Mitochondria: sensors and mediators of innate immune receptor signaling

Abstract

By integrating stress signals with inputs from other cellular organelles, eukaryotic mitochondria are dynamic sensing systems that can confer substantial impact on innate immune signaling in both health and disease. This review highlights recently discovered elements of innate immune receptor signaling (TLR, RLR, NLR, and CLR) associated with mitochondrial function and discusses the role of mitochondria in the initiation and/or manifestation of inflammatory diseases and disorders. We also highlight the role of mitochondria as therapeutic targets for inflammatory disease.

Figure.1. Innate immune signaling by PRRs

Cytosolic viral RNA is recognized by the RIG I-like receptors that activate MAVS. MAVS interacts with RIG-I via TRAF, resulting in the induction of antiviral and inflammatory responses including NF-kB and IRF signaling pathways. TLRs recognize PAMPS from viruses, bacteria, parasites and fungi. TLRs are responsible for the recruitment of various adaptor molecules to activate downstream signaling pathways, including NF-kB, leading to the transcription of proinflammatory cytokines such as IL-1β, IL-6 and TNF-α. The glycoprotein, Fetuin-A acts as an adaptor between saturated FFAs and TLR4. Members of the cytosolic NLR family act as central components of the multiprotein inflammasome complex. The best-characterized inflammasome is that consisting of NLRP3, ASC and caspase-1.Inflammasome components assemble, by a yet undefined mechanism in response to a number of physically and chemically diverse triggers including endogenous DAMPS, ATP, lysosomal rupture and calcium. This in turn promotes the activation of caspase-1 leading to the maturation and secretion of IL-1β, IL-18, and IL-33.

Figure. 2. Mitochondrial and innate immune signaling

The TLR signaling protein, TRAF6 bind to the mitochondrial protein, ECSIT, a complex I ETC subunit enhancing TLR signaling. ECSIT also interacts with TRIM59, which negatively regulates TLR signaling. The mitochondrial protein, MARCH5, a regulator of mitochondrial fission and fusion positively regulates TLR7 signaling. Mitochondrial regulated glutamine modulates the expression of TLR by regulating the expression of TRIF. LPS stimulation reduces the expression of mitochondrial enzymes involved in the Krebs cycle and increases T-FAM, cytochrome c oxidase subunits I and IV and cytoplasmic citrate and succinate levels. SARM, a conserved TLR adaptor localizes to the mitochondria and triggers intrinsic apoptosis by generating ROS and depolarizing Δψm. The fusion regulators, MFN1 or OPA1 increase the activation of the transcription factors, NF-κB and IRF-3, whereas the fission regulators DRP1 and FIS-1 decrease RLR signaling. Another mitochondrial fusion/fission protein, MUL1 directly interacts with MAVS and modulates RLR responses. The mitophagy related genes ATG5/12 and SMURF1 inhibit RLR signaling. MMP-2 and TOM70 activate RLR signaling. Upon activation, NLRP3 translocates to mitochondria and to MAMs. mtDNA that is released from dysfunctional mitochondria contributes to macrophage inflammasome activation. The mitochondrial channel VDAC, ATP and mROS originating from the mitochondria are important for NLRP3 activation. NLRP3 interacts with the mitochondrial protein TXNIP. Mitophagy inhibits NLRP3 inflammasome activation, mROS production and IL-1β secretion

Figure 3. Mitochondria and ROS production

The established sites for mitochondrial ROS production at the IMM are complex I, II and III (CI-III) of the ETC. Electrons flow down the ETC redox gradient reaching complex V with 1– 3% of electrons leaking to prematurely react with oxygen, at CI and CIII, to form superoxide and other ROS’ (mROS). The IMM enzyme glycerol-3-phosphate dehydrogenase (GPDH) also produces superoxide and ROS are released in the matrix during β-oxidation of fatty acids. UCPs allow protons to leak back through the IMM and reduce the production of superoxide by the ETC. TRAF6 ubiquitination of ECSIT at the mitochondrion promotes CI assembly and enhances mROS production.