Mitochondria in innate immunity

Abstract

Mitochondria are cellular organelles involved in host-cell metabolic processes and the control of programmed cell death. A direct link between mitochondria and innate immune signalling was first highlighted with the identification of MAVS-a crucial adaptor for RIGI-like receptor signalling-as a mitochondria-anchored protein. Recently, other innate immune molecules, such as NLRX1, TRAF6, NLRP3 and IRGM have been functionally associated with mitochondria. Furthermore, mitochondrial alarmins-such as mitochondrial DNA and formyl peptides-can be released by damaged mitochondria and trigger inflammation. Therefore, mitochondria emerge as a fundamental hub for innate immune signalling.

Figure 1

Overview of the RIGI-like receptor pathway. Viral RNAs are recognized in the cytosol by the helicases RIGI or MDA5. The amino-termini of RIGI and MDA5 contain two CARD domains that interact with the CARD domain of the mitochondrial adaptor MAVS. MAVS, after recruitment of transactivators, induces phosphorylation of IRF3 and IRF7 and NF-κB activation, leading to the production of type I IFNs and pro-inflammatory cytokines, respectively. dsRNA, double-stranded RNA; ER, endoplasmic reticulum; IκBα, inhibitor of κ light polypeptide gene enhancer in B cells, α; IKKε, IκB kinase; IRF, interferon response factor; MDA5, melanoma differentiation associated gene 5; NAP, NF-κB-activating kinase-associated protein; NEMO, NF-κB essential modifier; NF-κB, nuclear factor κB; pppssRNA, 5′ triphosphate single stranded RNA; RIGI, retinoic acid-inducible gene I; STING, stimulator of interferon genes; TAB, TAK1-associated binding protein; TAK, TGF-β-activated kinase; TANK, TRAF family member-associated NF-κB activator; TBK, TANK-binding kinase; TRAF, TNF-receptor-associated factor.

Figure 2

Mitochondrial dynamics and innate immunity. In the mitochondrial outer membrane, MAVS interacts with both MFN1 and MFN2. MFN2 is a direct MAVS inhibitor. RLR activation induces MAVS oligomerization, which recruits TRAF3 and other E3 ubiquitin ligases that catalyse Lys 63 polyubiquitination of target proteins, including TRAF3. Polyubiquitin chains recruit TANK and NEMO, which in turn bind and activate TBK1, leading to the phosphorylation of IRF3. Simultaneously, MFN1 leads to the redistribution of MAVS along mitochondria and a fusion of the mitochondrial network that promotes the interaction between MAVS and STING. Low ΔΨm or decreased ROS inhibit MAVS-mediated signalling. ΔΨm, mitochondrial membrane potential; ER, endoplasmic reticulum; IRF, interferon response factor; MAVS, mitochondria-associated viral sensor; MFN, mitofusin; NEMO, NF-κB essential modifier; RLR, RIG-I-like receptor; ROS, reactive oxygen species; STING, stimulator of interferon genes; TANK, TRAF family member-associated NF-κB activator; TBK, TAK1-associated binding protein; TRAF, TNF-receptor-associated factor.

Figure 3

Innate immune signalling at the mitochondria. On induction of mitochondrial reactive oxygen species (ROS), NLRP3 localizes to the mitochondrial-associated endoplasmic reticulum membrane (MAM) with ASC and pro-caspase 1, inducing caspase-1 activation and the production of IL-1β and IL-18. MAVS is located on the outer mitochondrial membrane and mediates antiviral signalling. On TLR1/2/4 stimulation, TRAF6 translocates to the mitochondria and interacts with ECSIT, contributing to ROS production. NLRX1 is internalized into the mitochondrial matrix where it interacts with UQCRC2, a protein of the complex III of the electron transfer chain, potentiating ROS production. IRGM binds to the mitochondrial lipid cardiolipin, influencing autophagy, mitochondrial fission, mitochondrial ΔΨm and cell death. ASC, apoptosis-associated speck-like protein containing a CARD; ECSIT, evolutionarily conserved signalling intermediate in Toll pathway; IL, interleukin; IRGM, immunity-related GTPase family M protein; LRR, leucine-rich repeat; MAVS, mitochondria-associated viral sensor; NAD, nicotinamide adenine dinucleotide; NLRP, NOD-like receptor family, pyrin domain containing; NLRX, NOD-like receptor family member X; PYD, pyrin domain; TLR, Toll-like receptor; TRAF, TNF-receptor-associated factor.

Figure 4

Release of mitochondrial DAMPs triggers cell death and inflammatory pathways. (A) Severe trauma can induce the release of mitochondrial DNA (mtDNA), which is detected by TLR9 located on the neutrophil surface, and thus activates p38 MAP kinase. N-formyl peptides are released by mitochondria and recruit polymorphonuclear neutrophils (PMNs) by binding to the formyl-peptide receptor 1 (FPR1) expressed on their surface. (B) Autophagy-deficient cells accumulate defective mitochondria, which release mtDNA into the cytosol, triggering activation of the inflammasome through an undefined cytosolic sensor. (C) Cell death signals induce the release of cytochrome c into the cytosol, leading to the recruitment of APAF1 and pro-caspase 9 into a multiprotein complex known as the apoptosome. After activation, caspase 9 induces apoptosis by cleaving effector caspases. DAMP, danger-associated molecular pattern; IL, interleukin; MAPK, mitogen-activated protein kinase; TLR, Toll-like receptor.