Mitochondria in innate immune signaling

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.