Mitochondrial Nucleic Acid as a Driver of Pathogenic Type I Interferon Induction in Mendelian Disease

Abstract

The immune response to viral infection involves the recognition of pathogen-derived nucleic acids by intracellular sensors, leading to type I interferon (IFN), and downstream IFN-stimulated gene, induction. Ineffective discrimination of self from non-self nucleic acid can lead to autoinflammation, a phenomenon implicated in an increasing number of disease states, and well highlighted by the group of rare genetic disorders referred to as the type I interferonopathies. To understand the pathogenesis of these monogenic disorders, and polyfactorial diseases associated with pathogenic IFN upregulation, such as systemic lupus erythematosus and dermatomyositis, it is important to define the self-derived nucleic acid species responsible for such abnormal IFN induction. Recently, attention has focused on mitochondria as a novel source of immunogenic self nucleic acid. Best appreciated for their function in oxidative phosphorylation, metabolism and apoptosis, mitochondria are double membrane-bound organelles that represent vestigial bacteria in the cytosol of eukaryotic cells, containing their own DNA and RNA enclosed within the inner mitochondrial membrane. There is increasing recognition that a loss of mitochondrial integrity and compartmentalization can allow the release of mitochondrial nucleic acid into the cytosol, leading to IFN induction. Here, we provide recent insights into the potential of mitochondrial-derived DNA and RNA to drive IFN production in Mendelian disease. Specifically, we summarize current understanding of how nucleic acids are detected as foreign when released into the cytosol, and then consider the findings implicating mitochondrial nucleic acid in type I interferonopathy disease states. Finally, we discuss the potential for IFN-driven pathology in primary mitochondrial disorders.

Enhanced inflammatory signaling driven by metabolic switch in Aicardi-Goutières syndrome

“…It has been shown that chronic mitochondrial stress drives a loss of mitochondrial membrane integrity 45 . Consequently, mtDNA and mtRNA can be released into the cytoplasm and then sensed by nucleic acid receptors, resulting in type I IFN production 45, 49, 50 .Thus, it is tempting to speculate that type I IFN inhibition of HIF1A expression could further fuel nucleic acid sensing in AGS through uncontrolled mitochondrial activity followed by mtDNA/RNA release in the cytosol, resulting in exacerbated inflammation.…”

Mitochondrial DNA Supplementation of Oocytes Has Downstream Effects on the Transcriptional Profiles of Sus scrofa Adult Tissues with High mtDNA Copy Number

“…These processes could explain the changes in expression in inflammatory response pathway genes in blastocysts [20,28]. Heteroplasmy (in this case the presence of two distinct mitochondrial genomes [22]) following heterologous third-party mtDNA supplementation could be one of the possible causes, especially given that the immune response may recognise this population of mtDNA as 'foreign' rather than 'self' mtDNA [40]. We have shown that supplemented heterologous mtDNA was detectable in tail samples from piglets and adult tissues (brain, calf muscle and heart), and levels of supplemented heterologous mtDNA varied amongst pigs and tissues but were at consistently low levels [29].…”

A cellular overview of immunometabolism in systemic lupus erythematosus

“…This defect results in promotion of autoreactivity of SLE monocytes in a STING-dependent fashion [ 76 ]. Intracellular sensing of mtDNA via the cGAS-STING pathway can induce a type I IFN response, a process that typically characterized by impaired OXPHOS and ATP production, loss of mitochondrial potential and mROS induction, leading to a loss of mitochondrial integrity and release of mitochondrial components [ 77 ]. Of note, inhibition of mTOR signalling pathway in vitro with rapamycin was shown to reduce type I IFN production by SLE monocytes [ 78 ].…”