Mitochondrial DNA in inflammation and immunity.

Joel S Riley,Stephen Wg Tait

doi:10.15252/embr.201949799

Joel S Riley, Stephen Wg Tait

Open Access

https://doi.org/10.15252/embr.201949799

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Abstract

Mitochondria are cellular organelles that orchestrate a vast range of biological processes, from energy production and metabolism to cell death and inflammation. Despite this seemingly symbiotic relationship, mitochondria harbour within them a potent agonist of innate immunity: their own genome. Release of mitochondrial DNA into the cytoplasm and out into the extracellular milieu activates a plethora of different pattern recognition receptors and innate immune responses, including cGAS‐STING, TLR9 and inflammasome formation leading to, among others, robust type I interferon responses. In this Review, we discuss how mtDNA can be released from the mitochondria, the various inflammatory pathways triggered by mtDNA release and its myriad biological consequences for health and disease.

Highlights

Serving as a first line of defence, the innate immune system guards us against a plethora of insults and invading microorganisms
We found that under caspase-inhibited conditions, mitochondrial permeabilisation leads to down-regulation of inhibitor of apoptosis proteins (IAPs), NF-jB-inducing kinase (NIK) activation and an NF-jB transcriptional program, in addition to Mitochondrial DNA (mtDNA) release-induced Cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) activation [64]
Mitochondria are multi-faceted organelles orchestrating key events in both life and death. They represent a rich source of damage-associated molecular patterns (DAMPs) which can potently trigger the innate immune system, such as ATP, formyl peptides and mtDNA

Summary

Introduction

Serving as a first line of defence, the innate immune system guards us against a plethora of insults and invading microorganisms. MtDNA-dependent activation of cGAS-STING signalling mtDNA release in infection Through necessity, cells have evolved elegant systems to detect the presence of invading pathogenic DNA. White et al and Rongvaux et al explored mtDNA release in the context of cell death (discussed later in this Review), whereas West et al provided evidence that TFAM deficiency promotes mitochondrial stress and mis-packaged mtDNA, resulting in their ejection into the cytoplasm where they bind and activate cGAS initiating a type I interferon response [39] (Fig 2).

Results

Conclusion