Innate Immune Function of Mitochondrial Metabolism

Abstract

Sensing of microbe-associated molecular patterns or danger signals by innate immune receptors drives a complex exchange of information. Innate receptor signaling not only triggers transcriptional events but also induces profound changes in metabolic fluxes, redox balance, and metabolite abundance thereby influencing immune cell function. Mitochondria are at the core of metabolic adaptation to the changing environment. The close interaction between mitochondrial metabolism and immune signaling has emerged as a central regulator of innate sensing. Metabolic processes generate a constant flow of electrons that eventually end up in the mitochondrial electron transport chain (ETC). Two electron carriers and four respiratory complexes that can assemble as larger molecular supercomplexes compose the ETC in the mitochondrial inner membrane. While the meaning and biological relevance of such structural organization is a matter of passionate debates, recent data support that innate stimuli remodel the ETC. We will review the function of mitochondrial metabolism and ETC dynamics as innate rheostats that regulate signaling, transcription, and epigenetics to orchestrate innate immune responses.

Keywords: cytokines; dendritic cells; electron transport chain; immunometabolism; inflammation; innate immune response; macrophages; mitochondria.

Figure 1

Mitochondrial respiratory chain adaptations following innate immune sensing. Mitochondrial respiratory complexes, except for CII, can associate into supercomplexes (SCs) including the respirasome, composed of CI + CIII₂ + CIV (left panel). In lipopolysaccharide (LPS)-stimulated mouse macrophages, SC assembly is preserved (upper left) but there are functional adaptations such as increase in CII (succinate dehydrogenase) activity, which enhances succinate oxidation along with increased mitochondrial membrane potential and decreased mitochondrial ATP synthase-mediated production of ATP (upper right). This is accompanied by a decrease in the NAD⁺/NADH ratio, supporting a possible reverse electron transport (RET) from coenzyme Q to CI thereby inducing the production of mitochondrial reactive oxygen species (mROS). Upon detection of live Escherichia coli, increase in phagosomal reactive oxygen species mediates Fgr-dependent activation of CII and decrease in CI-containing SCs probably due to CI disassembly. This provokes a change in electron flow in the electron transport chain, with a drop in the entry of electron derived from NADH that is compensated by the induction of the activities of FADH₂-consuming enzymes CII and mitochondrial glycerol-3-phosphate dehydrogenase (mG3PDH). The increase in CII activity generates fumarate that modulates macrophage function.

Figure 2

Mitochondrial metabolism contributions to macrophage effector functions. Sensing of live Gram-negative bacteria by toll-like receptors (TLR) induces the production of phagosomal reactive oxygen species (ROS) by phagosomal NADPH oxidase. Phagosomal ROS directly contribute to the killing of the bacteria inside the phagosome and induce CII activity thereby promoting fumarate accumulation, which exerts bactericidal properties and modulates histone posttranslational modifications to control cytokine production. The increase in CII activity is associated with a reduction in CI activity and a subsequent increase in mitochondrial ROS (mROS). TLR mediates recruitment of the mitochondria to the phagosome through tumor necrosis factor receptor-associated factor 6 (TRAF6)–evolutionarily conserved signaling intermediate in toll pathways (ECSIT) interaction and concomitantly increases mROS, which contribute to bacteria killing in the phagosome and inhibit prolyl hydroxylase (PHD), thus promoting hypoxia-inducible factor-1α (HIF-1α) stabilization. TLR signaling also induces accumulation of succinate, which, together with fumarate, inhibits α-ketoglutarate-dependent DNA hydroxylases and histone demethylases, regulating cytokine expression and glycolytic switch. Succinate oxidation, in turn, is required to induce mROS production at the level of CI, thereby inhibiting PHD, stabilizing HIF-1α, and further controlling cytokine production. In addition to fumarate, other tricarboxylic acid cycle-related metabolites exhibit antibactericidal properties. Citrate is used to produce itaconate through the decarboxylation of cis-aconitate by IRG1. Itaconate was found to have antimicrobial properties and to regulate succinate dehydrogenase (CII) activity in lipopolysaccharide-activated macrophages.