inflammatory genes. Further, mROS can enhance RLR signaling by upregulating MAVS expression on the outer membrane.
Figure 2.
Figure 2.. Mitochondrial metabolism in immune cell polarization and innate immune responses.
A. In resting macrophages, glucose and fatty acids are broken down to acetyl CoA that enters the TCA cycle. As the TCA cycle progresses, NADH and FADH2 are regenerated as electron donors for the ETC. Most electrons in the ETC are used to generate ATP although some leak off and combine with oxygen to create ROS. B. Activated M1 macrophages have modifications in their metabolism that drives their pro-inflammatory characteristics. (1) M1 macrophages downregulate isocitrate dehydrogenase, resulting in a block in the cycle moving forward from citrate. (2) Citrate accumulates. (3) The metabolic products of citrate are converted to itaconate by IRG1 (immune response gene 1 protein), which is markedly upregulated in M1 macrophages (4) In addition to direct antimicrobial effects, itaconate also inhibits complex II (also known as succinate dehydrogenase), preventing forward progression of the ETC. (5) Reverse transfer of electrons to complex 1 results in increased ROS generation. (6) increased ROS results in stabilization of the transcription factor HIF-1a with subsequent upregulation of inflammatory gene expression, including the potent inflammatory cytokine IL-1 β. C. The metabolic signature of activated M2 macrophages is necessary for their function. (1) M2 macrophages have enhanced fatty acid oxidation driving the TCA cycle to generate ATP. (2) M2 macrophages also require glycolysis, hydrolyzing glucose and using glutamine through the hexosamine pathway to generate uridine diphosphate (UDP)-N-acetylglucosamine (UDP- GIcNAc). This production of UDP-GIcNAc is necessary for (3) glycosolation of immune receptors and (4) the upregulation of expression of specific M2 markers.
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