Mitochondrial DNA in inflammation and immunity

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.

Keywords: cell death; immunity; inflammation; mitochondria; mtDNA.

Figure 1. Overview of pro‐inflammatory signalling pathways engaged by mitochondrial DNA

Mitochondrial DNA (mtDNA) can trigger various pro‐inflammatory signalling pathways by endosomal localised TLR9 or via cytosolic cGAS‐STING or via cytosolic inflammasome (AIM2 or NLRP3). Top: TLR9 binds mtDNA in the endosome eliciting an NF‐κB‐dependent pro‐inflammatory signalling program. Middle: cGAS recognises mtDNA in the cytosol and activates endoplasmic reticulum (ER)‐localised STING triggering an interferon response. Bottom: mtDNA‐dependent inflammasome activity leads to caspase‐1‐dependent maturation or pro‐inflammatory IL‐1 and IL‐8.

Figure 2. mtDNA‐dependent activation of cGAS‐STING signalling

Various mitochondrial stresses including bacterial or viral infection can lead to mtDNA release. Alternatively, activation of BAX and BAK leads to outer mitochondrial membrane permeabilisation (MOMP) and mtDNA release. Once cytoplasmic, mtDNA can bind the DNA sensing protein cGAS that catalyses the production of the secondary messenger 2′3′ cyclic GMP–AMP (2′3′cGAMP) from ATP and GTP. cGAMP binds the adaptor molecule STING on the ER leading to activation of TBK1 kinase. Active TBK1 phosphorylates the transcription factor IRF3 initiating a type I interferon response.

Figure 3. BAX/BAK‐dependent initiation of inflammation

Following a pro‐apoptotic stress, BAX and BAK are activated leading to mitochondrial outer membrane permeabilisation. This enables the release of caspase‐activating proteins from the mitochondrial intermembrane space. Following this, macropores form on the mitochondrial outer membrane causing extrusion and permeabilisation of the inner membrane. This enables release of mtDNA. Mitochondrial double‐stranded RNA (dsRNA) can also be released. Collective release of these molecules triggers inflammation via MAVS, cGAS‐STING and NF‐κB. Caspase activity is anti‐inflammatory, in part, through direct cleavage and inactivation of inflammatory signalling molecules.

Figure 4. Non‐cell autonomous effects of mtDNA

(A) Upon pathogen encounter, neutrophils can extrude DNA (both nuclear and mitochondrial) that forms an extracellular trap for extracellular microbes. Due to pro‐inflammatory properties, these DNA neutrophil extracellular traps (NETs) can also have pathological effects in diseases such as lupus. (B) mtDNA can transfer via exosomes or in intact mitochondria to neighbouring cells, impacting on the metabolism and survival of the recipient cell. Inflammatory responses to mtDNA can also have non‐cell autonomous effects. The cGAS‐induced secondary messenger cGAMP has been shown to transfer via gap junctions eliciting anti‐viral interferon responses in neighbouring cells.