Loss of MTPAP disrupts mitochondrial RNA processing causing upregulation of type I interferon signalling
Pierga, A.; de Souza Angelo, Y.; Safieddine, A.; Benassy, M.-N.; Didry-Barca, B.; Rozen, M.; Seabra, L.; Lovo, C.; Bannwarth, S.; Lacas-Gervais, S.; Kollberg, G.; Hedberg Oldfors, C.; Savvidou, A.; Weil, D.; Crow, Y.; Lepelley, A.
Show abstract
Mitochondrial poly-A polymerase (MTPAP) is essential for mitochondrial mRNA (mt-mRNA) polyadenylation, a critical step in mt-mRNA maturation. Mutations in MTPAP have been reported to cause a mitochondrial cytopathy. Here, we provide evidence of enhanced type I interferon (IFN) signalling in the blood of patients carrying mutations in MTPAP. Further, deletion of MTPAP in a fibroblast cell model led to abnormalities in mitochondrial respiration and mtRNA processing, and an upregulation of type I IFN signalling. Notably, both in patients fibroblast and in MTPAP-deleted cells, we observed the accumulation of non-coding mtRNA and mitochondrial double-stranded RNA (mt-dsRNA) within enlarged mitochondrial RNA granules. Cytosolic release of mt-dsRNA led to type I IFN induction mediated primarily by the RNA sensor MDA5 and its adaptor MAVS. Our findings reveal a novel consequence of MTPAP dysfunction, highlighting how impaired mtRNA maturation can drive innate immune system activation.
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