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.

doi:10.64898/2026.05.04.722669

bioRxiv · 10.64898/2026.05.04.722669

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.

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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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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.. 2026-05-07. Loss of MTPAP disrupts mitochondrial RNA processing causing upregulation of type I interferon signalling. https://doi.org/10.64898/2026.05.04.722669

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