Mitochondria in innate immune responses

Abstract

The innate immune system has a key role in the mammalian immune response. Recent research has demonstrated that mitochondria participate in a broad range of innate immune pathways, functioning as signalling platforms and contributing to effector responses. In addition to regulating antiviral signalling, mounting evidence suggests that mitochondria facilitate antibacterial immunity by generating reactive oxygen species and contribute to innate immune activation following cellular damage and stress. Therefore, in addition to their well-appreciated roles in cellular metabolism and programmed cell death, mitochondria appear to function as centrally positioned hubs in the innate immune system. Here, we review the emerging knowledge about the roles of mitochondria in innate immunity.

Conflict of interest statement

Competing interests statement

The authors declare no competing financial interests.

Figures

Figure 1. Mitochondrial antiviral signalling pathways

a | Cytosolic viral RNA is recognized by the RIG-I-like receptors (RLRs) retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5), which activate mitochondrial antiviral signalling protein (MAVS) through caspase-recruitment domain (CARD)–CARD interactions. MAVS then recruits various signalling molecules to transduce downstream signalling, such as TNF receptor-associated factor 6 (TRAF6) and TRAF5. TRAF6, along with TNFR1-associated death domain protein (TRADD), activates canonical nuclear factor-κB (NF-κB) signalling via receptor-interacting protein 1 (RIP1) and FAS-associated death domain protein (FADD). Canonical NF-κB signalling occurs as the IκB kinase (IKK) complex — consisting of IKKα, IKKβ and IKKγ — phosphorylates NF-κB inhibitor-α (IκBα), resulting in the proteasomal degradation of IκBα and thus liberating NF-κB to translocate into the nucleus and initiate pro-inflammatory cytokine gene expression. MAVS also interacts with various molecules that activate interferon regulatory factor (IRF) signalling (such as stimulator of interferon genes (STING)). These molecules, together with the translocon-associated protein (TRAP) complex and the SEC61 translocon, mediate the activation of TANK-binding kinase 1 (TBK1), which phosphorylates IRF3 and IRF7. In addition, MAVS interacts with translocase of the outer membrane 70 (TOM70), which also interacts with heat shock protein 90 (HSP90) and thereby localizes TBK1 and IRF3 in proximity to the MAVS signalosome. Finally, MAVS binds TRAF2 and TRAF3 and, through TRADD and TRAF family member-associated NF-κB activator (TANK) interactions, promotes IKKε- and/or TBK1-mediated phosphorylation of IRF3. This promotes IRF3 nuclear translocation, leading to the expression of type I interferon (IFN) genes. b | MAVS signalling can also be inhibited by various molecules. For example, hepatitis C virus (HCV) encodes a serine protease, termed NS3–4A, that inhibits MAVS by cleaving it from the outer mitochondrial membrane and preventing the formation of MAVS–IKKε signalling complexes. Hepatitis A virus (HAV) and GB virus B (GBV-B) also encode proteases that disrupt the mitochondrial targeting of MAVS, and hepatitis B virus (HBV) X protein was shown to promote polyubiquitin conjugation to MAVS, leading to its degradation. Endogenous molecules such as poly(rC)-binding protein 2 (PCBP2) and the 20S proteasomal subunit PSMA7 can negatively regulate MAVS signalling during viral infection by promoting its degradation. Other molecules, such as mitofusin 2 (MFN2), receptor for globular head domain of complement component 1q (gC1qR) and NLR family member X1 (NLRX1) are also thought to inhibit MAVS signalling by direct interaction, although gC1qR and NLRX1 are thought to localize predominately to the mitochondrial matrix. Therefore, the mechanisms by which these molecules inhibit MAVS signalling remain under investigation (dashed lines). ER, endoplasmic reticulum; MAM, mitochondria-associated membrane.

Figure 2. Mitochondrial dynamics regulate MAVS signalling

a | During infection, retinoic acid-inducible gene I (RIG-I) and mitochondrial antiviral signalling protein (MAVS)-enriched mitochondria are recruited around centres of viral replication to promote MAVS signalling. This occurs as mitofusin 1 (MFN1) and MFN2 induce fusion of the mitochondrial network, which also serves to increase MAVS interactions with downstream signalling molecules. Mitochondrial MFN1 and MFN2 also interact with endoplasmic reticulum-localized MFN2, which promotes interactions between MAVS and stimulator of interferon genes (STING) at mitochondria-associated membranes (MAMs). b | Fragmentation of the mitochondrial network — which is induced by viral infection, mitofusin deficiency or overexpression of fission-promoting molecules — results in decreased mitochondrial membrane potential and blocks interactions between MAVS and signalling molecules such as STING. This leads to reduced signalling by nuclear factor-κB (NF-κB), interferon regulatory factor 3 (IRF3) and IRF7.

Figure 3. Mitochondrial ROS and innate immune responses

a | Mitochondrial distress and/or rotenone treatment augment mitochondrial reactive oxygen species (mROS) generation from oxidative phosphorylation complexes, and this potentiates RIG-I-like receptor (RLR)–mitochondrial antiviral signalling protein (MAVS) signalling to nuclear factor-κB (NF-κB) and interferon regulatory factor 3 (IRF3) and IRF7. This increases the production of type I interferons (IFNs) and pro-inflammatory cytokines, which limit viral replication. NLR family member X1 (NLRX1) and receptor for globular head domain of complement component 1q (gC1qR) interact with oxidative phosphorylation complexes and may increase mROS generation, whereas uncoupling protein 2 (UCP2) decreases mROS production. Mitophagy mediated by autophagy-related gene 5 (ATG5) and ATG12 also decreases mROS production and subsequent RLR–MAVS signalling by removing dysfunctional, mROS-generating mitochondria. b | Phagocytized bacteria activate Toll-like receptor 1 (TLR1), TLR2 and TLR4, and this promotes the translocation of TNF receptor-associated factor 6 (TRAF6) to mitochondria, where it engages ECSIT (evolutionary conserved signalling intermediate in Toll pathways) to potentiate mROS generation from oxidative phosphorylation complexes. This leads to increased ROS-dependent bactericidal responses and/or activation of NF-κB and mitogen-activated protein kinase (MAPK) signalling to augment pro-inflammatory cytokine production. IFNγ signalling can also promote mROS generation and increased antibacterial innate immunity by engaging oestrogen-related receptor-α (ERRα) and the co-activator peroxisome proliferator-activated receptor-γ co-activator 1β (PGC1β), which upregulate mitochondrial biogenesis and the expression of nuclear-encoded oxidative phosphorylation genes. UCP2 is a negative regulator of mROS generation, whereas NLRX1 can enhance mROS production under certain circumstances. RIG-I, retinoic acid-inducible gene I.

Figure 4. Mitochondrial involvement in cellular damage responses

a | Cellular injury and necrosis release damaged mitochondria into the extracellular space, where they leak mitochondrial damage-associated molecular patterns (DAMPs) such as mitochondrial DNA (mtDNA), N-formyl peptides and mitochondrial transcription factor A (TFAM). Leukocytes, such as macrophages and neutrophils, detect mtDNA through Toll-like receptor 9 (TLR9), N-formyl peptides via formyl peptide receptor 1 (FPR1), and TFAM through TLRs or an uncharacterized receptor, leading to leukocyte activation and transcription of pro-inflammatory cytokine genes. Necrotic cells can also release intact mitochondria that secrete ATP. This ATP engages the leukocyte purinergic receptor P2RX7, which promotes NOD-, LRR- and pyrin domain-containing 3 (NLRP3) inflammasome activation and the subsequent processing and secretion of the cytokines interleukin-1β (IL-1β) and IL-18. b | Exposure of leukocytes to inflammasome activators — such as lipopolysaccharide (LPS) and ATP, rotenone, monosodium urate (MSU), alum and nigericin — leads to mitochondrial dysfunction and mitochondrial ROS (mROS) generation. mROS promote inflammasome activation at mitochondria-associated membranes (MAMs) of the endoplasmic reticulum (ER), by nucleating and activating a complex of NLRP3, ASC and caspase 1. This induces the proteolytic processing of pro-IL-1β and pro-IL-18 into mature and secreted forms. mROS also promote the release of mtDNA into the cytosol, and this DNA engages the absent in melanoma 2 (AIM2) inflammasome or other receptors to further augment IL-1β and IL-18 processing and secretion. Mitophagy serves as a brake on inflammasome activation by mediating the clearance of damaged, mROS-generating mitochondria.