Multifaceted mitochondria in innate immunity

Abstract

The ability of mitochondria to transform the energy we obtain from food into cell phosphorylation potential has long been appreciated. However, recent decades have seen an evolution in our understanding of mitochondria, highlighting their significance as key signal-transducing organelles with essential roles in immunity that extend beyond their bioenergetic function. Importantly, mitochondria retain bacterial motifs as a remnant of their endosymbiotic origin that are recognised by innate immune cells to trigger inflammation and participate in anti-microbial defence. This review aims to explore how mitochondrial physiology, spanning from oxidative phosphorylation (OxPhos) to signalling of mitochondrial nucleic acids, metabolites, and lipids, influences the effector functions of phagocytes. These myriad effector functions include macrophage polarisation, efferocytosis, anti-bactericidal activity, antigen presentation, immune signalling, and cytokine regulation. Strict regulation of these processes is critical for organismal homeostasis that when disrupted may cause injury or contribute to disease. Thus, the expanding body of literature, which continues to highlight the central role of mitochondria in the innate immune system, may provide insights for the development of the next generation of therapies for inflammatory diseases.

Keywords: Energy metabolism; Mitochondria.

Fig. 1. Mitochondrial bioenergetics in innate immunity.

A NO produced by inducible nitric oxide synthase (iNOS) inhibits OxPhos and increases mtROS following prolonged LPS stimulation. Increased mtROS has bactericidal activity. Impaired OxPhos promotes tolerance and prevents alternative activation with subsequent IL-4 challenge. IL-10 antagonises NO by increasing mitochondrial Arg2. B IL-4/IL-13 increases OxPhos by enhancing glutamine anaplerosis and FAO. Increased OxPhos following IL-4/IL-13 training facilitates a hyperinflammatory response with subsequent LPS challenge and exhibits improved anti-mycobacterial responses. C NLRP3 inflammasome activation depends on mitochondrial PCr that is converted to ATP in the cytosol by CKB.

Fig. 2. Mitochondrial nucleic acid signalling in innate immunity.

Infection with bacteria or viruses, as well as tissue injury, can lead to mitochondrial damage and the release of mitochondrial nucleic acids, including mtDNA and mt-dsRNA. mt-dsRNA can be sensed by RIG-I and MDA5, which signal via MAVS, to promote the expression of type I IFN and pro-inflammatory cytokines. Ox-mtDNA is a reported ligand for the NLRP3 inflammasome triggering pyroptosis and IL-1β maturation. mtDNA also activates the AIM2 inflammasome, cGAS-STING pathway, and TLR9 to drive type I IFN and NETosis. 25-HC can inhibit mtDNA release and AIM2 activation arising from elevated cholesterol.

Fig. 3. Mitochondrial metabolite signalling and anti-bacterial activity in innate immunity.

A TCA cycle remodelling during early and later phases of stimulation post LPS and IFN-γ. Early- to mid-phase changes lead to increased itaconate and succinate levels that can signal through a variety of mechanisms before decreasing at a later stage. B IL-4-mediated increases in glutamine anaplerosis leads to high levels of α-KG that promotes anti-inflammatory gene expression via increased PHD and JMJD3 activity. C Mitochondrial-derived itaconate is trafficked into phagolysosomes in a TFEB, Rab32, Lrrk2-dependent manner where it is directly anti-bactericidal via inhibition of ICL, PCC, or MUT. Itaconate also activates TFEB to promote lysosome biogenesis.

Fig. 4. Mitochondrial signalling platform in innate immunity.

MAVS localized to the OMM integrates the sensing of viral RNA by RIG-I or MDA5 to trigger a type I IFN response and recruit NLRP3 to mitochondria, an event also attributed to cardiolipin. HK2 association with MAVS and mitochondria promotes its enzymatic activity, which can lead to increased lactate and MAVS inhibition. An inhibition that’s relieved when HK2 dissociates from mitochondria. HK2 can also associate with VDAC and sense NAG, a breakdown product of bacterial peptidoglycan. HK2 dissociation from VDAC promotes mitochondrial Ca²⁺ uptake, VDAC oligomerisation, and mtDNA release to activate the NLRP3 inflammasome.