Mitochondrial DNA (mtDNA), which is well known for its role in oxidative phosphorylation and cellular energetics, is increasingly being recognized as an agonist of the innate immune system that engages various pattern-recognition receptors, including Toll-like receptors (TLRs), NOD-like receptors (NLRs) and interferon-stimulatory DNA receptors.
Several features of mtDNA are potentially immunomodulatory. Unique methylation signatures and/or hypomethylation may cause mtDNA to appear more 'foreign' than 'self'. The three-stranded D-loop regulatory region or unique nucleic acid species generated during mtDNA replication and/or transcription may accumulate rapidly or resist degradation by cellular nucleases.
Loss of mitochondrial membrane integrity, cellular damage or a failure to fully degrade mitochondrial constituents by autophagy can result in mtDNA-dependent triggering of endolysosomal TLR9 or cytosolic inflammasomes, such as NOD, LRR and Pyrin domain-containing protein 3 (NLRP3) and absent in melanoma 2 (AIM2), causing pro-inflammatory responses. These include cytokine and chemokine secretion (of interleukin-1β, CXC-chemokine ligand 8 and tumour necrosis factor, for example), and immune cell chemotaxis and recruitment.
Intracellular mtDNA triggers type I interferon responses by engaging TLR9 or the cytosolic cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) signalling pathway. These responses culminate in the activation of interferon regulatory factors to enhance interferon secretion and interferon-stimulated gene expression. Extracellular mtDNA can also be taken up by neighbouring dendritic cells or macrophages, where it activates cGAS- or TLR9-dependent interferon expression.
An ever-growing clinical and experimental literature implicates mtDNA in human inflammatory, metabolic and infectious diseases. Unravelling the mechanistic aspects of mtDNA release, sensing and resulting inflammatory pathology should have important implications for understanding the mitochondrial aetiology of human disease and ageing.
Mitochondrial DNA (mtDNA) — which is well known for its role in oxidative phosphorylation and maternally inherited mitochondrial diseases — is increasingly recognized as an agonist of the innate immune system that influences antimicrobial responses and inflammatory pathology. On entering the cytoplasm, extracellular space or circulation, mtDNA can engage multiple pattern-recognition receptors in cell-type- and context-dependent manners to trigger pro-inflammatory and type I interferon responses. Here, we review the expanding research field of mtDNA in innate immune responses to highlight new mechanistic insights and discuss the physiological and pathological relevance of this exciting area of mitochondrial biology.
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The authors thank B. Kaufman for helpful comments on the manuscript, and we acknowledge L. Ciaccia West for assistance with the figures. G.S.S. is the Joseph A. and Lucille K. Madri Endowed Professor of Experimental Pathology, and this work was supported by US National Institutes of Health grant R01 AG047632.
The authors declare no competing financial interests.
- Pattern-recognition receptors
(PRRs). Evolutionarily conserved receptors of the innate immune system that detect foreign viral, bacterial and/or fungal constituents, as well as endogenous molecules released from injured cells and tissues.
- Damage-associated molecular patterns
(DAMPs). Molecules that are exposed or released by injured, necrotic or dying cells and are recognized by pattern-recognition receptors.
Functional mitochondrial DNA packaging complexes in the mitochondrial matrix that consist of one or more mitochondrial DNA genomes and associated proteins.
- Transcription factor A, mitochondrial
(TFAM). A dual high-mobility-group box protein in mitochondria that promotes packaging of mitochondrial DNA and regulates transcription from mitochondrial DNA promoters.
Multi-protein complexes that activate caspase 1 to induce processing of pro-interleukin-1β and pro-interleukin-18 into mature and secreted forms.
Clusters of single-nucleotide polymorphisms in mitochondrial DNA that define inherited lineages.
- Cyclic GMP–AMP synthase
(cGAS). A cytosolic DNA sensor that catalyses the production of the second messenger cyclic GMP–AMP (cGAMP) on binding to DNA.
- Stimulator of interferon genes
(STING). An endoplasmic reticulum-resident adaptor protein that binds to cyclic GMP–AMP (cGAMP) to trigger type I interferon production.
- Aicardi–Goutières syndrome
A disease in which mutations in the cytosolic enzyme 3 repair exonuclease 1 (TREX1) or other nucleases lead to the intracellular accumulation of endogenous nucleic acids, triggering chronic type I interferon responses that cause debilitating autoinflammatory and neurodegenerative pathology.
A stable three-stranded DNA structure in mammalian mitochondrial DNA that is caused by premature termination of replication.
- Systemic lupus erythematosus
(SLE). A chronic autoimmune disease that is linked to aberrant type I interferon responses in which autoantibodies specific for DNA, RNA or proteins associated with nucleic acids form immune complexes that accumulate in multiple tissues to cause pathology.
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West, A., Shadel, G. Mitochondrial DNA in innate immune responses and inflammatory pathology. Nat Rev Immunol 17, 363–375 (2017). https://doi.org/10.1038/nri.2017.21
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