PLX205344

GSE94957: Mitochondrial dsRNA triggers antiviral signalling in humans

• Organsim human
• Type RNASEQ
• Target gene
• Project ARCHS4

Mitochondria as descendants of endosymbiotic bacteria retain essential prokaryotic features such as a compact circular genome. Consequently, in mammals, the mitochondrial DNA (mtDNA) is subjected to bidirectional transcription that generates overlapping transcripts capable of forming long double-stranded RNA (dsRNA) structures. Nevertheless, mitochondrial (mt) dsRNA has not been previously characterized in vivo. Here, we describe the presence of a highly unstable native mtdsRNA species at single cell level and identify key roles for the degradosome components, mitochondrial dsRNA helicase SUV3 and exoribonuclease PNPase in restricting mtdsRNA levels. Loss of either enzyme results in massive accumulation of mtdsRNA that escapes into the cytoplasm in a PNPase dependent manner. This engages the cytosolic RIG-I like receptor signalling pathway that triggers a type I interferon response. Consistent with these data, patients carrying hypomorphic mutations in PNPT1 display mtdsRNA accumulation coupled with upregulation of interferon stimulated genes (ISGs) and other markers of immune activation. The localization of PNPase to both the mitochondrial inter-membrane space (IMS) and matrix suggests a dual role in preventing formation and release of mtdsRNA into the cytoplasm. This in turn prevents the activation of potent innate immune defence mechanisms which have evolved to protect eukaryotic cells against microbial and viral attack. SOURCE: Nicholas Proudfoot Sir William Dunn School of Pathology, University of Oxford