Review: Mitochondrial DNA in innate immune responses and inflammatory pathology, 2017, West & Shadel

Andy · Mar 11, 2019

Abstract

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.

Key points

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.

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Paywalled at https://www.nature.com/articles/nri.2017.21
Sci Hub, https://sci-hub.se/https://www.nature.com/articles/nri.2017.21

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Review: Mitochondrial DNA in innate immune responses and inflammatory pathology, 2017, West & Shadel

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Review: Mitochondrial DNA in innate immune responses and inflammatory pathology, 2017, West & Shadel

Andy Committee Member

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