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Mitochondria in innate immune responses

Key Points

  • 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, including RIG-I-like receptor (RLR) signalling, antibacterial immunity and the sterile inflammatory response.

  • RLR signalling in response to viral infection requires mitochondrial antiviral signalling protein (MAVS), a mitochondrially localized adaptor that induces nuclear factor-κB (NF-κB) and interferon regulatory factor 3 (IRF3) and IRF7 signalling to initiate the production of pro-inflammatory cytokines and type I interferons (IFNs). The mechanisms of MAVS signalling remain under investigation, although recent studies have indicated that mitochondrial proteins such as translocase of the outer membrane 70 (TOM70), mitofusin 1 (MFN1), MFN2 and NLR family member X1 (NLRX1) influence MAVS signalling.

  • Mitochondrial fusion regulates MAVS signalling, as cells deficient in mitofusins display decreased antiviral innate immune responses. Mitochondrial fusion facilitates proper interactions between MAVS and downstream signalling molecules (such as stimulator of interferon genes (STING)), and maintains mitochondrial membrane potential, which is necessary for MAVS signalling.

  • Mitochondrial reactive oxygen species (mROS) appear to influence both RLR signalling and antibacterial innate immune responses. Mitophagy-deficient cells accumulate damaged, mROS-producing mitochondria, and consequently produce more IFNβ. mROS-deficient macrophages and mice display increased susceptibility to bacteria and protozoan parasites, and Toll-like receptor (TLR) signalling can directly augment mROS generation for enhanced bactericidal activity.

  • Mitochondrial damage-associated molecular patterns (DAMPs; such as mtDNA and N-formylated peptides) are released following cellular necrosis and activate innate immune receptors, which initiate sterile inflammatory responses. Exposure to DAMPs promotes mROS generation, which initiates NOD-, LRR- and pyrin domain-containing 3 (NLRP3) inflammasome signalling, caspase 1 activation and IL-1β and IL-18 secretion.

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.

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Figure 1: Mitochondrial antiviral signalling pathways.
Figure 2: Mitochondrial dynamics regulate MAVS signalling.
Figure 3: Mitochondrial ROS and innate immune responses.
Figure 4: Mitochondrial involvement in cellular damage responses.

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Acknowledgements

We regret that several important studies could only be cited indirectly through comprehensive reviews, owing to space and reference number limitations. We thank L. Ciaccia for assistance with the figures. This work was supported by grants from the US National Institutes of Health to S.G. (R37-AI33443) and G.S. (ES-011,163).

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Correspondence to Sankar Ghosh.

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Glossary

Programmed cell death

A common form of cell death that is also referred to as apoptosis. Many physiological and developmental stimuli cause apoptosis, and this mechanism is frequently used to delete unwanted, superfluous or potentially harmful cells, such as those undergoing transformation.

Oxidative phosphorylation

The metabolic pathway that occurs at the inner mitochondrial membrane and uses an electrochemical gradient created by the oxidation of electron carriers to generate ATP.

Mitochondrial dynamics

Mitochondrial dynamics refers to the movement of mitochondria along the cytoskeleton and the regulation of mitochondrial morphology and distribution mediated by tethering, and fusion and fission events.

Sterile inflammation

Inflammation that results from trauma, ischaemia–reperfusion injury or chemically induced injury that typically occurs in the absence of any microorganisms.

Canonical NF-κB signalling

A typical pathway of NF-κB activation that involves phosphorylation and degradation of the prototypical NF-κB inhibitor, IκBα.

TOM complex

The translocase of the outer membrane (TOM) is a complex of proteins localized to the outer mitochondrial membrane that recognizes and imports nuclear-encoded mitochondrial proteins into the intermembrane space.

Heat shock protein

(HSP). A member of a class of functionally related proteins that function as molecular chaperones and have crucial roles in protein folding and intracellular trafficking.

Mitochondria-associated membranes

(MAMs). Regions of the endoplasmic reticulum that are closely juxtaposed to mitochondria and support communication between the organelles via calcium and phospholipid exchange.

E3 ubiquitin ligase

An enzyme that is required to attach the molecular tag ubiquitin to proteins. Depending on the number of ubiquitin molecules that are attached and the positioning of the links between them, the ubiquitin tag can target proteins for degradation in the proteasomal complex, sort them to specific subcellular compartments or modify their biological activity.

Mitofusin

An outer mitochondrial membrane protein that regulates mitochondrial fusion and ER–mitochondrial interactions by tethering adjacent organelles.

Mitophagy

A term referring to the selective removal of mitochondria by macroautophagy under conditions of nutrient starvation or mitochondrial stress.

Mitochondrial uncoupling

A process involving the disassociation of mitochondrial respiration from ATP generation that is characterized by increased permeability of the inner mitochondrial membrane to protons and subsequent dissipation of mitochondrial membrane potential.

Respiratory burst

A large increase in oxygen consumption and reactive oxygen species generation that accompanies the exposure of neutrophils to microorganisms and/or inflammatory mediators.

NADPH oxidase

A plasma membrane- and phagosomal membrane-bound enzyme complex that transfers electrons from NADPH to molecular oxygen, promoting the generation of the reactive oxygen species superoxide.

Necrosis

The premature death of living cells or tissue, resulting in the release of cellular constituents that promote inflammatory responses.

Haemorrhagic shock

A condition often caused by traumatic injury that results in reduced tissue perfusion and leads to inadequate delivery of oxygen and nutrients to cells and tissues.

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West, A., Shadel, G. & Ghosh, S. Mitochondria in innate immune responses. Nat Rev Immunol 11, 389–402 (2011). https://doi.org/10.1038/nri2975

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